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Credentials

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University of California at Davis (1973)
  •  
Top 50%

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American Board of Internal Medicine

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Dr. Longhurst is affiliated with 2 hospitals.

Hospital Affiliations

Score

Rankings

  • University of California, Irvine Medical Center
    Cardiology
    1310 W Stewart Dr, Orange, CA 92868
    •  
    Top 50%
  • University of California Davis Medical Center
    Cardiology
    2315 Stockton Blvd, Sacramento, CA 95817
    •  
    Top 50%
  • Publications & Research

    Dr. Longhurst has contributed to 132 publications.
    Title Central and Peripheral Mechanisms Underlying Gastric Distention Inhibitory Reflex Responses in Hypercapnic-acidotic Rats.
    Date May 2011
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    We have observed that in chloralose-anesthetized animals, gastric distension (GD) typically increases blood pressure (BP) under normoxic normocapnic conditions. However, we recently noted repeatable decreases in BP and heart rate (HR) in hypercapnic-acidotic rats in response to GD. The neural pathways, central processing, and autonomic effector mechanisms involved in this cardiovascular reflex response are unknown. We hypothesized that GD-induced decrease in BP and HR reflex responses are mediated during both withdrawal of sympathetic tone and increased parasympathetic activity, involving the rostral (rVLM) and caudal ventrolateral medulla (cVLM) and the nucleus ambiguus (NA). Rats anesthetized with ketamine and xylazine or α-chloralose were ventilated and monitored for HR and BP changes. The extent of cardiovascular inhibition was related to the extent of hypercapnia and acidosis. Repeated GD with both anesthetics induced consistent falls in BP and HR. The hemodynamic inhibitory response was reduced after blockade of the celiac ganglia or the intraabdominal vagal nerves with lidocaine, suggesting that the decreased BP and HR responses were mediated by both sympathetic and parasympathetic afferents. Blockade of the NA decreased the bradycardia response. Microinjection of kainic acid into the cVLM reduced the inhibitory BP response, whereas depolarization blockade of the rVLM decreased both BP and HR inhibitory responses. Blockade of GABA(A) receptors in the rVLM also reduced the BP and HR reflex responses. Atropine methyl bromide completely blocked the reflex bradycardia, and atenolol blocked the negative chronotropic response. Finally, α(1)-adrenergic blockade with prazosin reversed the depressor. Thus, in the setting of hypercapnic-acidosis, a sympathoinhibitory cardiovascular response is mediated, in part, by splanchnic nerves and is processed through the rVLM and cVLM. Additionally, a vagal excitatory reflex, which involves the NA, facilitates the GD-induced decreases in BP and HR responses. Efferent chronotropic responses involve both increased parasympathetic and reduced sympathetic activity, whereas the decrease in BP is mediated by reduced α-adrenergic tone.

    Title Nucleus Raphe Pallidus Participates in Midbrain-medullary Cardiovascular Sympathoinhibition During Electroacupuncture.
    Date November 2010
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    We have shown that electroacupuncture (EA) inhibits sympathoexcitatory rostral ventrolateral medulla (rVLM) neurons and reflex responses following activation of a long-loop pathway in the arcuate nucleus and ventrolateral periaqueductal gray (vlPAG). Additionally, EA at P 5-6 acupoints (overlying the median nerve) activates serotonin-containing neurons in the nucleus raphé pallidus (NRP), which, in turn, inhibit rVLM neurons. Although direct projections from the vlPAG to the rVLM exist, it is uncertain whether an indirect pathway through the NRP serves an important role in vlPAG-rVLM cardiovascular modulation. Therefore, the splanchnic nerve (SN) was stimulated to induce cardiovascular sympathoexcitatory reflexes, and EA was applied at P 5-6 acupoints in α-chloralose-anesthetized cats. A single-barreled recording electrode was inserted into the NRP or rVLM. Microinjection of DL-homocysteic acid (DLH) into the vlPAG increased the NRP neuronal response to SN stimulation (5 ± 1 to 12 ± 2 spikes/30 stim). Likewise, EA at P 5-6 for 30 min increased the NRP response to SN stimulation (3 ± 1 to 10 ± 2 spikes/30 stim), an effect that could be blocked by microinjection of kynurenic acid (KYN) into the caudal vlPAG. Furthermore, the reflex increase in blood pressure induced by application of bradykinin to the gallbladder and the rVLM cardiovascular presympathetic neuronal response to SN stimulation was inhibited by injection of DLH into the vlPAG, a response that was reversed by injection of KYN into the NRP. These results indicate that EA activates the vlPAG, which excites the NRP to, in turn, inhibit rVLM presympathetic neurons and reflex cardiovascular sympathoexcitatory responses.

    Title An Interview with Professor John C. Longhurst: Cardiovascular Modulation by Electroacupuncture.
    Date October 2010
    Journal Journal of Acupuncture and Meridian Studies
    Title Electroacupuncture Enhances Preproenkephalin Mrna Expression in Rostral Ventrolateral Medulla of Rats.
    Date July 2010
    Journal Neuroscience Letters
    Excerpt

    Electroacupuncture (EA) causes prolonged suppression of reflex elevations in blood pressure for at least 60min in anesthetized preparations. Thus, EA can modify sympathetic outflow and elevated blood pressure through actions in a number of hind brain regions, including the rostral ventrolateral medulla (rVLM). Since our previous data show that the opioid system plays a role in EA-related prolonged inhibition of presympathetic neuronal activity in the rVLM, we postulated that EA increases preproenkephalin (PPE) mRNA in this region, possibly for prolonged periods of time. Under alpha-chloralose anesthesia, rats received EA (1-2mA, 2Hz, 0.5ms) at P5-P6 acupoints (overlying median nerves) or sham (needle placement without electrical stimulation) for 30min. PPE mRNA in the rVLM also was evaluated in control rats that received surgery but no EA, or sham treatment. 20min, 1.5h or 4h following EA or sham treatment, PPE mRNA in the rVLM was analyzed by reverse transcription and quantitative real-time PCR. Relative ratios of PPE mRNA levels (normalized with 18s house keeping gene) were increased 1.5h after EA stimulation (7.77+/-1.39, n=6) relative to sham (2.84+/-0.37, n=5) but were unchanged both 20min and 4h after EA, compared to the sham or surgery groups at the same time points. Thus, 30min of EA transiently stimulates the production of enkephalin in a region of the brain that importantly regulates sympathetic outflow suggesting that even a single brief acupuncture treatment can increase the expression of this modulatory neuropeptide.

    Title Review of Trials Examining the Use of Acupuncture to Treat Hypertension.
    Date May 2010
    Journal Future Cardiology
    Excerpt

    Although hypertension is a major risk factor for heart attack and stroke in the US, only approximately a quarter of adults receive adequate hypertension treatment and control their blood pressure (BP) effectively. There are disparities in the prevalence of hypertension, its treatment and control with respect to age, sex, racial groups and education. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of high BP (JNC 7 report) provides lifestyle modification with and without pharmacological intervention recommendations for preventing and treating different stages of hypertension. Recently, nonpharmacological approaches including yoga, meditation, acupressure and acupuncture have been considered as potential therapeutic options. Acupuncture has been used empirically for nearly 3000 years to treat a variety of diseases, including cardiovascular disorders such as hypertension, hypotension, coronary disease and certain arrhythmias. Previous studies suggest that short and chronic elevation in BP can be lowered in animal models and human subjects. However, the mechanisms underlying the antihypertensive effects of acupuncture are not yet fully understood. An increasing interest in acupuncture healthcare has led to a growing number of investigators to pursue research in this field. This article briefly summarizes available studies, including our own reports, that demonstrate evidence for acupuncture modulation of cardiovascular function, particularly BP reduction, and concludes that future treatment of hypertension can potentially include acupuncture as a nonpharmacological intervention.

    Title Bradykinin and Thromboxane A2 Reciprocally Interact to Synergistically Stimulate Cardiac Spinal Afferents During Myocardial Ischemia.
    Date January 2010
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Myocardial ischemia is a complex process leading to the simultaneous release of a number of mediators, including thromboxane A(2) (TxA(2)) and bradykinin (BK), that activate cardiac spinal afferents. The present study tested the hypothesis that TxA(2) and BK reciprocally interact to excite ischemically sensitive cardiac afferents. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) of anesthetized cats. Fifty-two ischemically sensitive afferents (conduction velocity = 0.27-3.35 m/s, 7 Adelta-fibers and 45 C-fibers) were identified. Repeated injections (1 microg) of BK into the left atrium (LA) 4 min after the administration of U-46619 (5 microg into the LA), a TxA(2) mimetic, induced a significantly larger cardiac afferent response than the first response to BK (0.61 +/- 0.14 to 1.95 +/- 0.29 vs. 0.66 +/- 0.09 to 2.75 +/- 0.34 impulses/s, first injection vs. second injection, n = 8). Conversely, blockade of TxA(2) receptors with BM-13,177 (30 mg/kg iv) attenuated the responses of eight other afferents to BK (1 microg into the LA) by 45%. In contrast, repeated BK (1 microg into the LA) induced consistent discharge activity in six separate afferents. We then observed that the coadministration of U-46619 (5 microg) and BK (1 microg into the LA) together caused a total response that was significantly higher than the predicted response by the simple addition of the individual responses. BK (1 microg) facilitated eight cardiac afferent responses to U-46619 (5 microg into the LA) by 64%. In contrast, repeated U-46619 (5 microg into the LA) without intervening BK stimulation evoked consistent responses in seven other ischemically sensitive afferents. Finally, inhibition of cyclooxygenase with indomethacin (5 mg/kg iv) eliminated the potentiating effects of BK on the cardiac afferent response to U-46619 (5 microg into the LA) but did not alter the afferent response to U-46619. These data suggest that BK and TxA(2) reciprocally interact to stimulate ischemically sensitive cardiac afferent endings leading to synergistic afferent responses and that the BK sensitization effect is mediated by cyclooxygenase products.

    Title Regulation of Cardiac Afferent Excitability in Ischemia.
    Date October 2009
    Journal Handbook of Experimental Pharmacology
    Excerpt

    The heart at the time of Sir William Harvey originally was thought to be an insensate organ. Today, however, we know that this organ is innervated by sensory nerves that course centrally though mixed nerve pathways that also contain parasympathetic or sympathetic motor nerves. Angina or cardiac pain is now well recognized as a pressure-like pain that occurs during myocardial ischemia when coronary artery blood flow is interrupted. Sympathetic (or spinal) afferent fibers that are either finely myelinated or unmyelinated are responsible for the transmission of information to the brain that ultimately allows the perception of angina as well as activation of the sympathetic nervous system, resulting in tachycardia, hypertension, and sometimes arrhythmias. Although early studies defined the importance of the vagal and sympathetic cardiac afferent systems in reflex autonomic control, until recently there has been little appreciation of the mechanisms of activation of the sensory endings. This review examines the role of a number of chemical mediators and their sources that are activated by the ischemic process. In this regard, patients with ischemic syndromes, particularly myocardial infarction and unstable angina, are known to have platelet activation, which leads to release of a number of chemical mediators, including serotonin, histamine, and thromboxane A(2), all of which stimulate ischemically sensitive cardiac spinal afferent endings in the ventricles through specific receptor-mediated processes. Furthermore, protons from lactic acid, bradykinin, and reactive oxygen species, especially hydroxyl radicals, individually and frequently in combination, stimulate these endings during ischemia. Cyclooxygenase products appear to sensitize the endings to the action of bradykinin and histamine. These studies of the chemical mechanisms of activation of cardiac sympathetic afferent endings during ischemia have the potential to provide targeted therapies that can modify the angina and the deleterious reflex responses that have the potential to exacerbate ischemia and myocardial cell death.

    Title Spinal Nociceptin Mediates Electroacupuncture-related Modulation of Visceral Sympathoexcitatory Reflex Responses in Rats.
    Date August 2009
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    The role of nociceptin and its spinal cord neural pathways in electroacupuncture (EA)-related inhibition of visceral excitatory reflexes is not clear. Nociceptin/orphanin FQ (N/OFQ) is an endogenous ligand for a G protein-coupled receptor, called the N/OFQ peptide (NOP) receptor, which has been found to be distributed in the spinal cord. The present study investigated the importance of this system in visceral-cardiovascular reflex modulation during EA. Cardiovascular pressor reflex responses were induced by gastric distension in Sprague-Dawley rats anesthetized by ketamine and xylazine. An intrathecal injection of nociceptin (10 nM) at T1-2 attenuated the pressor responses by 35%, similar to the influence of EA at P 5-6 (42% decrease). An intrathecal injection of the NOP antagonist, [N-Phe(1)]nociceptin(1-13) NH(2), partially reversed the EA response. Pretreatment with the opioid receptor antagonist naloxone did not alter the EA-like inhibitory effect of nociceptin on the pressor reflex, whereas a combination of nociceptin receptor antagonist with naloxone completely abolished the EA response. An intrathecal injection of nociceptin attenuated the pressor responses to the electrical stimulation of the rostral ventrolateral medulla by 46%, suggesting that nociceptin can regulate sympathetic outflow. Furthermore, a bilateral microinjection of NOP antagonist into either the dorsal horn or the intermediolateral column at T1 partially reversed the EA inhibitory effect. These results suggest that nociceptin in the spinal cord mediates part of the EA-related modulation of visceral reflex responses.

    Title Processing Cardiovascular Information in the Vlpag During Electroacupuncture in Rats: Roles of Endocannabinoids and Gaba.
    Date July 2009
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    A long-loop pathway, involving the hypothalamic arcuate nucleus (ARC), ventrolateral periaqueductal gray (vlPAG), and the rostral ventrolateral medulla (rVLM), is essential in electroacupuncture (EA) attenuation of sympathoexcitatory cardiovascular reflex responses. The ARC provides excitatory input to the vlPAG, which, in turn, inhibits neuronal activity in the rVLM. Although previous studies have shown that endocannabinoid CB(1) receptor activation modulates gamma-aminobutyric acid (GABA)-ergic and glutamatergic neurotransmission in the dorsolateral PAG in stress-induced analgesia, an important role for endocannabinoids in the vlPAG has not yet been observed. We recently have shown (Fu LW, Longhurst JC. J Appl Physiol; doi:10.1152/japplphysiol.91648.2008) that EA reduces the local vlPAG concentration of GABA, but not glutamate, as measured with high-performance liquid chromatography from extracellular samples collected by microdialysis. We, therefore, hypothesized that, during EA, endocannabinoids, acting through CB(1) receptors, presynaptically inhibit GABA release to disinhibit the vlPAG and ultimately modulate excitatory reflex blood pressure responses. Rats were anesthetized, ventilated, and instrumented to measure heart rate and blood pressure. Gastric distention-induced blood pressure responses of 18 +/- 5 mmHg were reduced to 6 +/- 1 mmHg by 30 min of low-current, low-frequency EA applied bilaterally at pericardial P 5-6 acupoints overlying the median nerves. Like EA, microinjection of the fatty acid amide hydrolase inhibitor URB597 (0.1 nmol, 50 nl) into the vlPAG to increase endocannabinoids locally reduced the gastric distention cardiovascular reflex response from 21 +/- 5 to 3 +/- 4 mmHg. This inhibition was reversed by pretreatment with the GABA(A) antagonist gabazine (27 mM, 50 nl), suggesting that endocannabinoids exert their action through a GABAergic receptor mechanism in the vlPAG. The EA-related inhibition from 18 +/- 3 to 8 +/- 2 mmHg was reversed to 14 +/- 2 mmHg by microinjection of the CB(1) receptor antagonist AM251 (2 nmol, 50 nl) into the vlPAG. Pretreatment with gabazine eliminated reversal following CB(1)-receptor blockade. Thus EA releases endocannabinoids and activates presynaptic CB(1) receptors to inhibit GABA release in the vlPAG. Reduction of GABA release disinhibits vlPAG cells, which, in turn, modulate the activity of rVLM neurons to attenuate the sympathoexcitatory reflex responses.

    Title Electroacupuncture Modulates Vlpag Release of Gaba Through Presynaptic Cannabinoid Cb1 Receptors.
    Date July 2009
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Previous studies have demonstrated that electroacupuncture (EA) attenuates sympathoexcitatory reflex responses by activating a long-loop pathway involving the hypothalamic arcuate nucleus (ARC), midbrain ventrolateral periaqueductal gray (vlPAG), and rostral ventrolateral medulla (rVLM). Neurons in the ARC provide excitatory input to the vlPAG, whereas the vlPAG inhibits neuronal activity in the rVLM. gamma-Aminobutyric acid (GABA) and glutamate (Glu) have been identified in the vlPAG. Endocannabinoids (ECs), acting as atypical neurotransmitters, inhibit the release of both neurotransmitters in the hypothalamus and midbrain through a presynaptic cannabinoid type 1 (CB(1)) receptor mechanism. The EC system has been observed in the dorsal but not in the vlPAG. Since it is uncertain whether ECs influence GABA and Glu in the vlPAG, the present study tested the hypothesis that EA modulates the release of these neurotransmitters in the vlPAG through a presynaptic CB(1) receptor mechanism. We measured the release of GABA and Glu simultaneously by using HPLC to assess samples collected with microdialysis probes inserted unilaterally into the vlPAG of intact anesthetized rats. Twenty-eight min of EA (2 Hz, 2-4 mA, 0.5 ms) at the P5-6 acupoints reduced the release of GABA by 39% during EA and by 44% 15 min after EA. Thirty-five minutes after EA, GABA concentrations returned to pre-EA levels. In contrast, sham EA did not change the vlPAG GABA concentration. Blockade of CB(1) receptors with AM251, a selective CB(1) receptor antagonist, reversed the EA-modulated changes in GABA concentration, whereas microinjection of vehicle into the vlPAG did not alter EA-modulated GABA changes. In addition, we observed no changes in the vlPAG Glu concentrations during EA, although the baseline concentration of Glu was much higher than that of GABA (3,541 +/- 373 vs. 33.8 +/- 8.7 nM, Glu vs. GABA). These results suggest that EA modulates the sympathoexcitatory reflex responses by decreasing the release of GABA, but not Glu, in the vlPAG, most likely through a presynaptic CB(1) receptor mechanism.

    Title Undiscovered Role of Endogenous Thromboxane A2 in Activation of Cardiac Sympathetic Afferents During Ischaemia.
    Date November 2008
    Journal The Journal of Physiology
    Excerpt

    Myocardial ischaemia activates blood platelets, which in turn stimulate cardiac sympathetic afferents, leading to chest pain and sympathoexcitatory reflex cardiovascular responses. Previous studies have shown that activated platelets stimulate ischaemically sensitive cardiac sympathetic afferents, and that thromboxane A(2) (TxA(2)) is one of the mediators released from activated platelets during myocardial ischaemia. The present study tested the hypothesis that endogenous TxA(2) stimulates cardiac afferents during ischaemia through direct activation of TxA(2) (TP) receptors coupled with the phospholipase C-protein kinase C (PLC-PKC) cellular pathway. Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) in anaesthetized cats. Single fields of 39 afferents (conduction velocity = 0.27-3.65 m s(-1)) were identified in the left or right ventricle initially with mechanical stimulation and confirmed with a stimulating electrode. Five minutes of myocardial ischaemia stimulated all 39 cardiac afferents (8 Adelta-, 31 C-fibres) and the responses of these 39 afferents to chemical stimuli were further studied in the following four protocols. In the first protocol, 2.5, 5 and 10 microg of the TxA(2) mimetic, U46619, injected into the left atrium (LA), stimulated seven ischaemically sensitive cardiac afferents in a dose-dependent manner. Second, BM13,177, a selective TxA(2) receptor antagonist, abolished the responses of six afferents to 5 microg of U46619 injected into the left atrium and attenuated the ischaemia-related increase in activity of seven other afferents by 44%. In contrast, cardiac afferents, in the absence of TP receptor blockade responded consistently to repeated administration of U46619 (n = 6) and to recurrent myocardial ischaemia (n = 7). In the fourth protocol, administration of PKC-(19-36), a selective PKC inhibitor, attenuated the responses of six other cardiac afferents to U46619 by 38%. Finally, using an immunohistochemical staining approach, we observed that TP receptors were expressed in cardiac sensory neurons in thoracic dorsal root ganglia. Taken together, these data indicate that endogenous TxA(2) contributes to the activation of cardiac afferents during myocardial ischaemia through direct stimulation of TP receptors probably located in the cardiac sensory nervous system and that the stimulating effect of TxA(2) on cardiac afferents is dependent, at least in part, upon the PLC-PKC cellular pathway.

    Title Electroacupuncture Treatment of Arrhythmias in Myocardial Ischemia.
    Date June 2007
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Title Role of Glutamate in the Rostral Ventrolateral Medulla in Acupuncture-related Modulation of Visceral Reflex Sympathoexcitation.
    Date May 2007
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Visceral sympathoexcitatory reflexes induced by stimulation of the gallbladder with bradykinin (BK) are attenuated by electroacupuncture (EA) at Neiguan-Jianshi (P5-6) acupoints located over the median nerve. Previous studies have shown that neurons in the rostral ventrolateral medulla (rVLM) receive convergent input from visceral organs and somatic nerves (activated by EA). Glutamate (Glu), an important excitatory neurotransmitter in the rVLM, processes visceral sympathoexcitatory cardiovascular reflexes. In the present study, we determined the relation between EA-mediated opioidergic modulation of visceral cardiovascular responses and Glu. Reflex cardiovascular responses were evoked by application of BK to the gallbladder before and after EA in anesthetized cats. Glu concentrations ([Glu]) were measured by HPLC from samples collected by microdialysis probe(s) inserted unilaterally or bilaterally into the rVLM. BK-induced reflex responses and [Glu] were attenuated by 45% and 70%, respectively, after 30 min of EA (n = 6). EA alone did not change [Glu] in the rVLM (n = 6, P > 0.05). However, microdialysis of naloxone (100 mM) into the rVLM reversed EA-related inhibition of blood pressure and [Glu] (n = 5). Immunohistochemical visualization showed that delta-opioid receptors colocalized with, and were in close apposition to, vesicular Glu transporter 3- and c-Fos-double-labeled perikarya and processes of rVLM neurons after gallbladder stimulation with BK. These data suggest that EA attenuates BK-induced visceral sympathoexcitatory reflexes through opioid-mediated inhibition of Glu's action in the rVLM.

    Title Responses of Neurons Containing Vglut3/nnos-cgmp in the Rvlm to Cardiac Stimulation.
    Date May 2006
    Journal Neuroreport
    Excerpt

    Responses of glutamatergic neurons in the rostral ventrolateral medulla to stimulation of cardiac sympathetic afferents have not been defined. Nitric oxide influences neural function of glutamate. We evaluated the relationship between vesicular glutamate transporter 3, c-Fos and neuronal nitric oxide synthase/soluble guanylyl cyclase in the rostral ventrolateral medulla following cardiac stimulation. In anesthetized cats with barodenervation and vagotomy, epicardial application of bradykinin, but not its vehicle, caused pressor responses. More vesicular glutamate transporter 3-containing neurons colocalized with c-Fos or c-Fos and neuronal nitric oxide synthase in the rostral ventrolateral medulla in bradykinin-treated cats (n = 6; P < 0.05) than in control animals (n = 4). Colocalization of neuronal nitric oxide synthase, soluble guanylyl cyclase and c-Fos or vesicular glutamate transporter 3 was noted following bradykinin stimulation. Findings indicate activation of rostral ventrolateral medulla glutamatergic neurons by cardiac stimulation, which may be influenced by nitric oxide via cGMP.

    Title Modulation of Cardiovascular Excitatory Responses in Rats by Transcutaneous Magnetic Stimulation: Role of the Spinal Cord.
    Date April 2006
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    This study investigated the efficacy of magnetic stimulation on the reflex cardiovascular responses induced by gastric distension in anesthetized rats and compared these responses to those influenced by electroacupuncture (EA). Unilateral magnetic stimulation (30% intensity, 2 Hz) at the Jianshi-Neiguan acupoints (pericardial meridian, P 5-6) overlying the median nerve on the forelimb for 24 min significantly decreased the reflex pressor response by 32%. This effect was noticeable by 20 min of magnetic stimulation and continued for 24 min. Median nerve denervation abolished the inhibitory effect of magnetic stimulation, indicating the importance of somatic afferent input. Unilateral EA (0.3-0.5 mA, 2 Hz) at P 5-6 using similar durations of stimulation similarly inhibited the response (35%). The inhibitory effects of EA occurred earlier and were marginally longer (20 min) than magnetic stimulation. Magnetic stimulation at Guangming-Xuanzhong acupoints (gallbladder meridian, GB 37-39) overlying the superficial peroneal nerve on the hindlimb did not attenuate the reflex. Intravenous naloxone immediately after termination of magnetic stimulation reversed inhibition of the cardiovascular reflex, suggesting involvement of the opioid system. Also, intrathecal injection of delta- and kappa-opioid receptors antagonists, ICI174,864 (n=7) and nor-binaltorphimine (n=6) immediately after termination of magnetic stimulation reversed inhibition of the cardiovascular reflex. In contrast, the mu-opioid antagonist CTOP (n=7) failed to alter the cardiovascular reflex. The endogenous neurotransmitters for delta- and kappa-opioid receptors, enkephalins and dynorphin but not beta-endorphin, therefore appear to play significant roles in the spinal cord in mediating magnetic stimulation-induced modulation of cardiovascular reflex responses.

    Title Brain Stem Mechanisms Underlying Acupuncture Modality-related Modulation of Cardiovascular Responses in Rats.
    Date October 2005
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    The present study was designed to investigate brain stem responses to manual acupuncture (MA) and electroacupuncture (EA) at different frequencies at pericardial P (5-6) acupoints located over the median nerve. Activity of premotor sympathetic cardiovascular neurons in the rostral ventral lateral medulla (rVLM) was recorded during stimulation of visceral and somatic afferents in ventilated anesthetized rats. We stimulated either the splanchnic nerve at 2 Hz (0.1-0.4 mA, 0.5 ms) or the median nerve for 30 s at 2, 10, 20, 40, or 100 Hz using EA (0.3-0.5 mA, 0.5 ms) or at approximately 2 Hz with MA. Twelve of 18 cells responsive to splanchnic and median nerve stimulation could be antidromically driven from the intermediolateral columns of the thoracic spinal cord, T2-T4, indicating that they were premotor sympathetic neurons. All 18 neurons received baroreceptor input, providing evidence of their cardiovascular sympathoexcitatory function. Evoked responses during stimulation of the splanchnic nerve were inhibited by 49 +/- 6% (n = 7) with EA and by 46 +/- 4% (n = 6) with MA, indicating that the extent of inhibitory effects of the two modalities were similar. Inhibition lasted for 20 min after termination of EA or MA. Cardiovascular premotor rVLM neurons responded to 2-Hz electrical stimulation at P 5-6 and to a lesser extent to 10-, 20-, 40-, and 100-Hz stimulation (53 +/- 10, 16 +/- 2, 8 +/- 2, 2 +/- 1, and 0 +/- 0 impulses/30 stimulations, n = 7). These results indicate that rVLM premotor sympathetic cardiovascular neurons that receive convergent input from the splanchnic and median nerves during low-frequency EA and MA are inhibited similarly for prolonged periods by low-frequency MA and EA.

    Title Interactions Between Histamine and Bradykinin in Stimulation of Ischaemically Sensitive Cardiac Afferents in Felines.
    Date September 2005
    Journal The Journal of Physiology
    Excerpt

    Cardiac spinal afferents are activated during myocardial ischaemia. Our previous studies have shown that during ischaemia, histamine and bradykinin (BK) stimulate cardiac spinal afferents. Because the two mediators are released together during ischaemia, the present study examined the interactions between these two mediators with respect to their influence on ischaemically sensitive cardiac afferents. Single-unit cardiac afferent activity was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) in anaesthetized cats. Fifty-five ischaemically sensitive cardiac afferents (conduction velocity (CV) = 0.2-5.6 m s(-1), 8 Adelta- and 47 C-fibres) were identified. Administration of histamine (10 microg kg(-1)) and BK (1 microg) in combination into the left atrium (LA) caused an additive response in 16 afferents compared with administration of either BK or histamine alone (2.62 +/- 0.39 versus 1.67 +/- 0.20 versus 1.24 +/- 0.23 impulses s(-1) (imp s(-1)), BK + histamine versus BK versus histamine). To further evaluate interactions between these mediators, we observed that injection of histamine (10 microg kg(-1), LA) 4 min after the administration of BK (1 microg, LA) induced a significantly larger cardiac afferent response than the response to histamine before BK (1.24 +/- 0.23 versus 1.96 +/- 0.39 imp s(-1), before versus after, n = 10). In contrast, six other afferents responded reproducibly to repeated injections of histamine (10 microg kg(-1), LA) in the absence of BK. BK sensitization of the afferent response to histamine lasted for less than 10 min. Cyclooxygenase blockade with indomethacin (5 mg kg(-1), i.v.) abolished BK sensitization of the response to histamine (1.09 +/- 0.11 versus 1.11 +/- 0.10 imp s(-1), n = 10). Conversely, the response of most (7/9) cardiac afferents to repeat application of BK (1 microg, LA) 4 min after histamine (10 microg kg(-1), LA) was attenuated compared with the BK response before histamine (1.84 +/- 0.25 versus 1.31 +/- 0.18 imp s(-1), before versus after, P < 0.05). Repeat BK (1 microg, LA) induced a consistent response in five other afferents in the absence of histamine. Thus, BK interacts with histamine, and together they cause a larger response than either one alone. BK sensitizes cardiac afferents responding to histamine in a time-dependent fashion, and the BK sensitization effect is dependent on an intact cyclooxygenase pathway. Conversely, histamine reduces the response of most afferents to BK.

    Title Integrating Complementary Medicine into Cardiovascular Medicine. A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine).
    Date July 2005
    Journal Journal of the American College of Cardiology
    Title Afferent Mechanisms Underlying Stimulation Modality-related Modulation of Acupuncture-related Cardiovascular Responses.
    Date June 2005
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Despite the use of acupuncture to treat a number of heart diseases, little is known about the mechanisms that underlie its actions. Therefore, we examined the influence of acupuncture on sympathoexcitatory cardiovascular responses to gastric distension in anesthetized Sprague-Dawley rats. Thirty minutes of low-current, low-frequency, (0.3-0.5 mA, 2 Hz) electroacupuncture (EA), at P 5-6, S 36-37, and H 6-7 overlying the median, deep peroneal, and ulnar nerves significantly decreased reflex pressor responses by 40, 39, and 44%, respectively. In contrast, sham acupuncture involving needle insertion without stimulation at P 5-6 or 30 min of EA at LI 6-7 acupoints overlying the superficial radial nerve did not attenuate the reflex. Similarly, EA at P 5-6 using 40- or 100-Hz stimulation frequencies did not inhibit the reflex. Compared with EA at P 5-6, EA at two sets of acupoints, including P 5-6 and S 36-37, did not lead to larger inhibition of the reflex. Two minutes of manual acupuncture (MA; 2 Hz) at P 5-6 every 10 min for 30 min inhibited the reflex cardiovascular pressor response by 33%, a value not significantly different from 2-Hz EA at P 5-6. Single-unit afferent activity was not different between electrical stimulation (ES) and manual stimulation. However, 2-Hz ES activated more somatic afferents than 10- or 20-Hz ES. These data suggest that, although the location of acupoint stimulation and the frequency of stimulation determine the extent of influence of EA, there is little difference between low-frequency EA and MA at P 5-6. Furthermore, simultaneous stimulation using two acupoints that independently exert strong effects did not lead to an additive or a facilitative interaction. The similarity of the responses to EA and MA and the lack of cardiovascular response to high-frequency EA appear to be largely a function of somatic afferent responses.

    Title Histamine Contributes to Ischemia-related Activation of Cardiac Spinal Afferents: Role of H1 Receptors and Pkc.
    Date March 2005
    Journal Journal of Neurophysiology
    Excerpt

    Myocardial ischemia activates cardiac spinal afferents that transmit the nociceptive information leading to chest pain and elicit excitatory cardiovascular reflexes. Previous studies have shown that histamine is increased in coronary sinus blood during myocardial ischemia and that this autacoid stimulates abdominal visceral afferents. The present investigation evaluated the role of endogenous histamine in stimulation of ischemically sensitive cardiac spinal afferents. Nerve activity of single-unit cardiac afferents was recorded from the left sympathetic chain or rami communicans (T2-T5) in anesthetized cats. Sixty-four cardiac afferents were identified. Injection (5-30 microg/kg) of histamine into the left atrium (LA) stimulated 7 ischemically sensitive cardiac afferents resulting in a significant increase in their activity in a dose-dependent manner. Also, LA injection of histamine (10 microg/kg) stimulated 7 of 8 ischemically insensitive cardiac spinal afferents. Administrations of 2-(3-chlorophenyl)histamine (250 microg/kg, LA), a specific H1 receptor agonist and histamine (10 microg/kg, LA), stimulated 9 other ischemically sensitive cardiac afferents (0.48 +/- 0.10 to 1.40 +/- 0.20 imp/s). In contrast, dimaprit (500 microg/kg, LA), an H2 receptor agonist, stimulated only one of the 9 afferents and thus did not alter their overall activity (0.40 +/- 0.09 to 0.54 +/- 0.09 imp/s). (R)alpha-Methyl-histamine (500 microg/kg, LA), an H3 receptor agonist, did not stimulate any of the 9 afferents. Pyrilamine (300 microg/kg, i.v.), a selective H1 receptor antagonist, attenuated the activity of 8 afferents during 5 min of ischemia from 3.32 +/- 0.38 to 1.87 +/- 0.28 imp/s and abolished the response of 9 other cardiac afferents to histamine. Finally, administration of PKC-(19-36) (30 microg/kg, i.v.), a selective inhibitor of protein kinase C, attenuated the response of 8 cardiac afferents to histamine by 32%. These data indicate that endogenous histamine contributes to activation of cardiac sympathetic afferents during myocardial ischemia through H1 receptors and that the action of histamine on these cardiac afferents is partially dependent on the intracellular PKC pathway.

    Title Electroacupuncture Induces C-fos Expression in the Rostral Ventrolateral Medulla and Periaqueductal Gray in Cats: Relation to Opioid Containing Neurons.
    Date February 2005
    Journal Brain Research
    Excerpt

    Our previous studies have shown that electroacupuncture (EA) at the Neiguan-Jianshi (P5-P6) acupoints inhibits sympathetic outflow and attenuates excitatory visceral cardiovascular reflexes through enkephalin- or beta-endorphin-related opioid receptors in the rostral ventrolateral medulla (rVLM). It is not known whether EA at these acupoints activates neurons containing enkephalin or beta-endorphin in the rVLM as well as in the periaqueductal gray (PAG) that are involved in EA-mediated central neural regulation of sympathetic activity. The present study evaluated activated neurons in the rVLM and PAG by detecting c-Fos immunoreactivity, and identified the relationship between c-Fos nuclei and neuronal structures containing enkephalin or beta-endorphin in these regions. To enhance the detection of cell bodies containing enkephalin or beta-endorphin, colchicine (90-100 microg/kg) was injected into the subarachnoid space in anesthetized cats 28-30 h prior to EA or the sham-operated control for EA. Following bilateral barodenervation and cervical vagotomy, EA (1-4 mA, 2 Hz, 0.5 ms) was performed at the P5-P6 acupoints (overlying median nerve; n=7) for 30 min. Identical procedures, with the exception of electrical stimulation, were carried out in five control animals. EA decreased blood pressure (BP) in four of seven cats (5-15 mm Hg) while the sham procedure for EA produced no responses. Perikarya containing enkephalin were found in the rVLM and rarely in the PAG, while no cell bodies labeled with beta-endorphin were identified in either region. Compared to animals in the control group, more c-Fos immunoreactivity, located principally in close proximity to fibers containing enkephalin or beta-endorphin, was observed in the rVLM and ventrolateral PAG (vlPAG) in EA-treated cats. Moreover, neurons double-labeled with c-Fos and enkephalin in the rVLM were significantly increased in cats following EA stimulation (P<0.05). These data indicate that EA at the P5-P6 acupoints activates neurons in the rVLM and vlPAG. These activated neurons contain enkephalin in the rVLM, and most likely interact with nerve fibers containing enkephalin or beta-endorphin in both the rVLM and vlPAG. The results from this study provide the first anatomical evidence showing that EA at the P5-P6 acupoints has the potential to influence neuronal structures (perikarya, axons and/or dendrites) containing enkephalin or beta-endorphin in specific regions of the brain stem. These neurons likely form the substrate for EA's influence on sympathoexcitatory cardiovascular reflexes.

    Title Inhibitory Effect of Electroacupuncture (ea) on the Pressor Response Induced by Exercise Stress.
    Date January 2005
    Journal Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society
    Excerpt

    We examined the effect of EA on the exercise stress-induced pressor response in healthy adult subjects of both sexes. Each subject was subjected to a bicycle exercise test using a ramp protocol once/week for three or four weeks. Subjects were asked to perform the following tests in random order: 1) a baseline exercise test without EA and 2) exercise after acupuncture at P 5-6, LI 4-L 7 and/or G 37-39 acupoints. Brachial systolic (SBP), diastolic (DBP), and mean blood pressures (MBP), heart rate (HR) and the rate-pressure product (RPP, systolic BP x HR/100) were measured every three min, while a 12 lead ECG was monitored continuously. We observed increases in MBP, SBP, HR and RPP in all 17 subjects during exercise. In 12 of the 17 subjects (71 %), EA for 30 min before exercise, either at Jianshi-Neiguan acupoints (P 5-6) or Hegu-Lique acupoints (LI 4-L 7), led to an increase in maximal workload, and reduced peak SBP, MBP and RPP responses to exercise; EA did not alter DBP or HR responses in these subjects. EA at control acupoints (Guangming-Xuanzhong acupoints, G 37-39) in five subjects did not alter the hemodynamic responses. Seven additional subjects were enrolled to study the effect of EA during a bicycle exercise test using a constant workload. The results were similar, in five of the seven subjects SBP, MBP and RPP after exercise were attenuated significantly by EA at P 5-6. We conclude that EA at specific acupoints improves exercise capacity and reduces the hemodynamic responses in approximately 70% of normal subjects.

    Title Medullary Substrate and Differential Cardiovascular Responses During Stimulation of Specific Acupoints.
    Date October 2004
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    Electroacupuncture (EA) at P5-P6 acupoints overlying the median nerve reduces premotor sympathetic cardiovascular neuronal activity in the rostral ventral lateral medulla (rVLM) and visceral reflex pressor responses. In previous studies, we have noted different durations of influence of EA comparing P5-P6 and S36-S37 acupoints, suggesting that point specificity may exist. The purpose of this study was to evaluate the influence of stimulating P5-P6 (overlying the median nerve), LI4-L7 (overlying branches of the median nerve and the superficial radial nerve), LI6-LI7 (overlying the superficial radial nerve), LI10-LI11 (overlying the deep radial nerves), S36-S37 (overlying the deep peroneal nerves), or K1-B67 (overlying terminal branches of the tibial nerves) specific acupoints, overlying deep and superficial somatic nerves, on the excitatory cardiovascular reflex and rVLM responses evoked by stimulation of chemosensitive receptors in the cat's gallbladder with bradykinin (BK) or direct splanchnic nerve (SN) stimulation. We observed point-specific differences in magnitude and duration of EA inhibition between P5-P6 or LI10-LI11 and LI4-L7 or S36-S37 in responses to 30-min stimulation with low-frequency, low-current EA. EA at LI6-LI7 and K1-B67 acupoints as well as direct stimulation of the superficial radial nerve did not cause any cardiovascular or rVLM neuronal effects. Cardiovascular neurons in the rVLM, a subset of which were classified as premotor sympathetic cells, responded to brief (30 s) stimulation of the SN as well as acupoints P5-P6, LI10-LI11, LI4-L7, S36-S37, LI6-LI7, or K1-B67, or underlying somatic pathways in a fashion similar to the reflex responses. In fact, we observed a significant linear relationship (r(2) = 0.71) between the evoked rVLM response and reflex change in mean arterial blood pressure. In addition, EA stimulation at P5-P6 and LI4-L7 decreased rVLM neuronal activity by 41 and 12%, respectively, for >1 h, demonstrating that prolonged input into the medulla during stimulation of somatic nerves, depending on the degree of convergence, leads to more or less inhibition of activity of these cardiovascular neurons. Thus EA at acupoints overlying deep and superficial somatic nerves leads to point-specific effects on cardiovascular reflex responses. In a similar manner, sympathetic cardiovascular rVLM neurons that respond to both visceral (reflex) and somatic (EA) nerve stimulation manifest graded responses during stimulation of specific acupoints, suggesting that this medullary region plays a role in site-specific inhibition of cardiovascular reflex responses by acupuncture.

    Title Asymmetric Septal Hypertrophy Presenting with Cardiogenic Shock, Complete Heart Block, and Septal Infarction Despite Normal Coronaries.
    Date May 2004
    Journal Reviews in Cardiovascular Medicine
    Excerpt

    A 37-year-old man, brought in following a syncopal episode, was found to be in cardiogenic shock with a complete infranodal heart block. A temporary transvenous pacemaker and an intra-aortic balloon pump were inserted emergently. Cardiac catheterization revealed a high left ventricular end-diastolic pressure but normal coronary vasculature. An echocardiogram demonstrated a hyperdynamic left ventricle, severe hypokinesis of the septum, and asymmetric septal hypertrophy. An endomyocardial biopsy showed myofibril hypertrophy and disarray. The patient required implantation of a permanent pacemaker for full recovery. Although arrhythmias are common in asymmetric septal hypertrophy, complete atrioventricular block is rare but can cause syncope and cardiogenic shock. This is the first case, reported in the literature, of asymmetric septal hypertrophy in which the patient presented with cardiogenic shock and complete heart block secondary to a septal infarction, despite normal coronaries, and in whom a myocardial biopsy was performed. The case report is followed by a review of the literature on hypertrophic cardiomyopathy associated with complete heart block.

    Title Activation of Nitric Oxide-producing Neurons in the Brain Stem During Cardiac Sympathoexcitatory Reflexes in the Cat.
    Date June 2003
    Journal Neuroscience
    Excerpt

    Our previous studies have shown that selective inhibition of nitric oxide in the brain reduces pressor responses to activation of cardiac sympathetic afferents, thus suggesting that nitric oxide is involved in central regulation of cardiac-cardiovascular sympathoexcitatory reflexes. Central neural regions in which nitric oxide-producing neurons are activated during these reflexes have not been well characterized. In the present study, we located nitric oxide-producing neurons in the brain stem activated by the input from cardiac sympathetic afferents by detecting colocalization of c-Fos immunoreactivity with nitric oxide synthesizing neurons. Expression of c-Fos has been used as a marker of activated neurons. Nitric oxide-producing neurons were identified by histochemical labeling of nicotine adenine dinucleotide phosphate-diaphorase (NADPH-d). In anesthetized cats with bilateral barodenervation and cervical vagotomy, bradykinin (1-10 microg in 0.1 ml; n=6) was applied to the anterior surface of the left ventricle six times every 20 minutes. Repetitive application of bradykinin consistently increased blood pressure, while the vehicle for bradykinin (0.9% saline, n=5) produced no responses. A substantial fraction (6-27%) of NADPH-d positive neurons displayed Fos immunoreactivity in the nucleus of the solitary tract, caudal and rostral ventral lateral medulla, lateral tegmental field, locus coeruleus and parabrachial nucleus in the bradykinin-treated cats. However, either no or rare (1-4%) double-labeled cells were found in these regions in control animals. Thus, nitric oxide-producing neurons are activated in several regions in the brain stem during stimulation of cardiac sympathetic afferents by bradykinin. Our data suggest that nitric oxide functions as a neurotransmitter/modulator in these areas to regulate the cardiac sympathoexcitatory reflexes.

    Title Effect of Electroacupuncture on Pressor Reflex During Gastric Distension.
    Date December 2002
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    The effect of electroacupuncture (EA) on the reflex cardiovascular response induced by mechanical distension of the stomach was studied in ventilated male Sprague-Dawley rats anesthetized by ketamine and alpha-chloralose. Repeated balloon inflation of the stomach to produce 20 mmHg tension on the gastric wall induced a consistent rise in mean arterial pressure, while heart rate (372 +/- 22 beats/min) was unchanged. This response was reversed by transection of the splanchnic nerves. Bilateral application of EA (1-2 mA, 2 Hz) at Neiguan-Jianshi acupoints (pericardial meridian, Pe 5-6) over the median nerve for 30 min significantly decreased the pressor response from 33 +/- 6 to 18 +/- 4 mmHg (n = 7, P < 0.05). This effect began after 10 min of EA and continued for 40 min after termination of EA. EA at Zusanli-Shangquxu acupoints (stomach meridian, St 36-37) over the deep peroneal nerve similarly inhibited the pressor response. The effect lasted for 10 min after EA was stopped (n = 6, P < 0.05), while EA at Guangming-Xuanzhong acupoints (gallbladder meridian, GB 37-39) over the superficial peroneal nerve did not inhibit the pressor response. Naloxone injected intravenously (n = 6) immediately after termination of EA or administered by microinjection into the rostral ventrolateral medulla (rVLM) 25 min after initiation of EA (n = 6) reversed the inhibition by EA, suggesting an opiate mechanism, including the rVLM, was involved.

    Title State of Complementary and Alternative Medicine in Cardiovascular, Lung, and Blood Research: Executive Summary of a Workshop.
    Date September 2002
    Journal Circulation
    Excerpt

    The National Heart, Lung, and Blood Institute and the National Center for Complementary and Alternative Medicine recently cosponsored a workshop on the use of complementary and alternative medicine (CAM) in cardiovascular, lung, and blood research. In view of the increasing use of CAM by the general public, it is imperative to promote credible research by the established biomedical community. The goal of this workshop was to enhance the exchange of information and ideas between alternative medicine practitioners and scientists in cardiovascular, lung, and blood research and to foster collaborative research among these researchers. The workshop focused on 5 areas of research, including a historical and cultural perspective of CAM, methodological issues in clinical trials, herbal medicine, chelation therapy, mind/body (meditation) therapy, and acupuncture. CAM has become widely used without rigorously proven efficacy and safety. To protect the public, it was recommended that the fundamental mechanistic research for these CAM approaches be vigorously pursued and that any large-scale clinical trial be carefully executed to avoid any waste of resources and any unnecessary risk. It was felt that standardization of botanical products and procedure-based CAM intervention, such as acupuncture and meditation, is essential for meaningful basic and clinical research. Although botanical products properly consumed are perceived as generally safe, potential herb-drug interactions are a major safety concern. Clearly, many challenges need to be addressed by the scientific community before the public can be assured of the proper use of CAM.

    Title Alternative Approaches to the Medical Management of Cardiovascular Disease: Acupuncture, Electrical Nerve, and Spinal Cord Stimulation.
    Date May 2002
    Journal Heart Disease (hagerstown, Md.)
    Title Role of Spinal Nmda and Non-nmda Receptors in the Pressor Reflex Response to Abdominal Ischemia.
    Date March 2002
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    Abdominal ischemia induces a pressor reflex caused mainly by C-fiber afferent stimulation. Because excitatory amino acids, such as glutamate, bind to N-methyl-D-aspartate (NMDA) and non-NMDA [dl-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)] receptors and serve as important spinal neurotransmitters, we hypothesized that both receptors play a role in the abdominal ischemia pressor reflex. In chloralose-anesthetized cats, NMDA receptor blockade with 25.0 mM dl-2-amino-5-phosphonopentanoate did not alter the pressor reflex (33 +/- 9 to 33 +/- 7 mmHg, P > 0.05, n = 4), whereas AMPA receptor blockade with 4.0 mM 6-nitro-7-sulfamylbenzo(f)quinoxaline-2,3-dione significantly attenuated the reflex (29 +/- 5 to 16 +/- 4 mmHg, P < 0.05, n = 6). Because several studies suggest that anesthesia masks the effects of glutamatergic receptors, this experiment was repeated on decerebrate cats, and in this group, NMDA receptor blockade with 25.0 mM dl-2-amino-5-phosphonopentanoate significantly altered the pressor reflex (36 +/- 3 to 25 +/- 4 mmHg, P < 0.05, n = 5). Our combined data suggest that spinal NMDA and AMPA receptors play a role in the abdominal ischemia pressor reflex.

    Title Role of Activated Platelets in Excitation of Cardiac Afferents During Myocardial Ischemia in Cats.
    Date January 2002
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Myocardial ischemia activates cardiac spinal afferents that mediate chest pain and excitatory reflex cardiovascular responses. Platelets are activated during myocardial ischemia and release 5-hydroxytryptamine, which stimulates abdominal spinal afferents. This study investigated the role of activated platelets in excitation of cardiac spinal afferents during ischemia. Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were obtained from cats and incubated with collagen (2 mg/ml) or thrombin (5 U/ml). We observed reduction of platelets in PRP indicative of platelet activation by collagen and thrombin, respectively. Activity of single-unit, ischemia-sensitive cardiac spinal afferents was recorded from the left sympathetic chain in anesthetized cats. Injection of 1.5 ml PRP + collagen (activated platelets) into the left atrium (LA) stimulated 12 of 13 cardiac afferents. PRP + saline (nonactivated platelets, LA) and PPP + collagen did not alter activity of these afferents. PRP + thrombin (1.5 ml, LA) stimulated eight of nine other cardiac afferents, whereas PPP + thrombin did not stimulate any of the nine afferents. Antiplatelet immune serum (1 ml/kg iv) significantly decreased circulating platelets as well as neutrophils (polymorphonuclear leukocytes, PMNs) in eight other cats, and in each animal, attenuated the ischemia-related increase in activity of cardiac afferents. Conversely, responses of five separate cardiac afferents to ischemia were not diminished after treatment with anti-PMN immune serum when concentration of circulating platelets was maintained by infusion of donated PRP despite the decrease in circulating PMNs. These data indicate activated platelets stimulate ischemia-sensitive cardiac spinal afferents and contribute to activation of these afferents during ischemia.

    Title Effects of Red Wine, Alcohol, and Quercetin on Coronary Resistance and Conductance Arteries.
    Date January 2002
    Journal Journal of Cardiovascular Pharmacology
    Excerpt

    Moderate consumption of alcoholic beverages is associated with a reduced risk of coronary heart disease (CHD). Some evidence suggests that red wine is particularly beneficial in this regard and may account in part for the French paradox, although the mechanism of this effect is unknown. We assessed the effects of red wine, ethanol, and quercetin, a major flavonoid constituent of red wine, in coronary resistance vessels (80-150 microm, i.d.) and conductance vessels (300-525 microm, i.d.) of the rabbit. Vessel wall tension was measured in isolated segments maintained in a wire-type myograph (37 degrees C) and preconstricted with 30 mM K+. At an alcohol concentration (14 mM) equivalent to moderate consumption, red wine evoked a small, transient constrictor effect in resistance and conductance vessels (9+/-4%, n = 5; 8+/-1%, n = 7, respectively; p < 0.05). Ethanol alone at this concentration was without effect. Quercetin (5.6, 8, and 30 microM) significantly relaxed resistance (-32+/-4%, n = 10; -47+/-2%, n = 7; -82+/-6%, n = 8, respectively) and conductance (-20+/-3%, n = 8; -32+/-4%, n = 8; -72+/-7%, n = 8, respectively) coronary arteries. Vasorelaxation by quercetin was endothelium-independent and was significantly greater in resistance than in conductance vessels. These data suggest that red wine and ethanol do not evoke relaxation in small coronary arteries at concentrations associated with moderate consumption. Quercetin elicits marked coronary vasorelaxation that is endothelium-independent. However, the concentrations of quercetin necessary to achieve this action are not attained with moderate red wine consumption.

    Title Nitric Oxide Modulates Sympathoexcitatory Cardiac-cardiovascular Reflexes Elicited by Bradykinin.
    Date December 2001
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    A number of studies have demonstrated an important role for nitric oxide (NO) in central and peripheral neural modulation of sympathetic activity. To assess the interaction and integrative effects of NO release and sympathetic reflex actions, we investigated the influence of inhibition of NO on cardiac-cardiovascular reflexes. In anesthetized, sinoaortic-denervated and vagotomized cats, transient reflex increases in arterial blood pressure (BP) were induced by application of bradykinin (BK, 0.1-10 microg/ml) to the epicardial surface of the heart. The nonspecific NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mg/kg iv) was then administered and stimulation was repeated. L-NMMA increased baseline mean arterial pressure (MAP) from 129 +/- 8 to 152 +/- 9 mmHg and enhanced the change in MAP in response to BK from 32 +/- 3 to 39 +/- 5 mmHg (n = 9, P < 0.05). Pulse pressure was significantly enhanced during the reflex response from 6 +/- 4 to 27 +/- 6 mmHg after L-NMMA injection due to relatively greater potentiation of the rise in systolic BP. Both the increase in baseline BP and the enhanced pressor reflex were reversed by L-arginine (30 mg/kg iv). Because L-NMMA can inhibit both brain and endothelial NOS, the effects of 7-nitroindazole (7-NI, 25 mg/kg ip), a selective brain NOS inhibitor, on the BK-induced cardiac-cardiovascular pressor reflex also were examined. In contrast to L-NMMA, we observed significant reduction of the pressor response to BK from 37 +/- 5 to 18 +/- 3 mmHg 30 min after the administration of 7-NI (n = 9, P < 0.05), an effect that was reversed by L-arginine (300 mg/kg iv, n = 7). In a vehicle control group for 7-NI (10 ml of peanut oil ip), the pressor response to BK remained unchanged (n = 6, P > 0.05). In conclusion, neuronal NOS facilitates, whereas endothelial NOS modulates, the excitatory cardiovascular reflex elicited by chemical stimulation of sympathetic cardiac afferents.

    Title Cardiac Sympathetic Afferent Activation Provoked by Myocardial Ischemia and Reperfusion. Mechanisms and Reflexes.
    Date August 2001
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Cardiac sympathetic afferents are known to reflexly activate the cardiovascular system, leading to increases in blood pressure, heart rate, and myocardial contractile function. During myocardial ischemia, these sensory nerves also transmit the sensation of pain (angina pectoris) and cause tachyarrhythmias. The authors' laboratory has been interested in defining the mechanisms of activation of this neural system during ischemia and reperfusion. During these periods, reactive oxygen species, particularly hydroxyl radicals, are produced from the breakdown of purine metabolites and lead to stimulation of sympathetic (and vagal) ventricular chemosensitive nerve endings. For example, stimulation with hydrogen peroxide leads to a small reflex increase in blood pressure from the predominant sympathetic afferent activation that is reduced by simultaneous activation of cardiac vagal afferents (known to exert predominantly depressor reflexes). Central integration of these two opposing reflexes likely occurs at several regions of the brain stem, including the nucleus tractus solitarii, where neural occlusion occurs during simultaneous cardiac sympathetic and vagal-afferent stimulation. Activation of platelets also appears to play a role during myocardial ischemia, leading to local release of serotonin (5HT), which, through a 5HT3 mechanism, stimulates sympathetic afferents. Finally, regional changes in pH from lactic acid (but not hypercapnia), stimulate ventricular afferents and may activate kallikrein to increase bradykinin (BK), which, in turn, breaks down arachidonic acid to form prostaglandins. Prostaglandins sensitize cardiac sympathetic afferents to BK. Thus, stimulation of cardiac sympathetic afferents during ischemia and reperfusion and the resulting reflex events form a multifactorial process resulting from activation of a number of chemical pathways in the myocardium.

    Title Hemodynamic Responses to Static and Dynamic Muscle Contractions at Equivalent Workloads.
    Date November 2000
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    We tested the hypothesis that static contraction causes greater reflex cardiovascular responses than dynamic contraction at equivalent workloads [i.e., same tension-time index (TTI), holding either contraction time or peak tension constant] in chloralose-anesthetized cats. When time was held constant and tension was allowed to vary, dynamic contraction of the hindlimb muscles evoked greater increases (means +/- SE) in mean arterial pressure (MAP; 50 +/- 7 vs. 30 +/- 5 mmHg), popliteal blood velocity (15 +/- 3 vs. 5 +/- 1 cm/s), popliteal venous PCO(2) (15 +/- 3 vs. 3 +/- 1 mmHg), and a greater decrease in popliteal venous pH (0.07 +/- 0.01 vs. 0.03 +/- 0.01), suggesting greater metabolic stimulation during dynamic contraction. Similarly, when peak tension was held constant and time was allowed to vary, dynamic contraction evoked a greater increase in blood velocity (13 +/- 1 vs. -1 +/- 1 cm/s) without causing any differences in other variables. To investigate the reflex contribution of mechanoreceptors, we stretched the hindlimb dynamically and statically at the same TTI. A larger reflex increase in MAP during dynamic stretch (32 +/- 8 vs. 24 +/- 6 mmHg) was observed when time was held constant, indicating greater mechanoreceptor stimulation. However, when peak tension was held constant, there were no differences in the reflex cardiovascular response to static and dynamic stretch. In conclusion, at comparable TTI, when peak tension is variable, dynamic muscle contraction causes larger cardiovascular responses than static contraction because of greater chemical and mechanical stimulation. However, when peak tensions are equivalent, static and dynamic contraction or stretch produce similar cardiovascular responses.

    Title Microvascular and Myocardial Contractile Responses to Ischemia: Influence of Exercise Training.
    Date March 2000
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    We hypothesized that exercise training preserves endothelium-dependent relaxation, lessens receptor-mediated constriction of coronary resistance arteries, and reduces myocardial contractile dysfunction in response to ischemia. After 10 wk of treadmill running or cage confinement, regional and global indexes of left ventricular contractile function were not different between trained and sedentary animals in response to three 15-min periods of ischemia (long-term; n = 17), one 5-min bout of ischemia (short-term; n = 18), or no ischemia (sham-operated; n = 24). Subsequently, coronary resistance vessels ( approximately 106 +/- 4 microm ID) were isolated and studied using wire myographs. Maximal ACh-evoked relaxation was approximately 25, 40, and 60% of KCl-induced preconstriction after the long-term, short-term, and sham-operated protocols, respectively, and was similar between groups. Maximal sodium nitroprusside-evoked relaxation also was similar between groups among all protocols, and vasoconstrictor responses to endothelin-1 and U-46619 were not different in trained and sedentary rats after short-term ischemia or sham operation. We did observe that, after long-term ischemia, maximal tension development in response to endothelin-1 and U-46619 was blunted (P < 0.05) in trained animals by approximately 70 and approximately 160%, respectively. These results support our hypothesis that exercise training lessens receptor-mediated vasoconstriction of coronary resistance vessels after ischemia and reperfusion. However, training did not preserve endothelial function of coronary resistance vessels, or myocardial contractile function, after ischemia and reperfusion.

    Title The Use of Phenylalanine to Detect Hydroxyl Radical Production in Vivo: a Cautionary Note.
    Date January 2000
    Journal Free Radical Biology & Medicine
    Title Reflex Cardiovascular Response to Brief Abdominal Visceral Ischemia is Mediated in Part by Prostaglandins.
    Date December 1999
    Journal The American Journal of Physiology
    Excerpt

    Prostaglandin concentrations are elevated in intestinal lymph during brief abdominal visceral ischemia, and exogenously applied prostaglandins can directly stimulate or sensitize ischemically sensitive visceral sympathetic nerve fibers. However, it is not known if prostaglandin production during abdominal ischemia is sufficient to contribute to the reflex cardiovascular response (e.g., hypertension). Accordingly, in anesthetized cats, the femoral artery was cannulated for measurement of arterial blood pressure, and the superior mesenteric and celiac arteries were isolated and fitted with snare occluders. After dual occlusion of these arteries (</=20 min), the cyclooxygenase inhibitors indomethacin (10-20 mg/kg iv, n = 5, group 1) or acetylsalicylic acid [50 mg/kg iv (n = 6) and ia (n = 2); group 2] were administered and ischemia was repeated. In group 1, indomethacin lowered the reflex arterial blood pressure increment by 39% from 31 +/- 7 to 19 +/- 5 mmHg (P > 0.05). In group 2, acetylsalicylic acid significantly (P < 0.05) reduced the reflex rise in blood pressure by 46% (28 +/- 3 to 15 +/- 4 mmHg). A second, more invasive preparation (group 3) was utilized to 1) minimize the confounding, transient, nonreflex rise in blood pressure associated with arterial ligation, and 2) further assess the inhibitory effect of indomethacin. In group 3, the ischemia-induced blood pressure rise of 28 +/- 6 mmHg was reduced by 43% to 16 +/- 4 mmHg after indomethacin (n = 4, P < 0.05). Thus blockade of the cyclooxygenase pathway by two structurally dissimilar inhibitors attenuated the visceral-cardiovascular reflex response to brief ischemia, suggesting that prostaglandins released during visceral ischemia contribute significantly to the activation of the reflex cardiovascular response.

    Title Role of Protons in Activation of Cardiac Sympathetic C-fibre Afferents During Ischaemia in Cats.
    Date October 1999
    Journal The Journal of Physiology
    Excerpt

    1. Chest pain caused by myocardial ischaemia is mediated by cardiac sympathetic afferents. The mechanisms of activation of cardiac afferents during ischaemia remain poorly understood. Increased lactic acid production is associated closely with myocardial ischaemia. The present study examined the role of protons generated during ischaemia in activation of cardiac sympathetic C-fibre afferents. 2. Single-unit activity of cardiac afferents innervating both ventricles was recorded from the left sympathetic chain in anaesthetized cats. Epicardial tissue pH was measured within 1-1.5 mm of the surface by a pH-sensitive needle electrode. Responses of cardiac afferents to myocardial ischaemia, lactic acid, sodium lactate, acidic phosphate buffer and hypercapnia were determined. 3. Occlusion of the coronary artery for 5 min decreased epicardial tissue pH from 7.35 +/- 0.21 to 6.98 +/- 0.22 (P < 0.05). Epicardial placement of isotonic neutral phosphate buffer, but not saline, prevented the ischaemia-induced decrease in epicardial pH. This manoeuvre significantly attenuated the response of 16 afferents to 5 min of ischaemia (1.56 +/- 0.23 pre-treatment vs. 0.67 +/- 0.18 impulses s-1). Topical application of 10-100 microg ml-1 of lactic acid, but not sodium lactate, concentration-dependently stimulated 18 cardiac afferents. Inhalation with high-CO2 gas failed to activate 12 separate cardiac afferents. Furthermore, lactic acid stimulated cardiac afferents to a greater extent than acidic phosphate buffer solution, applied at a similar pH to the same afferents. 4. Collectively, this study provides important in vivo evidence that protons contribute to activation/sensitization of cardiac sympathetic C-fibre afferents during myocardial ischaemia.

    Title Naloxone Reverses Inhibitory Effect of Electroacupuncture on Sympathetic Cardiovascular Reflex Responses.
    Date July 1999
    Journal The American Journal of Physiology
    Excerpt

    Acupuncture and electroacupuncture (EA) have been used in traditional Chinese medicine to treat a wide range of diseases and conditions, including angina pectoris and myocardial infarction. In a feline model of reflex-induced reversible myocardial ischemia, electrical stimulation of the median nerves to mimic EA (Neiguan acupoint) significantly improved ischemic dysfunction, secondary to an inhibitory effect of EA on reflex pressor effects evoked by bradykinin (BK). The central mechanism of EA's inhibitory effect in this model is unknown. Accordingly, in alpha-chloralose-anesthetized cats, BK (10 micrograms/ml) was applied to the gallbladder to elicit a cardiovascular reflex response that significantly (P < 0.05) increased arterial blood pressure and heart rate; normalized systolic wall thickening (%WTh) of the left ventricle, measured by ultrasonic single-crystal sonomicrometer, increased by 31 +/- 11% (P < 0.05). After ligation of a side branch of the left anterior descending coronary artery, the reflex pressor response to BK resulted in a significant decrease of %WTh (-32 +/- 6%) in the ischemic region. When bilateral EA of the Neiguan acupoints was performed, the pressor response to BK was inhibited and regional myocardial function was significantly improved (+19 +/- 20%). The inhibitory effects of EA on blood pressure and %WTh were reversed by intravenous injection of naloxone (0.4 mg/kg; n = 9) or microinjection of naloxone (10 nM in 0.1 microliter/site; n = 14) into the rostral ventrolateral medulla (rVLM). Thus %WTh with intravenous naloxone was reduced to -13 +/- 29% (P<0.05) during stimulation of the gallbladder. Our results indicate that the inhibitory effect of EA on the BK-induced pressor response and the consequent improvement of ischemic dysfunction is dependent on the activation of opioid receptors, specifically receptors located in the rVLM.

    Title Reflex Pressor Response to Arterial Phenylbiguanide: Role of Abdominal Sympathetic Visceral Afferents.
    Date January 1999
    Journal The American Journal of Physiology
    Excerpt

    Phenylbiguanide (PBG), a 5-HT3 (serotonin) receptor agonist, has been used in many studies as a "selective" agonist to elicit reflex bradycardia and hypotension through activation of cardiac and pulmonary vagal afferents. Because we have shown that endogenous 5-HT stimulates ischemically sensitive abdominal sympathetic afferents through 5-HT3 receptors, we investigated the possibility that left ventricular (LV) and intra-arterial administration of PBG may evoke a competing reflex response by increasing the activity of sympathetic visceral afferents in anesthetized cats. Mean arterial pressure (MAP) and heart rate (HR) were monitored. When both vagal and sympathetic afferents were intact, PBG (40 microgram/kg, injected into the LV) significantly decreased MAP and HR in 8 of 10 cats but increased MAP in the remaining 2 cats. After bilateral cervical vagotomy, LV PBG significantly increased MAP. PBG (40 microgram/kg ia) significantly increased MAP and HR, whereas intravenous PBG significantly decreased MAP and HR (n = 10 cats). Furthermore, the pressor response to PBG (40 microgram /kg ia) was reduced by 68% (P < 0.05; n = 4 cats) by celiac and mesenteric ganglionectomies. In studies of single-unit abdominal sympathetic afferents, intra-arterial but not intravenous PBG (40 microgram/kg) significantly increased activity of 10 ischemically sensitive afferents but not ischemically insensitive afferents. Blockade of 5-HT3 receptors with tropisetron (200 microgram/kg iv) eliminated the response of the afferents and the pressor response to PBG. These data indicate that PBG administered into the LV usually, but not always, evokes a depressor response that is converted to a pressor response following cervical vagotomy. Also, intra-arterial PBG induces a pressor response by stimulating 5-HT3 receptors largely associated with ischemically sensitive abdominal sympathetic afferents.

    Title Bradykinin Bk2 Receptors Contribute to Reflex Cardiovascular Responses During Brief Abdominal Ischemia.
    Date February 1998
    Journal The American Journal of Physiology
    Excerpt

    Ischemically sensitive visceral sympathetic nerve fibers, which are thought to represent the afferent limb of a strong cardiovascular pressor reflex, can be stimulated by exogenously applied bradykinin (BK). During ischemia, BK also is known to be produced locally and to serve as an endogenous stimulus for activation of ischemically sensitive nerve endings. It is unclear, however, whether ischemically induced BK production is sufficient to elicit a reflex cardiovascular response. Accordingly, femoral arterial and venous catheters were positioned in anesthetized cats, and the superior mesenteric and celiac arteries were isolated for placement of snare occluders. After dual occlusion of these arteries (20 min), one of two chemically dissimilar specific kinin B2 (BK2) receptor antagonists, HOE-140 (30-40 micrograms/kg iv, n = 8) or NPC-17731 (30-40 micrograms/kg iv, n = 11), was administered and dual occlusion was repeated. The reflex rise of mean arterial blood pressure (BP) of 16 +/- 3.7% was significantly (P < 0.05) reduced by HOE-140 to 8.4 +/- 2.0%. NPC-17731 similarly attenuated the reflex BP increment from 13 +/- 1.2 to 6.2 +/- 1.6% (P < 0.05). In a separate set of control animals the first and second periods of ischemia induced reflex BP increments that did not differ significantly (16 +/- 2.7 and 16 +/- 5.7%, respectively). Qualitatively similar decrements of the BP response were produced by the BK2 receptor antagonists in two additional groups in which blood flow to the superior mesenteric and celiac arteries was diverted to a venous reservoir to eliminate the initial transient (mechanically induced) rise in BP associated with artery ligation that is known not to be associated with the reflex response. These results indicate that the stimulation of BK2 receptors on visceral afferent nerves by BK is responsible, at least in part, for the reflex cardiovascular response during visceral ischemia.

    Title Endogenous Histamine Stimulates Ischemically Sensitive Abdominal Visceral Afferents Through H1 Receptors.
    Date February 1998
    Journal The American Journal of Physiology
    Excerpt

    Abdominal ischemia stimulates sympathetic visceral afferents to reflexly activate the cardiovascular system. We have shown previously that topical application of histamine (HA) to the gastric wall causes reflex cardiovascular responses and have documented increased histamine concentrations in intestinal lymph and portal venous plasma during brief abdominal ischemia. In the present study, we hypothesized that histamine produced during ischemia activates ischemically sensitive C-fiber afferents by stimulation of H1 receptors. Nerve activity of single-unit abdominal visceral C-fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats. Injection of histamine (25 micrograms/kg ia) significantly increased activity of nine ischemically sensitive C fibers from 0.09 +/- 0.06 to 1.11 +/- 0.20 imp/s. An H1-receptor agonist, 2-(3-chlorophenyl)histamine (250 micrograms/kg ia), also increased activity of these afferents from 0.11 +/- 0.04 to 0.64 +/- 0.18 imp/s (P < 0.05). Furthermore, an H1-receptor antagonist (pyrilamine, 0.2 mg/kg i.v.) significantly attenuated the increased activity in 11 other C fibers from 0.91 +/- 0.16 to 0.35 +/- 0.06 imp/s ischemia vs. pyrilamine + ischemia) and eliminated the response of 9 separate ischemically sensitive afferents to histamine. Conversely, both the H2-receptor agonist dimaprit (500 micrograms/kg ia) and the H3-receptor.agonist (R)-alpha-methylhistamine (250 micrograms/kg ia) did not significantly alter the activity of these nine afferents. In nine separate cats treated with indomethacin (5 mg/kg i.v.), pyrilamine (0.2 mg/kg i.v.) further significantly attenuated the increased activity in seven of nine C fibers during ischemia, and indomethacin (5 mg/kg i.v.) attenuated the response of eight other afferents to histamine. These data suggest that during mesenteric ischemia endogenous histamine contributes to the activation of afferents through direct stimulation of histamine H1 receptors and that histamine's stimulating effect on these afferents is dependent partially on production of prostaglandins.

    Title Increased Histamine and 5-ht in Portal Vein Plasma and Mesenteric Lymph During Brief Ischemia and Reperfusion.
    Date October 1997
    Journal The American Journal of Physiology
    Excerpt

    Brief mesenteric ischemia (10 min) can stimulate both visceral A delta- and C-fiber afferents and evoke reflex excitation of the cardiovascular system. We have shown that exogenous histamine causes reflex cardiovascular responses and that intra-arterial injection of 5-hydroxytryptamine (5- HT) into a mesenteric artery stimulates visceral A delta- and C-fiber afferents. We therefore hypothesized that brief abdominal ischemia is associated with release of histamine and 5-HT into the interstitium, where these mediators could stimulate or sensitize ischemically sensitive visceral afferent nerve endings. Accordingly, we measured concentrations of histamine and 5-HT in portal venous blood plasma and intestinal lymph fluid in cats. Cannulas were placed in a portal vein and in an intestinal lymphatic duct distal to the lymph node. Lymph and plasma histamine and 5-HT concentrations were measured by high-performance liquid chromatography before, during, and immediately after 10-min occlusion of the descending thoracic aorta. Histamine concentration increased significantly (P < 0.01) in portal venous blood plasma from a preocclusion level of 2.2 +/- 0.6 to 4.6 +/- 1.0 and 6.4 +/- 1.3 nmol/ml and in lymph fluid from a preocclusion level of 3.4 +/- 1.0 to 6.3 +/- 1.3 and 6.4 +/- 1.3 nmol/ml (n = 18) during brief ischemia and reperfusion, respectively. Also, the 5-HT concentration was significantly (P < 0.01) elevated in portal venous blood plasma from a preocclusion concentration of 1.1 +/- 0.5 to 2.7 +/- 0.8 and 2.5 +/- 0.8 nmol/ml and in lymph from a preocclusion level of 1.8 +/- 0.7 to 4.0 +/- 1.4 and 4.6 +/- 1.3 nmol/ml (n = 13) during brief ischemia and reperfusion, respectively. Because visceral afferent nerve endings are located in the interstitium, elevation of the interstitial concentration of histamine and 5-HT may contribute to the stimulation or sensitization of these nerve terminals during the brief ischemia and reperfusion period.

    Title The Power Athlete.
    Date October 1997
    Journal Cardiology Clinics
    Excerpt

    A number of normal daily and athletic activities require isometric or static exercise. Sports such as weight lifting and other high-resistance activities are used by power athletes to gain strength and skeletal muscle bulk. Static exercise, the predominant activity used in power training, significantly increases blood pressure, heart rate, myocardial contractility, and cardiac output. These changes occur in response to central neural irradiation, called central command, as well as a reflex originating from statically contracting muscle. Studies have demonstrated that blood pressure appears to be the regulated variable, presumably because the increased pressure provides blood flow into muscles whose arterial inflow is reduced as a result of increases in intramuscular pressure created by contraction. Thus, static exercise is characterized by a pressure load on the heart and can be differentiated from the hemodynamic response to dynamic (isotonic) exercise, which involves a volume load to the heart. Physical training with static exercise (i.e., power training) leads to concentric cardiac (particularly left ventricular) hypertrophy, whereas training with dynamic exercise leads to eccentric hypertrophy. The magnitude of cardiac hypertrophy is much less in athletes training with static than dynamic exercise. Neither systolic nor diastolic function is altered by the hypertrophic process associated with static exercise training. Many of the energy requirements for static exercise, particularly during more severe levels of exercise, are met by anaerobic glycolysis because the contracting muscle becomes comes deprived of blood flow. Power athletes, training with repetitive static exercise, derive little benefit from an increase in oxygen transport capacity, so that maximal oxygen consumption is increased only minimally or not at all. Peripheral cardiovascular adaptations also can occur in response to training with static exercise. Although the studies are controversial, these adaptations include modest decreases in resting blood pressure, reduced increases in blood pressure and sympathetic nerve activity during a given workload, enhanced baroreflex function, increases in muscle capillary-to-fiber ratio, possible improvements in lipid and lipoprotein profiles, and increases in glucose and insulin responsiveness. Some of these adaptations can occur in cardiac or hypertensive patients with no concomitant cardiovascular complications. In both healthy individuals and those with cardiovascular disease, the manner in which resistance training is performed may dictate the extent to which these adjustments take place. Specifically, training that involves frequent repetitions of moderate weight (and hence contains dynamic components) seems to produce the most beneficial results.

    Title Spatiotemporal Aspects of Sympathetic C-fiber Afferent Activity in Pressor Reflex During Abdominal Ischemia.
    Date May 1997
    Journal The American Journal of Physiology
    Excerpt

    Activation of abdominal sympathetic visceral afferents during ischemia elicits excitatory cardiovascular reflexes. The present study examined the time course and discharge patterns of activation of ischemically sensitive sympathetic C-fiber afferents, and then the relationship between summated afferent activity and the pressor reflex induced by prolonged abdominal ischemia was determined. Single-unit activity of abdominal C-fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats during 30 min of ischemia. The reflex pressor response to abdominal ischemia was induced by occlusion of celiac and superior mesenteric arteries. Of 68 C-fiber afferents studied, 36 (approximately 53%) were activated during 30 min of ischemia, whereas the activity of the remaining 32 were not altered. Onset latencies of 36 C-fiber afferents activated by ischemia ranged from 1.0 to 17.4 min with an average of 6.1 +/- 0.8 min. The majority of activated afferents manifested a bursting pattern of discharge activity as ischemia was prolonged beyond 10 min. Summated response of activated afferents, but not individual afferent activity, was related closely to the reflex pressor response during 30 min of ischemia. These results suggest that both recruitment of sufficient numbers of C-fiber afferents and adequate discharge frequency of afferents constitute an encoding mechanism for the pressor reflex during abdominal ischemia.

    Title Cardiovascular Reflex Responses to Ischemia During Occlusion of Celiac And/or Superior Mesenteric Arteries.
    Date April 1997
    Journal The American Journal of Physiology
    Excerpt

    Global abdominal visceral ischemia leads to profound cardiovascular reflex adjustments. However, the separate contributions of the celiac artery and superior mesenteric artery (SMA) vascular beds to this reflex are unknown. Accordingly, we compared the effects of single and combined occlusions of these vessels on blood pressure (BP) in anesthetized cats. Tissue mass and pH of selected organs, regional blood gases, pH, and lactate also were measured as potential contributing factors. Occlusion of the SMA or celiac artery produced significantly (P < 0.05) different increments in BP (30 +/- 4 vs. 18 +/- 4 mmHg, respectively). Combined occlusion of the two vessels augmented BP by 53 +/- 12 mmHg, a significantly greater increase than during celiac ligation. Venous lactate levels increased significantly during SMA, but not celiac, occlusion, and the decline in venous pH was significantly greater in the SMA than in the celiac vascular bed (-0.20 +/- 0.03 vs. -0.08 +/- 0.02 pH units, P < 0.05, respectively). The decline in tissue pH of SMA-perfused organs during SMA occlusion was significantly greater than in celiac-perfused organs during celiac occlusion. Conversely, tissue mass subserved by the celiac artery was significantly greater than that subserved by the SMA (182 +/- 27 vs. 131 +/- 17 g, respectively). These data suggest that the larger cardiovascular reflex produced by SMA occlusion compared with celiac occlusion may be related to a greater increase of lactic acid concentration in tissue supplied by the SMA. In addition, the large reflex increase in BP produced by combined occlusion of these vessels is an additive effect, presumably related to larger organ mass and recruitment of more sensory nerve fibers.

    Title Mechanical Stimulation is Not Responsible for Activation of Gastrointestinal Afferents During Ischemia.
    Date March 1997
    Journal The American Journal of Physiology
    Excerpt

    Abdominal ischemia reflexly excites the cardiovascular system through activation of visceral sympathetic afferents. Although a number of ischemic metabolites are known to stimulate sympathetic afferents, the contribution of mechanical stimulation to activation of afferents during abdominal ischemia remains uncertain. Thus the present study examined the role of changes in motility in activation of gastrointestinal afferents during ischemia. Single-unit activity of C fiber afferents located on the stomach, duodenum, jejunum, or colon was recorded from the right sympathetic chain of anesthetized cats during 15 min of ischemia. Intraluminal pressure, as a reflection of local mechanical activity, was measured by an open catheter placed in the lumen of the gastrointestinal tract. The results show that gastrointestinal motility was mainly inhibited during abdominal ischemia. Changes in intraluminal pressure did not correlate with afferent discharge activity during ischemia (r = -0.32, n = 10). Furthermore, discharge frequency of gastrointestinal afferents during ischemia was not altered significantly by topical application of 100 micrograms/ml of atropine (3.98 +/- 0.62 to 3.83 +/- 0.59 imp/s, n = 12), which profoundly inhibited local gastrointestinal motility. Collectively, these data indicate that gastrointestinal motility changes during abdominal ischemia do not contribute to activation of gastrointestinal sympathetic C fiber afferents.

    Title Production of Hydroxyl Radicals in Contracting Skeletal Muscle of Cats.
    Date February 1997
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Reactive oxygen species increase during exhaustive contraction of skeletal muscle, but characterization of the specific species involved and their rates of production during nonexhaustive muscle contraction have not been investigated. We hypothesized that the production rate of hydroxyl radical (.OH) increases in contracting muscle and that this rate is attenuated by pretreatment with deferoxamine (Def) or dimethylthiourea (DMTU). We measured the rate of production of .OH before, during, and after 5 min of intermittent static contraction of the triceps surae muscles in cats (n = 6) using the formation of p-, m-, and o-tyrosines by hydroxylation of phenylalanine. L-Phenylalanine (30 mg/kg i.v.) was administered to each animal 3 min before contraction. Blood samples were collected from the popliteal vein 1 min before contraction; 1, 3, and 4.5 min during contraction; and 1 min after contraction. During and after contraction, the cumulative production rates of p-, m-, and o-tyrosines were elevated by 42.84 +/- 5.41, 0.25 +/- 0.04, and 0.21 +/- 0.03 nmol.min-1.g-1, respectively, compared with noncontracting triceps surae muscles. Pretreatment with Def (10 mg/kg i.v.; n = 5) or DMTU (10 mg/kg i.v.; n = 4) decreased the cumulative rates of production of p-, m-, and o-tyrosines during and after contraction. Additionally, the rate of tyrosine production increased in proportion to the percentage of maximal tension developed by the triceps surae muscles. These results directly demonstrate that .OH is produced in vivo in the skeletal muscle of cats during intermittent static contraction and that production can occur before the onset of fatigue.

    Title Reactive Oxygen Species Modify Reflex Cardiovascular Responses to Static Contraction.
    Date February 1997
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Reactive oxygen species can reflexly activate the cardiovascular system through stimulation of abdominal visceral afferents. The mechanism appears to involve hydroxyl radicals. We tested the hypothesis that reactive oxygen species contribute to the reflex cardiovascular response to static muscle contraction (i.e., the exercise pressor reflex). Thus blood pressure and heart rate responses to 5 min of intermittent electrically stimulated static contraction of the triceps surae muscles (15 s on, 15 s off) in anesthetized cats were compared before and after intravenous administration of the free radical scavengers dimethylthiourea (DMTU; 10 mg/kg; n = 8) or deferoxamine (Def; 10 mg/kg; n = 15). The contraction-induced pressor response was augmented from 51 +/- 6 to 61 +/- 7 mmHg after treatment with DMTU (P < 0.05) and from 44 +/- 8 to 58 +/- 8 mmHg after administration of Def (P < 0.05). Corresponding heart rate responses were not affected by either drug. Because this DMTU- or Def-induced augmentation of the exercise pressor reflex may have been due to a reduction in free radical-evoked vasodilation in the contracting skeletal muscle, popliteal artery blood velocity was measured with a Doppler flow transducer before and during contraction in the absence and presence of Def (n = 8). Blood velocity during contraction was not altered by Def (16 +/- 5 vs. 24 +/- 6 cm/s). These data suggest that reactive oxygen species exert an inhibitory effect on the exercise pressor reflex that is not associated with their local vasodilator properties. This response is opposite to that observed during stimulation of visceral afferents by reactive oxygen species.

    Title Role of Summation of Afferent Input in Cardiovascular Reflexes from Splanchnic Nerve Stimulation.
    Date October 1996
    Journal The American Journal of Physiology
    Excerpt

    Stimulation of abdominal sympathetic visceral afferents reflexly excites the cardiovascular system. The present study examined the role of summation of afferent input in this reflex. Single-unit activity of A delta- and C-fiber afferents was recorded from the right thoracic sympathetic chain in anesthetized cats to determine the relationship between intensities of electrical stimulation and the types of nerve fibers within the right greater splanchnic nerve. The differential effect of cooling on A delta- and C-fiber axons in the sympathetic chain also was examined by recording single-unit afferent activity. Reflex cardiovascular responses were induced by electrical stimulation of the central cut end of the right greater splanchnic nerve. We observed that the numbers of A delta and C fibers activated by electrical stimulation were proportional to the intensity of stimulation. However, neither local cooling nor intensity of stimulation provided a means to separate A delta and C fibers contained in the sympathetic chain. The results demonstrate that the magnitude of excitatory cardiovascular reflexes is frequency dependent and is related directly to intensity of electrical stimulation, suggesting that both adequate discharge frequency of the afferent and sufficient numbers of afferents recruited are crucial factors for full expression of reflex cardiovascular responses.

    Title Ischaemia-sensitive Sympathetic Afferents Innervating the Gastrointestinal Tract Function As Nociceptors in Cats.
    Date October 1996
    Journal The Journal of Physiology
    Excerpt

    1. Activation of sympathetic visceral afferents during mesenteric ischaemia induces visceral pain and reflexly excites the cardiovascular system. The present study investigated the differential responses of ischaemically sensitive and insensitive sympathetic C fibre afferents to graded distension of the gastrointestinal tract. 2. Single-unit activity of C fibre afferents innervating the stomach, duodenum and jejunum was recorded from the right thoracic sympathetic chain of anaesthetized cats. Ischaemically sensitive and insensitive C fibre afferents were identified according to their response to 5-20 min of ischaemia. The functional characteristics of the stimulus-response relationships of afferents were determined by distension of a balloon placed in the corresponding segment of gastrointestinal tract. 3. The results show that ischaemically insensitive C fibre afferents had a lower threshold in response to distension (13 +/- 5 mmHg, n = 10). The discharge frequency of these afferents was saturated within a low pressure range of distension. However, ischaemically sensitive C fibre afferents had a high threshold (86 +/- 12 mmHg, n = 10) and a larger peak response to mechanical distension in the noxious range (60-180 mmHg). There were no differences between ischaemically sensitive and insensitive C fibre afferents with regard to their testing activity or responses to bradykinin (10 micrograms I.A.). 4. This study demonstrates that the gastrointestinal system is innervated by low and high threshold sympathetic C fibre afferents, the latter having the distinct ability to encode nociceptive information such as excessive distension and ischaemia.

    Title Hypoxia Does Not Directly Stimulate Ischemically Sensitive Abdominal Visceral Afferents During Ischemia.
    Date October 1996
    Journal The American Journal of Physiology
    Excerpt

    Abdominal ischemia activates ischemically sensitive sympathetic visceral afferents and evokes reflex excitation of the cardiovascular system. These afferents respond to ischemic metabolites, including lactic acid, bradykinin, prostaglandins, and reactive oxygen species. Severe hypoxemia also has been shown to activate these afferents. It is not known, however, if the regional tissue hypoxia induced by abdominal ischemia directly or indirectly activates ischemically sensitive visceral afferents. To determine the role of tissue hypoxia in activation of ischemically sensitive abdominal afferents, continuous single-unit activity of ischemically sensitive abdominal sympathetic C-fiber afferents (conduction velocity = 0.51-1.48 m/s) and regional tissue PO2, measured by a polarographic oxygen electrode in the porta hepatis, duodenum, or pancreas, were recorded simultaneously in anesthetized cats before and during 10-15 min of ischemia. Abdominal ischemia rapidly decreased regional tissue PO2 from 161 +/- 10 to 8 +/- 2 mmHg (P < 0.01) within an interval of 136 +/- 12 s. By contrast, after longer latency (399 +/- 24 s, P < 0.01 vs. PO2 interval), the activity of these afferents increased from 0.06 +/- 0.01 to 0.33 +/- 0.07 imp/s (P < 0.01). Furthermore, the activity of ischemically sensitive afferents gradually increased throughout ischemia with peak activity (0.68 +/- 0.14 imp/s) occurring at 600 +/- 39 s, although tissue PO2 remained constant. There was no correlation between the changes of tissue PO2 and discharge activity of these afferents (r = -0.428, P = 0.144). These data suggest that tissue hypoxia induced by abdominal ischemia is not directly responsible for activation of ischemically sensitive sympathetic visceral afferents but likely acts in an indirect fashion by promoting formation of other metabolic products capable of activating these nerve endings.

    Title Cardiac Reflex Effects of Intracoronary Bradykinin in Humans.
    Date August 1996
    Journal Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research
    Excerpt

    BACKGROUND: Endogenous production of bradykinin (BK) has been postulated to cause hemodynamic changes and cardiac pain during myocardial ischemia, presumably because of the stimulation of cardiac afferent fibers. METHODS: To test the hypothesis that BK results in cardiac reflex responses and can cause the sensation of angina, 10 patients with and without coronary atherosclerosis had BK injected into their right (RCA) and left (LCA) coronary arteries in graded concentrations up to 10(-5) m. Patients were monitored for hemodynamic changes and the presence and quality of pain. RESULTS: Intracoronary BK 10(-5) m caused a significant reduction in blood pressure in most patients with either injection into the RCA or LCA (RCA: 151 +/- 10/90 +/- 5 mm Hg to 119 +/- 11/70 +/- 6 mm Hg, LCA: 161 +/- 11/88 +/- 6 mm Hg to 118 +/- 10/65 +/- 6 mm Hg) that began 12 to 14 seconds after injection. Injection into the LCA also resulted in a significant increase in heart rate (69 +/- 4 to 81 +/- 7 beats/minute), while injection into the RCA did not. Pain occurred after changes in blood pressure in all but one patient, which was present in 5 of 9 patients with RCA injection and 8 of 9 patients with LCA injection, and was often associated with flushing and nausea. Pain caused by BK was not similar to previous clinical ischemic pain in the patients with coronary atherosclerosis. CONCLUSIONS: The absence of a chronotropic response associated with arterial hypotension following injection of BK into the RCA is consistent with activation of cardiac vagal afferents in the left ventricle. The latency and quality of pain in these patients following injection of BK suggests that, while BK is nociceptive, it likely is not the cause of angina in patients with myocardial ischemia.

    Title Limitation of Reperfusion Injury by a Monoclonal Antibody to C5a During Myocardial Infarction in Pigs.
    Date February 1995
    Journal The American Journal of Physiology
    Excerpt

    The complement system has been implicated in reperfusion injury during acute myocardial infarction. We therefore attempted to reduce reperfusion injury with a monoclonal antibody (MAb) to the complement component, C5a. In 13 control pigs and 9 pigs pretreated with this MAb, ischemia was induced by a 50-min occlusion of the left anterior descending coronary artery, followed by 3 h of reperfusion. Infarct area (as percent of risk area) was reduced from 58 +/- 5% in controls to 38 +/- 7% (P < 0.05) in MAb-treated animals. Heart rate-systolic blood pressure product, left ventricular (LV) first derivative of pressure, LV end-diastolic pressure, and coronary blood flow were similar (P > 0.05) in the two groups. At 15 min of reperfusion, immunoreactive factor Bb began to increase significantly (P < 0.05) in regional coronary venous plasma, consistent with activation of the alternative complement pathway. The anti-C5a MAb did not attenuate formation of the membrane attack complex (C5b-9) as assessed by a hemolytic complement assay. Myocardial myeloperoxidase activity, a marker of tissue neutrophil concentration, was similar in the risk regions of the two groups, suggesting that neutrophil infiltration was unaltered by the MAb. However, in vitro the MAb (15 and 30 micrograms/ml) reduced C5a-stimulated neutrophil aggregation (67.4 and 70.9%), chemotaxis (52.5 and 81.4%), degranulation (66.7 and 75.8%), and superoxide generation (26.7 and 100%). In conclusion, myocardial infarction-reperfusion is associated with activation of the alternative complement pathway. Furthermore, a MAb to C5a that inhibits neutrophil cytotoxic activity, but neither the membrane attack complex nor myocardial neutrophil accumulation, decreases infarct size in pigs. These data suggest an important role of the alternative complement pathway and C5a in the propagation of ischemia cardiac damage during reperfusion.

    Title Endogenous Bk Stimulates Ischemically Sensitive Abdominal Visceral C Fiber Afferents Through Kinin B2 Receptors.
    Date January 1995
    Journal The American Journal of Physiology
    Excerpt

    Abdominal ischemia and reperfusion reflexly activate the cardiovascular system. In the present study, we evaluated the role of endogenously produced bradykinin (BK) in the stimulation of ischemically sensitive visceral afferents. Single-unit activity of abdominal visceral C fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats during 5 min of abdominal ischemia. Abdominal ischemia increased the portal venous plasma BK level from 49 +/- 10 to 188 +/- 66 pg/ml (P < 0.05). Injection of BK (1 microgram/kg ia) into the descending aorta significantly increased impulse activity (0.88 +/- 0.16 impulses/s) of 10 C fibers, whereas a kinin B1-receptor agonist, des-Arg9-BK (1 microgram/kg), did not alter the discharge rate. Inhibition of kininase II activity with captopril (4 mg/kg i.v.) potentiated impulse activity of 14 ischemically sensitive C fibers (0.44 +/- 0.09 vs. precaptopril, 0.33 +/- 0.08 impulses/s; P < 0.05). In addition, a kinin B2-receptor antagonist (NPC-17731; 40 micrograms/kg i.v.) attenuated activity of afferents during ischemia (0.39 +/- 0.08 vs. pre-NPC-17731, 0.72 +/- 0.13 impulses/s; P < 0.05) and eliminated the response of 10 C fibers to BK. Another kinin B2-receptor antagonist, Hoe-140 (30 micrograms/kg iv), had similar inhibitory effects on six other ischemically sensitive C fibers. In 15 separate cats treated with aspirin (50 mg/kg i.v.), Hoe-140 (30 micrograms/kg i.v.) attenuated impulse activity of only 3 of 16 ischemically sensitive C fibers. These data suggest that BK produced during abdominal ischemia contributes to the stimulation of ischemically sensitive visceral C fiber afferents through kinin B2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Cardiovascular Reflexes During Abdominal Ischemia in Cats.
    Date August 1994
    Journal The American Journal of Physiology
    Excerpt

    The cardiovascular effects of regional abdominal ischemia and reperfusion were studied in cats anesthetized with alpha-chloralose. In group 1 (n = 9), central venous pressure was kept constant by a servo-controller while the celiac and superior mesenteric arteries were occluded by loop snares for 10 min. In group 2 (n = 9), a constant-perfusion circuit to the celiac and superior mesenteric arteries that could divert flow to the femoral vein was used to induce abdominal ischemia. In group 3 (n = 7), venous return from the inferior vena cava was controlled, and a constant-perfusion circuit was used to induce abdominal ischemia. Abdominal ischemia significantly (P < 0.05) increased portal venous blood lactate from 4.3 +/- 0.6 to 6.0 +/- 0.6 mM in group 3. The early increases in blood pressure caused by passive volume shifts in groups 1 and 2 were abolished in group 3. The late, i.e., 10 min, response to abdominal ischemia consisted of significant (P < 0.05) increases in mean arterial pressure (29 +/- 7, 24 +/- 7, and 33 +/- 8 mmHg in groups 1, 2, and 3, respectively). Abdominal ischemia also significantly (P < 0.05) increased the first derivative of left ventricular pressure at 40 mmHg developed pressure from 4,355 +/- 377 to 4,839 +/- 407 mmHg/s in group 3. Celiac and superior mesenteric ganglionectomy abolished the late but not the early hemodynamic changes. Ganglionectomy also significantly (P < 0.05) enhanced the decrease in mean arterial pressure during reperfusion in all groups. We conclude that the pressor and contractile responses during 10 min of abdominal ischemia and the relative maintenance of blood pressure during reperfusion after ischemia are reflex in nature.

    Title Brief Mesenteric Ischemia Increases Pge2, but Not Pgi2, in Intestinal Lymph of Cats.
    Date July 1994
    Journal The American Journal of Physiology
    Excerpt

    Mesenteric ischemia of short duration (5-10 min) can stimulate A delta- and C-fiber afferent nerve endings in the viscera to reflexly activate the cardiovascular system. The mechanism of activation of abdominal visceral afferents is probably multifactorial and may involve prostaglandins (PGs), which have been shown to directly stimulate and/or sensitive visceral afferents when administered exogenously. We hypothesized that brief visceral ischemia is accompanied by release of PGI2 and PGE2 into the interstitium, where these cyclooxygenase products could stimulate or sensitize visceral afferent nerve endings. Accordingly, we measured immunoreactive PGE2 (iPGE2) and 6-keto-PGF1 alpha (i6-keto-PGF1 alpha), the stable metabolite of PGI2, in lymph draining the ischemic viscera as well as in portal venous blood. An intestinal lymph duct distal to the lymph node was cannulated in pentobarbital sodium-anesthetized cats. Lymph and plasma iPGE2 and i6-keto-PGF1 alpha concentrations were measured by radioimmunoassay before, during, and immediately after a 5- to 10-min occlusion of the descending aorta. The i6-keto-PGF1 alpha concentration increased significantly (P < 0.001) in portal venous plasma (61 +/- 12 to 107 +/- 18 pg/0.1 ml; n = 14) but not in lymph (148 +/- 30 to 159 +/- 24 pg/0.1 ml; n = 16). In contrast, iPGE2 concentration was significantly (P < 0.01) elevated in both venous plasma (156 +/- 16 to 207 +/- 26 pg/0.1 ml; n = 19) and lymph (520 +/- 48 to 590 +/- 52 pg/0.1 ml; n = 20).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Localized Pericardial Effusion and Right-sided Heart Tamponade: Complications of Cardiac Surgery in a Hanford Miniature Pig.
    Date December 1993
    Journal Laboratory Animal Science
    Title C5a-induced Myocardial Ischemia: Role for Cd18-dependent Pmn Localization and Pmn-platelet Interactions.
    Date December 1993
    Journal The American Journal of Physiology
    Excerpt

    Intracoronary C5a in swine decreases coronary blood flow and regional myocardial segment shortening, responses mediated by thromboxane (Tx) A2-induced coronary vasoconstriction and intramyocardial trapping of granulocytes (PMNs). We sought to determine the origin of TxA2 and to investigate the role of CD18-dependent PMN function by utilizing an anti-CD18 monoclonal antibody, IB4. Isolated C5a-stimulated PMNs or platelets did not produce TxB2. However, together, C5a-stimulated PMNs and platelets produced TxB2. IB4 bound porcine PMN surface CD18 and blocked C5a-induced PMN functions. In vivo, IB4 loading (2 mg/kg) transiently decreased arterial blood pressure and circulating platelet counts in six of nine animals (390 +/- 31 vs. 176 +/- 41 X 10(6)/ml, control vs. IB4; P < 0.002) and significantly ameliorated C5a-induced decreases in coronary venous PMN count (-4.1 +/- 0.6 vs. -1.4 +/- 0.8 X 10(6) cells/ml), coronary artery blood flow (-10 +/- 1 vs. -4 +/- 1 ml/min), and segment shortening (-15 +/- 2 vs. -8 +/- 2%, C5a vs. C5a + IB4). We conclude that 1) production of TxB2 in response to C5a is mediated by a PMN-platelet interaction, 2) IB4 functionally blocks CD18 on porcine PMNs, and 3) C5a-induced myocardial PMN extraction is mediated, in part, by a CD18-dependent mechanism. These results suggest that PMN-platelet interactions and CD18-dependent PMN extraction are important in C5a-induced myocardial ischemia.

    Title Limitation of Myocardial Infarct Size in Pigs with a Dual Lipoxygenase-cyclooxygenase Blocking Agent by Inhibition of Neutrophil Activity Without Reduction of Neutrophil Migration.
    Date December 1993
    Journal Journal of the American College of Cardiology
    Excerpt

    OBJECTIVES. The purpose of this study was to assess the effect of the dual cyclooxygenase-lipoxygenase blocking agent BW755C on the extent of myocardial infarction in the pig and to identify the mechanisms of any cardioprotective action of this drug. BACKGROUND. Activated neutrophils contribute to reperfusion injury after myocardial infarction and inhibition of neutrophil function can limit infarct size. METHODS. In 9 control and 10 study pigs pretreated with intravenous BW755C (10 mg/kg body weight) 30 min before coronary occlusion, ischemia was induced by a 50-min occlusion of the mid-left anterior descending coronary artery, followed by 3 h of reperfusion. Heart rate, arterial pressure, left ventricular end-diastolic pressure, the first derivative of left ventricular pressure (dP/dt) and regional myocardial blood flow were measured during control, occlusion and reperfusion periods. Infarct size was determined by histochemical staining; and myeloperoxidase activity, a marker for tissue neutrophil content, was assessed in normal and infarcted myocardium. The effect of BW755C on the function of isolated neutrophils stimulated with zymosan-activated serum was evaluated by measuring neutrophil degranulation, leukotriene B4 production, superoxide generation and chemotaxis. RESULTS. Hemodynamic function and regional myocardial blood flow were similar in control and BW755C-treated animals. BW755C significantly reduced myocardial infarct size compared with that in control animals, as measured by infarct/risk areas by histochemical staining (39 +/- 5% vs. 63 +/- 7%, p < 0.05). Myocardial myeloperoxidase activity was similar in normal, salvaged and infarcted areas in the control and treated groups, indicating that neutrophil accumulation in injured myocardium was unaltered by BW755C. However, this agent attenuated function of isolated, stimulated (zymosan-activated serum) neutrophils. At a concentration of 0.03 mg/ml, BW755C inhibited degranulation (-46%), leukotriene B4 production (-48%) and superoxide generation (-74%), but there was minimal inhibition of chemotaxis in vitro. CONCLUSIONS. These findings demonstrate that myocardial infarct size can be reduced by selective inhibition of neutrophil cytotoxic activity without affecting neutrophil migration into injured myocardium.

    Title Repeated Dipyridamole Administration Enhances Collateral-dependent Flow and Regional Function During Exercise. A Role for Adenosine.
    Date September 1993
    Journal Circulation Research
    Excerpt

    Two main hypotheses concerning the mechanisms responsible for coronary collateral growth suggest the involvement of chemical or mechanical factors. Since we recently demonstrated that the development of the coronary collateral circulation is not closely related to the extent or duration of myocardial ischemia, we hypothesized that chronic repeated vasodilation and increased myocardial blood flow using dipyridamole would enhance collateral development in miniswine with an ameroid-occluded left circumflex coronary artery (LCx). Two days after surgical instrumentation, the animals received dipyridamole (n = 9), diltiazem as an adenosine-independent vasodilator (n = 8), or control vehicle (n = 7) 90 minutes per day, 5 days per week for 8 weeks. At 5 and 8 weeks, transmural blood flow and systolic wall thickening were measured during infusion of dipyridamole, diltiazem, or vehicle. Transmural blood flow increased similarly in the LCx and nonoccluded regions at 30 and 60 minutes during infusion of either vasodilator. Thus, we believe that similar mechanical stimulation resulted from dipyridamole and diltiazem infusion. There was no change in blood flow during administration of the vehicle. Systolic wall thickening in the collateral-dependent region was not altered by infusion of dipyridamole, diltiazem, or vehicle. Therefore, both vasodilators increased blood flow without eliciting ischemia. After 8 weeks of repeated treatment with each pharmacological agent, at least 24 hours after the last drug infusion, near maximal physiological capacity of the coronary collateral vessels was assessed during treadmill running (approximately 240 beats per minute). Transmural myocardial blood flow ratios, expressed as flow in the LCx divided by flow in the nonoccluded region of the left ventricle, were similar at rest for animals treated with dipyridamole (0.90 +/- 0.03), diltiazem (0.97 +/- 0.05), and control vehicle (0.89 +/- 0.02). However, collateral-dependent myocardial blood flow during exercise was greater (P < .05) in the dipyridamole-treated animals (0.78 +/- 0.04) than in either diltiazem-treated (0.63 +/- 0.09) or vehicle-treated (0.62 +/- 0.02) animals. LCx systolic wall thickening at rest was similar in animals treated with dipyridamole (44.4 +/- 6.3%), diltiazem (42.2 +/- 3.0%), and control vehicle (38.1 +/- 2.8%). During exercise, however, myocardial function in the collateral-dependent region was greater (P < .05) in the dipyridamole-treated (39.2 +/- 5.2%) compared with diltiazem-treated (23.9 +/- 4.0%) and vehicle-treated (26.9 +/- 2.9%) animals.(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Biotelemetry of Cardiovascular Hemodynamic Measurements in Miniswine.
    Date January 1993
    Journal Ieee Transactions on Bio-medical Engineering
    Excerpt

    A three-channel biotelemetry system has been designed and implemented for use in a chronically instrumented animal model of cardiovascular disease. A dual-channel ultrasonic transit-time micrometer allows monitoring of left-ventricular wall motion for the regions perfused by the left circumflex and left anterior descending coronary arteries. A third channel provides left ventricular blood pressure obtained from a high-fidelity blood pressure transducer implanted in the left ventricle. The biotelemetry system features a high voltage dc-dc converter for improved ultrasonic signal strength, a time-to-voltage converter that is highly immune to synchronization frequency variations, low power consumption (approx. 100 mW), small size (4 x 6 x 12 cm), and low weight (approx. 200 g). This three-channel system has enabled our laboratory to continuously monitor untethered animals for 24-h periods. Data obtained from this miniature biotelemetry system can be utilized to quantify myocardial oxygen demand and regional left-ventricular wall thickening.

    Title Contractile Actions of C5a on Isolated Porcine Myocardium.
    Date October 1992
    Journal The American Journal of Physiology
    Excerpt

    Although intracoronary administration of the complement component, C5a, produces deleterious effects on regional coronary blood flow and segmental ventricular function, it is unclear whether a direct myocardial action contributes to the dysfunction induced by the anaphylatoxin. We therefore evaluated the effects of purified porcine C5a on contractile tension of isolated supported ventricular trabeculae from pig hearts. Muscles were studied in a myograph bath at 30 degrees C, electrically stimulated 12 times per minute, and stretched to produce maximal isometric developed tension. C5a concentrations of 30, 100, and 300 ng/ml increased tension (P less than 0.05) 9.8, 5.5, and 20.9%, respectively. In seven of nine muscles exposed to 300 ng/ml C5a, tension initially decreased 10.5% (P less than 0.05) before the positive inotropic effect. Tachyphylaxis was demonstrated by lack of contractile response to a second administration of C5a greater than 70 min after the initial exposure to the complement fragment. Blockade of histamine H1 receptors with diphenhydramine (10(-6) M) markedly attenuated both the positive and negative contractile responses to C5a. beta-Adrenoceptor blockade with propranolol (5.6 x 10(-7) M) did not alter the response to C5a. Levels of thromboxane (Tx)B2, the stable metabolite of TxA2, were augmented in the bath after exposure to C5a (59 +/- 27.3 to 104 +/- 28.2 pg/ml, P less than 0.05). Although the TxA2 agonist, U-46619 (50 ng/ml), significantly increased tension, TxA2 receptor blockade with SQ 29548 (50 ng/ml) did not alter the response to C5a.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Analysis of Beat-to-beat Cardiovascular Hemodynamic Variables Obtained from Long-term Biotelemetry.
    Date September 1992
    Journal Computer Methods and Programs in Biomedicine
    Excerpt

    Manual methods of large volume data storage, retrieval, and analysis are difficult, time consuming, and present numerous opportunities for calculation errors. We have designed and implemented a comprehensive computer-based system for performing these functions. Development of this system was necessary since left ventricular (LV) blood pressure and two regional LV wall thickness measurements were obtained during long-term extracorporeal biotelemetry of miniswine for 24-h periods. During a single recording period over 100,000 individual cardiac cycles were recorded on analog tape and later analysed for determination of global myocardial oxygen demand and regional myocardial function. In addition, custom designed software was developed to determine the extent and duration of myocardial dysfunction. Batch file commands enabled the customized software to operate without prompting by the user thus optimizing the time usage of the computer, and the computer based data acquisition and analysis system. Although this system was designed specifically for analysing cardiovascular hemodynamic variables, it is flexible and can be applied to other experimental applications.

    Title Chronic Reduction of Myocardial Ischemia Does Not Attenuate Coronary Collateral Development in Miniswine.
    Date September 1992
    Journal Circulation
    Excerpt

    Myocardial ischemia is considered to be a possible stimulus for development of the coronary collateral circulation. We therefore hypothesized that chronic reduction of myocardial oxygen demand to lessen ischemia would attenuate coronary collateral development over an 8-week period using left circumflex coronary artery (LCx) ameroid-induced constriction in pigs.

    Title Increased Concentration of Leukotriene B4 but Not Thromboxane B2 in Intestinal Lymph of Cats During Brief Ischemia.
    Date June 1992
    Journal The American Journal of Physiology
    Excerpt

    Mesenteric ischemia stimulates both A delta- and C-fiber afferents to reflexly activate the cardiovascular system. Leukotriene B4 (LTB4) concentration is increased in intestinal mucosa following prolonged ischemia (3 h) followed by reperfusion. Because LTB4 sensitizes afferent nerve endings in the skin, we determined whether LTB4 is produced during brief mesenteric ischemia and thus would be present to sensitize afferent nerve endings in the abdominal visceral region. Cannulas were placed in the portal vein and in a mesenteric lymphatic vessel distal to the lymph node. Mesenteric lymph and portal venous immunoreactive LTB4 (iLTB4) and immunoreactive thromboxane B2 (iTxB2) concentrations were measured before, during, and after 5-7 min of ischemia induced by occlusion of the descending thoracic aorta in cats. Simultaneously, lymph and plasma lactate concentrations were measured. During arterial occlusion, femoral arterial pressure dropped to less than 30 mmHg, and portal venous and mesenteric lymph lactate concentrations were increased significantly (3.3 +/- 0.6 to 6.3 +/- 1.0 mM and 5.2 +/- 0.9 to 7.2 +/- 1.1 mM, respectively, P less than 0.05). During ischemia, iLTB4 concentration increased in lymph from 261 +/- 70 to 424 +/- 102 pg/0.1 ml (P less than 0.05) but did not increase in portal venous blood (135 +/- 26 vs. 168 +/- 44 pg/0.1 ml, control vs. ischemia). iTxB2 concentration was not increased during ischemia in either portal venous blood or lymph (12 +/- 4 to 24 +/- 9 pg/0.1 ml and 19 +/- 7 to 24 +/- 11 pg/0.1 ml, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title The Isometric Athlete.
    Date June 1992
    Journal Cardiology Clinics
    Excerpt

    A number of normal daily and athletic activities require isometric or static exercise. Such sports as weight lifting and other high-resistance activities are used by athletes to gain strength and skeletal muscle bulk. However, static exercise also causes significant increases in blood pressure, heart rate, myocardial contractility, and cardiac output. These changes occur in response to central neural irradiation, called central command, as well as a reflex originating from statically contracting muscle. Studies have demonstrated that blood pressure appears to be the regulated variable, presumably because the increased pressure provides blood flow into muscles that have compressed their arterial inflow as a result of increases in intramuscular pressure created by contraction. Thus, static exercise is characterized by a pressure load to the heart and can be differentiated from dynamic (isotonic) exercise, which involves a volume load to the heart. Physical training with static exercise leads to concentric cardiac, particularly left ventricular, hypertrophy, whereas training with dynamic exercise leads to eccentric hypertrophy. Furthermore, the magnitude of cardiac hypertrophy is much less in athletes training with static than dynamic exercise. Neither systolic nor diastolic function is altered by the hypertrophic process associated with static exercise training. Many of the energy requirements for static exercise, particularly during more severe levels of exercise, are met by anaerobic glycolysis because the contracting muscle becomes deprived of blood flow. Training with repetitive static exercise therefore causes little increase in oxygen transport capacity, so that maximal oxygen consumption is either not or only minimally increased. Peripheral cardiovascular adaptations also can occur in response to static exercise training. Although controversial, these adaptations include modest decreases in resting blood pressure, smaller increases in blood pressure during a given workload, increases in muscle capillary-to-fiber ratio, improved lipid and lipoprotein profiles, and increases in glucose and insulin responsiveness. Some of these adaptations also have been found in cardiac patients and hypertensive patients and without any concomitant cardiovascular complications. However, in both healthy individuals and those with cardiovascular disease, the manner in which resistance training is performed may dictate the extent to which these adjustments take place. Specifically, training that involves frequent repetitions of moderate weight (and hence contains dynamic components) seems to produce the most beneficial results.

    Title Ischemically Sensitive Visceral Afferents: Importance of H+ Derived from Lactic Acid and Hypercapnia.
    Date May 1992
    Journal The American Journal of Physiology
    Excerpt

    Ischemically sensitive abdominal visceral afferents reflexly stimulate the cardiovascular system. To explore the role of H+ contribution by lactic acid and hypercapnia, we recorded single-unit activity of ischemically sensitive abdominal afferents in anesthetized cats. The individual responses to sodium lactate, lactic acid, and hypercapnia then were examined. Abdominal ischemia significantly decreased organ tissue pH from an average of 7.21 +/- 0.03-7.05 +/- 0.03 (P less than 0.05), during which impulse activity of 13 A delta- and 32 C-fibers significantly increased. Although hypercapnia (12% CO2) induced a similar decrease in tissue pH, impulse frequency increased in 0 of 4 A delta- and only 2 of 13 C-fibers. In contrast, lactic acid decreased tissue pH significantly less than ischemia or hypercapnia but increased impulse activity in 7 of 10 A delta- and 11 of 12 C-fibers. Conversely, only 1 of 3 A delta- and 0 of 10 C-fibers responded to sodium lactate. Thus ischemically sensitive visceral afferents respond to the H+ derived from lactic acid rather than hypercapnia. However, these afferents do not respond to sodium lactate. These data suggest that ischemically sensitive abdominal visceral afferents are responsive specifically to lactic acid rather than to the dissociated ions lactate or H+ or to changes in PCO2.

    Title Modulation of Bradykinin-induced Gastric-cardiovascular Reflexes by Histamine.
    Date February 1992
    Journal The American Journal of Physiology
    Excerpt

    Both histamine and bradykinin induce gastric-cardiovascular reflexes and are released during several pathophysiological conditions. This study examined the possibility that histamine modulates the magnitude of the reflex response to stimulation by bradykinin. Thus in chloralose anesthetized cats, the cardiovascular response to stimulation of the gastric serosa with 1 microgram/ml bradykinin was monitored before and after topical application of 100 micrograms/ml histamine (n = 6) or 1 mg/ml diphenhydramine (H1-receptor antagonist) and histamine (n = 5). After application of histamine, bradykinin-induced increases in mean arterial pressure and left ventricular pressure were attenuated by 23 and 27%, respectively. Conversely, when the H1-receptors on the serosal surface of the stomach were blocked (n = 5) before application of histamine, the pressor response to bradykinin was augmented by 26%. To determine the afferents that might contribute to the attenuating effect of histamine, we recorded single unit activity in 14 A delta and 21 C visceral afferent fibers in response to bradykinin stimulation before and after histamine stimulation. We observed that the impulse activity of 10 of the A delta and 14 of the C fibers to bradykinin stimulation was reduced after treatment with histamine. These results suggest that histamine induces an inhibitory effect on the nerve endings of visceral A delta and C fibers to the action of bradykinin through an H1-receptor mechanism. This inhibitory effect attenuates the magnitude of the consequent cardiovascular reflex response.

    Title Intramuscular Accumulation of Prostaglandins During Static Contraction of the Cat Triceps Surae.
    Date February 1992
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    We previously demonstrated that muscle afferent endings are sensitized by exogenous prostaglandins during static contraction of skeletal muscle. The purpose of this study was to determine whether 30 s of static hindlimb contraction, induced by electrical stimulation of the cat sciatic nerve, increases the concentration of immunoreactive prostaglandin E2 (iPGE2) and 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha, the stable metabolite of prostaglandin I2) in muscle tissue. In addition, the role of ischemia in augmenting prostanoid production was examined. Gastrocnemius muscle was obtained by freeze-clamping tissue, and prostaglandins were extracted from muscle homogenates and measured by radioimmunoassay. Compared with precontraction values, high-intensity (68% of maximal tension) static contraction elevated gastrocnemius iPGE2 and i6-keto-PGF1 alpha by 45 and 53%, respectively (P less than 0.01). Likewise, when blood flow to the gastrocnemius was attenuated by arterial occlusion during and 2 min before low-intensity contraction (29% maximal tension), the intramuscular iPGE2 concentration was increased by 71% (P less than 0.01). Conversely, low-intensity contraction (30% of maximal tension) and arterial occlusion without contraction did not alter the concentration of either prostanoid. Our findings demonstrate that prostaglandins accumulate in muscle during static contraction. We believe that local muscle ischemia may provide a stimulus for this phenomenon. These prostaglandins therefore are available to sensitize afferent endings responsible for reflex adjustments during static muscle contraction.

    Title Ischemically Sensitive Abdominal Visceral Afferents: Response to Cyclooxygenase Blockade.
    Date January 1992
    Journal The American Journal of Physiology
    Excerpt

    Ischemically sensitive abdominal visceral afferents are known to reflexly stimulate the cardiovascular system. These nerve endings respond to severe hypoxia as well as to exogenously administered bradykinin and prostaglandins such as PGI2, PGE, and PGF2 alpha. We have shown previously that these prostaglandins can sensitize some previously unresponsive afferents to respond to ischemia. To determine if endogenously produced prostaglandins contribute to the observed increase in activity during ischemia, we recorded activity of 6 A delta- and 23 C-fiber sympathetic afferents in anesthetized cats during 5 min of ischemia before and 15-30 min after intravenous administration of either indomethacin (5 mg/kg) or aspirin (50 mg/kg). Before cyclooxygenase inhibition, we noted repeatable increases of 1.44 +/- 0.22 and 1.44 +/- 0.36 impulses/s in the A delta- and C-fibers, respectively, in response to ischemia. After indomethacin or aspirin, these increases were significantly reduced (P less than 0.05) in both thinly myelinated and unmyelinated afferents (0.69 +/- 0.36 and 0.46 +/- 0.21 impulses/s, respectively). In a second protocol, we observed that the activity of six A delta- and seven C-fibers was significantly reduced by aspirin or indomethacin when a single period of ischemia preceded cyclooxygenase blockade. These data, in conjunction with our previous observations, indicate that prostaglandins significantly contribute to the increased afferent discharge activity associated with ischemia of the abdominal visceral region.

    Title Role of Granulocytes and C5a in Myocardial Response to Zymosan-activated Serum.
    Date August 1991
    Journal The American Journal of Physiology
    Excerpt

    Although previous studies have demonstrated that complement (C)5a causes myocardial ischemia and mechanical dysfunction, the cardiac response of endogenously produced C5a and C5a des-Arg in zymosan-activated serum (ZAS) and the critical role of granulocytes in this process are poorly understood. Therefore, we compared the coronary and cardiac effects of ZAS and purified C5a and investigated the role of leukocyte adhesion-promoting receptors (i.e., CD11/CD18). Like purified C5a, ZAS (0.5 ml) significantly reduced coronary artery blood flow and regional segment shortening, whereas coronary venous granulocyte concentration and myocardial lactate extraction were significantly decreased. A monoclonal antibody (MoAb) to C5a/C5a des-Arg attenuated ZAS-induced cardiac alterations. Three minutes of continuous infusion of C5a or ZAS induced sustained decreases in coronary venous granulocyte concentrations, although coronary flow and segment shortening returned to control levels after 2 min. Another MoAb, IB4, directed against CD18, significantly inhibited ZAS-induced granulocyte extraction and associated cardiac effects. Thus, cardiac dysfunction occurs after activation of the complement cascade with zymosan resulting in extraction of granulocytes mediated by the CD18 adherence glycoprotein. Furthermore, intramyocardial retention of granulocytes appears necessary for the initial and full ZAS-induced cardiac dysfunction.

    Title Cardiovascular Reflexes Evoked by Histamine Stimulation of the Stomach.
    Date May 1991
    Journal The American Journal of Physiology
    Excerpt

    This study examined the potential for histamine to cause cardiovascular reflexes when applied to the serosal or mucosal surface of the stomach. Thus, in chloralose-anesthetized cats, histamine was applied to the serosal surface of the stomach in concentrations ranging from 0.5 to 1,000 micrograms/ml. This resulted in graded increases in mean arterial pressure (MAP), maximal left ventricular pressure over time (dP/dt), and heart rate ranging from 9 +/- 4 to 30 +/- 3 mmHg, 450 +/- 103 to 1,710 +/- 610 mmHg/s, and 2 +/- 1 to 13 +/- 4 beats/min, respectively. Histamine stimulation of the gastric serosa evoked a greater pressor response than that observed when the same concentration of histamine (100 micrograms/ml) was applied to the gastric mucosa (43 +/- 7 vs. 13 +/- 3 mmHg, respectively). In six cats, celiac ganglionectomy abolished the previously observed cardiovascular response to histamine stimulation of the serosal surface of the stomach. When the gastric serosa was treated with the H1-receptor antagonist diphenhydramine (1 mg/ml) (n = 5), the cardiovascular response to histamine was abolished. In five other cats, administration of the H2-antagonist ranitidine (1 mg/ml) had no effect on the histamine-induced responses. When indomethacin (2-5 mg/ml), was applied to the serosal surface of the stomach (n = 6), histamine-induced increases in MAP and dP/dt were attenuated. However, application of PGE2 (1 microgram/ml) restored these two responses. These results suggest that histamine stimulates H1-receptors in the gastric wall to cause reflex cardiovascular responses that are dependent, in part, on the local production of prostaglandins.

    Title Contrasting Effects of Vasopressin and Angiotensin Ii on Rabbit Aortic Baroreceptors.
    Date April 1991
    Journal The American Journal of Physiology
    Excerpt

    Arginine vasopressin (AVP) reportedly enhances, whereas angiotensin II (ANG II) attenuates, baroreflex control of the circulation. Here we examine whether these responses can be attributed, in part, to local actions on myelinated baroreceptor (BR) afferents, either directly or via changes in vascular tone. An in vitro rabbit aortic arch/aortic nerve preparation was used to study regularly discharging presumably myelinated BRs under controlled static and pulsatile pressures. At constant suprathreshold pressures, AVP (10(-13) M to 10(-6) M) had no effect on arch diameter or BR frequency, whereas equimolar concentrations of ANG II evoked dose-dependent vasoconstriction and associated BR inhibition. Differences were not caused by limited diffusion to BR endings lying outside the media, since similar results were obtained with either luminal or adventitial applications. AVP also had no effect on diameter or discharge in arches preconstricted with norepinephrine, whereas acetylcholine (ACh) relaxed the arch and thereby increased BR activity. These results eliminate possible AVP-induced endothelium-dependent vasodilation or potentiation of adrenergic vasoconstriction that would not be evident in isolated arches lacking tone. Finally, AVP did not sensitize BRs to changes in pressure, since ramp-evoked pressure-discharge curves remained constant and pulsatile discharge in response to sine-wave pressure inputs was unaltered. ANG II, however, shifted pressure-discharge curves to higher pressures and, with pulsatile inputs at constant mean pressure, reduced peak and average discharge firing rates. In conclusion, AVP has no apparent peripheral effect on aortic myelinated BRs in rabbits that could contribute to amplification of the baroreflex when AVP levels are elevated. In contrast, ANG II can inhibit BR firing as a consequence of local vasoconstriction, which may contribute to attenuation of the reflex when ANG II levels are elevated.

    Title Bradykinin Release from Contracting Skeletal Muscle of the Cat.
    Date January 1991
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Results of previous studies from our laboratory suggest that bradykinin has a role in the exercise pressor reflex elicited by static muscle contraction. The purpose of this study was to quantify the release of bradykinin from contracting skeletal muscle. In 18 cats, blood samples were withdrawn directly from the venous effluent of the triceps surae muscles immediately before and after 30 s of static contraction producing peak muscle tensions of 33, 50, and 100% of maximum electrically stimulated contraction. Contractions producing muscle tensions of 50 and 100% of maximum increased muscle venous bradykinin levels by 27 +/- 9 and 19 +/- 10 pg/ml, respectively. Conversely, 33% maximum contraction did not alter muscle venous bradykinin concentrations. However, when captopril was administered to slow the degradation of bradykinin, muscle venous bradykinin increased from 68 +/- 15 pg/ml at rest to 106 +/- 18 after contractions of 33% of maximum. When muscle ischemia was induced by 2 min of arterial occlusion before and during 30 s of 33% of maximum contraction, muscle venous bradykinin increased by 15 +/- 5 pg/ml. In addition, contraction-induced changes in muscle venous pH and lactate strongly correlated with bradykinin concentrations (r = 0.80 and 0.83, respectively). These data demonstrate that static contraction of relatively high intensity evokes the release of bradykinin from skeletal muscle and that ischemia, decreased pH, and increased lactate are strongly correlated with this release.

    Title Effect of Long-term Exercise on Regional Myocardial Function and Coronary Collateral Development After Gradual Coronary Artery Occlusion in Pigs.
    Date December 1990
    Journal Circulation
    Excerpt

    The effect of myocardial ischemia, induced by long-term exercise, on regional myocardial function and coronary collateral development was examined in pigs after gradual occlusion of the left circumflex coronary artery (LCx) with an ameroid occluder. Thirty days after surgery, regional myocardial function and blood flow were assessed during exercise in 22 pigs separated into exercise (n = 12) and sedentary groups (n = 10). The exercise group trained on a treadmill for 25 +/- 1 days, 30-50 min/day, at heart rates of 210-220 beats/min. After 5 weeks, another exercise test was performed. In the exercise group, after training, we observed an improvement in systolic wall thickening, expressed as a percentage of rest, in the collateral-dependent LCx region from 64 +/- 8% to 87 +/- 6% (p less than 0.01) at moderate exercise levels (220 beats/min) and from 45 +/- 7% to 73 +/- 7% (p less than 0.01) at severe exercise levels (265 beats/min). Transmural myocardial blood flow in the LCx region expressed as a ratio of flow in the nonoccluded region of the left ventricle also increased significantly (p less than 0.01) during severe exercise after 5 weeks. The sedentary group showed an improvement in systolic wall thickening in the LCx region during moderate exercise compared with the initial exercise test (p less than 0.05) but no significant change in systolic wall thickening or myocardial blood flow ratios during severe exercise after 5 weeks. We conclude that long-term exercise after gradual LCx coronary artery occlusion in pigs improves myocardial function and coronary collateral reserve in collateral-dependent myocardium during exercise.

    Title Coronary Arteriolar Vasoconstriction in Myocardial Ischaemia: Reflexes, Sympathetic Nervous System, Catecholamines.
    Date August 1990
    Journal European Heart Journal
    Excerpt

    The sympathetic nervous system exerts important control over the coronary circulation. Studies from our laboratory have demonstrated that reflex input from skeletal muscle during static contraction causes coronary vasoconstriction. Similarly, stimulation of abdominal visceral chemosensitive afferents can, on occasions, elicit coronary vasoconstriction or limit the extent of vasodilation so that the myocardium needs to extract additional oxygen from arterial blood. Recently, we have examined the innervation of the coronary collateral circulation and found that these vessels contain catecholamines which demonstrate a pattern of fluorescence similar to that of catecholamines in the native circulation. Furthermore, stimulation of alpha 2- but not alpha 1-adrenoceptors can cause an increase in collateral vascular resistance. Thus, reflex input into the coronary circulation, perhaps during static exercise or post-prandially, can cause coronary vasoconstriction. Such constriction occurs in native coronary vessels and has the potential to be present in the coronary collateral circulation.

    Title Sensitization of Group Iii Muscle Afferents to Static Contraction by Arachidonic Acid.
    Date June 1990
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    The afferent arm of the reflex are responsible for the pressor response to static contraction is comprised of group III and IV fibers. The nature of the contraction-induced stimulus activating these fibers remains unclear. Evidence suggests that most group III afferents are sensitive to mechanical stimuli, whereas most group IV afferents are sensitive to metabolic stimuli. Recently, in anesthetized cats, stimulation of group III mechanoreceptors has been shown to have a role in the reflex pressor response to static contraction. In skin, the sensitivity of thin fiber mechanoreceptors to distortion of their receptive fields has been shown to be increased by both cyclooxygenase and lipoxygenase products of arachidonic acid metabolism. Therefore, in barbiturate-anesthetized cats we recorded the responses of group III muscle afferents to static contraction before and after arachidonic acid (1-2 mg ia) and/or indomethacin (5 mg/kg iv). Arachidonic acid increased the responses of group III afferents (n = 11) to contraction by 265% (from 0.17 +/- 0.07 to 0.62 +/- 0.24 impulses/s; P less than 0.025). Indomethacin decreased the responses of group III afferents (n = 9) to contraction by 61% (from 1.00 +/- 0.37 to 0.39 +/- 0.16 impulses/s; P less than 0.025). Arachidonic acid given after indomethacin increased the responses of two of four group III afferents to contraction. We conclude that both cyclooxygenase and lipoxygenase products of arachidonic acid metabolism sensitize group III muscle afferents to static contraction.

    Title Role of Thromboxane A2 in the Cardiovascular Response to Intracoronary C5a.
    Date May 1990
    Journal Circulation Research
    Excerpt

    Intracoronary administration of complement component C5a induces transient decreases in coronary blood flow and regional left ventricular segment shortening, associated with intramyocardial granulocyte trapping. We evaluated the influence of a cyclooxygenase inhibitor (acetylsalicylic acid, n = 8) or a thromboxane A2/prostaglandin H2 receptor antagonist (SQ29548, n = 6) on these C5a-induced cardiovascular responses. Open-chest anesthetized pigs were instrumented to monitor heart rate, arterial blood pressure, left anterior descending coronary blood flow, regional left ventricular segment shortening, and dP/dt. Oxygen content, lactate concentration, leukocyte count, and thromboxane B2, the stable metabolite of thromboxane A2, were measured in arterial and regional coronary venous blood. Repetitive injections of intracoronary C5a (500 ng) given 60 minutes apart showed no tachyphylaxis of the hemodynamic response. However, tachyphylaxis was seen in coronary blood flow changes when injections were spaced 30 minutes apart. An increase in myocardial oxygen extraction and lactate production was observed after intracoronary C5a. Administration of acetylsalicylic acid (50 mg/kg i.v.) attenuated C5a-induced decreases in coronary blood flow (-8 +/- vs. -3 +/- 1 ml/min) and regional left ventricular segmental shortening (-10 +/- 3% vs. -2 +/- 1%) and blocked the maximal increase in coronary venous thromboxane B2 (2.0 +/- 0.1 vs. 0.2 +/- 0.1 pmol/ml plasma). Furthermore, SQ29548 (30 micrograms/kg/min) reduced C5a-induced changes in coronary blood flow (-13 +/- 2 vs. -4 +/- 2 ml/min) and segmental shortening (-14 +/- 2% vs. -3 +/- 1%). Neither cyclooxygenase inhibition nor thromboxane A2/prostaglandin H2 antagonism blocked the decrease in coronary venous granulocyte count.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title In Vivo and in Vitro Assessment of Porcine Neutrophil Activation Responses to Chemoattractants: Flow Cytometric Evidence for the Selective Absence of Formyl Peptide Receptors.
    Date May 1990
    Journal Journal of Leukocyte Biology
    Excerpt

    Interest in the role that activated granulocytes play in C5a-induced myocardial ischemia prompted us to investigate and compare activation responses of pig and human neutrophils. The responses of Hypaque-Ficoll purified porcine (P-PMN) and human neutrophils (H-PMN) to stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP), C5a, phorbol myristate acetate (PMA), and calcium ionophore A23187 (A23187) were compared by flow cytometrically measured changes in the cells' forward (FWD-SC) (a measure of shape/volume change) and right angle (90 degrees-SC) light scatter (a measure of secretion), and in the distribution of the membrane potential sensitive fluorescent probe di-O-C (3). FMLP, C5a, and Zymosan-activated serum (ZAS stimulated chemotaxis and FMLP vs. PMA-stimulated adherence to plastic were also compared. Unstimulated P-PMN had lower FWD-SC and 90 degrees-SC than H-PMN (39.4 +/- 1.4 vs. 48.4 +/- 2.0 P less than 0.05, and 32.7 +/- 2.7 vs. 52.4 +/- 1.5 units, P less than 0.005, for FWD-SC and 90 degrees-SC of P-PMN vs. H-PMN, respectively). P-PMN selectively failed to increase their FWD-SC upon stimulation with FMLP (0.0 +/- 0.5% vs. 26.1 +/- 6.8%, P-PMN vs. H-PMN), or decrease their 90 degrees-SC when treated with cytochalasin B + FMLP (secretion) (2.4 +/- 0.1% vs. -35.8 +/- 4.6% change in 90 degrees-SC, P-PMN vs. H-PMN), while responding comparably to C5a, PMA, and A23187. P-PMN failed to depolarize in response to FMLP but responded similarly to H-PMN when activated by C5a, A23187, and PMA. P-PMN's chemotactic response to FMLP was selectively absent since the cells responded well to purified pig C5a. FMLP stimulated significant increases in H-PMN adherence to bovine serum albumin-coated plastic (44.1 +/- 6.7% vs. 12.6 +/- 3.7%, FMLP vs. buffer, P less than 0.025), but failed to increase adherence of P-PMN above baseline 0.68 +/- 0.20% vs. 2.12 +/- 1.90%, FMLP vs. buffer, P greater than 0.05. PMA (100 ng/ml) stimulated comparable increases in adherence in both PMN types (48.6 +/- 5.2% vs. 58.7 +/- 4.9%, P-PMN vs. H-PMN, P less than 0.025). Binding studies using the fluoresceinated N-formyl peptide f-met-leu-phe-lysine-fluorescein-isothiocyanate (FMLPL-FITC) in the absence and presence of excess non-fluoresceinated FMLPL indicated that P-PMN lack specific binding sites for the N-formyl peptides.(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Distribution of Cell Bodies for Primary Afferent Fibers from the Stomach of the Cat.
    Date January 1990
    Journal Neuroscience Letters
    Excerpt

    The distribution of primary afferent cell bodies supplying the stomach of the cat was localized using lectin-conjugated horseradish peroxidase. Labelled cells were found in the nodose ganglia and dorsal root ganglia T4-L2 or T4-L1. The spinal entry levels of the stomach afferents do not overlap extensively with those of the cardiac afferents.

    Title Potentiation of the Exercise Pressor Reflex by Muscle Ischemia.
    Date June 1989
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    The reflex responses to static contraction are augmented by ischemia. The metabolic "error signals" that are responsible for these observed responses are unknown. Therefore this study was designed to test the hypothesis that static contraction-induced pressor responses, which are enhanced during muscle ischemia, are the result of alterations in muscle oxygenation, acid-base balance, and K+. Thus, in 36 cats, the pressor response, active muscle blood flow, and muscle venous pH, PCO2, PO2, lactate, and K+ were compared during light and intense static contractions with and without arterial occlusion. During light contraction (15-16% of maximal), active muscle blood flow increased without and decreased with arterial occlusion (+35 +/- 12 vs. -60 +/- 11%). Arterial occlusion augmented these pressor responses by 132 +/- 25%. Without arterial occlusion, changes (P less than 0.05) were seen in PO2, O2 content, PCO2, and K+. Lactate and pH were unchanged. With arterial occlusion, changes in muscle PCO2 were augmented and significant changes were seen in pH and lactate. During intense static contraction (67-69% of maximal), muscle blood flow decreased without arterial occlusion (-39 +/- 9%) and decreased further during occlusion (-81 +/- 6%). Arterial occlusion augmented the pressor responses by 39 +/- 12%. All metabolic variables increased during contraction without arterial occlusion, but occlusion failed to augment any of these changes. These data suggest that light static ischemic contractions cause increases in muscle PCO2 and lactate and decreases in pH that may signal compensatory reflex-induced changes in arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Coronary Vascular Responses to Chemical Stimulation of Abdominal Visceral Organs.
    Date April 1989
    Journal The American Journal of Physiology
    Excerpt

    Topical application of bradykinin or capsaicin to abdominal visceral organs produces adrenergically mediated, reflex increases in mean arterial pressure and cardiac work. To determine the effects on coronary blood flow, the left main coronary artery of anesthetized cats was perfused at constant pressure with a servo-controlled pump. Cardiovascular parameters were measured during reflex stimulation before and after beta-adrenoceptor blockade with propranolol. Before propranolol, reflex activation led to increases in the double product and myocardial oxygen consumption, usually accompanied by increases in coronary blood flow. However, in 32% of the observations, decreases in flow were observed. During beta-adrenoceptor blockade, reflex stimulation produced increases in cardiac work, whereas the increases in coronary blood flow were attenuated. Marked decreases in average coronary blood flow were observed more frequently (42%). In the presence of propranolol, contrary to the unblocked state, increases in oxygen consumption were achieved by increased oxygen extraction. Subsequent alpha-adrenoceptor blockade with phentolamine abolished all reflex changes. These data indicate that during stimulation of abdominal visceral chemoreceptors, the major coronary response is vasodilation, but in a sizable fraction of cases, abdominal visceral reflexes can produce sympathetically mediated coronary vasoconstriction.

    Title Reflex Effect of Skeletal Muscle Mechanoreceptor Stimulation on the Cardiovascular System.
    Date December 1988
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    To determine the potential for mechanical stimulation of skeletal muscle to contribute to the reflex cardiovascular response to static contraction (exercise reflex), we examined the cardiovascular effects caused by either passive stretch or external pressure applied to the triceps surae muscles. First, the triceps surae were stretched to an average developed tension of 4.8 +/- 0.3 kg. This resulted in increases in mean arterial pressure (MAP) of 28 +/- 7 mmHg, dP/dt of 1,060 +/- 676 mmHg/s, and heart rate (HR) of 6 +/- 2 beats/min (P less than 0.05). Additionally, increments of 0.3, 0.5, 1.0, 2.0, 4.0, and 8.0 kg of tension produced by passive stretch elicited pressor responses of -6 +/- 1, 7 +/- 1, 16 +/- 3, 21 +/- 8, 28 +/- 6, and 54 +/- 9 mmHg, respectively. External pressure, applied with a cuff to the triceps surae to produce intramuscular pressures (125-300 mmHg) that were similar to those seen during static contraction, also elicited small increases in MAP (4 +/- 1 to 10 +/- 1 mmHg) but did not alter HR. Transection of dorsal roots L5-L7 and S1 abolished the responses to passive stretch and external pressure. Moreover, when the triceps surae were stretched passively to produce a pattern and amount of tension similar to that seen during static hindlimb contraction, a significant reflex cardiovascular response occurred. During this maneuver, the pressor response averaged 51% of that seen during contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Evaluation of Coronary Native and Coronary Collateral Pressure Gradients in the Conscious Dog.
    Date October 1988
    Journal The American Journal of Cardiovascular Pathology
    Excerpt

    Sixteen dogs were instrumented chronically with a left circumflex (CIRC) Ameroid constrictor, and with CIRC, left anterior descending (LAD), aortic, left atrial and pulmonary artery (PA) catheters. Premature mortality was 12.5% prior to the last measurements of pressure at 50 +/- 3 days (mean +/- SE). Five animals developed closure of the Ameroid constrictor at 5 +/- 1 days with an LAD to CIRC pressure gradient of 57 +/- 8 mm Hg. Eleven animals developed closure of the Ameroid constrictor at 18 +/- 1 days with an LAD to CIRC pressure gradient of 29 +/- 3 mm Hg. Three animals in the former group had gross evidence of a myocardial infarction on postmortem examination. None of the animals in the latter group showed evidence of a myocardial infarction. Thus, closure of a CIRC Ameroid constrictor and subsequent collateral vessel development can be monitored chronically by the LAD to CIRC pressure gradient with a high survival, low infarction rate. This chronic model thus provides an accurate measure of coronary native and collateral pressures in unsedated dogs.

    Title C5a Decreases Regional Coronary Blood Flow and Myocardial Function in Pigs: Implications for a Granulocyte Mechanism.
    Date August 1988
    Journal Circulation Research
    Excerpt

    Granulocytes cause some of the pathophysiological effects associated with the capillary no-reflow phenomenon during ischemia and in ischemia-reperfusion injury. However, no study has examined the consequences of in vivo granulocyte activation during normal perfusion pressures. In this study, we examined the effects of intracoronary administration of the complement component C5a, which is known to be a potent granulocyte activating factor. Nine open-chest, anesthetized pigs were instrumented to monitor regional coronary blood flow and segment shortening, left ventricular dP/dt, heart rate, and pulmonary artery and aortic blood pressures and to sample arterial and regional coronary venous blood for oxygen content and complete blood counts. Intracoronary infusion of human or porcine C5a in doses ranging from 10 to 500 ng produced a significant reduction in regional coronary blood flow and myocardial function. Although perfusion pressure and heart rate remained constant, venous oxygen content fell, indicating an imbalance between myocardial oxygen supply and demand. In addition, the arteriovenous difference of white blood cells was increased significantly after anaphylatoxin infusion, indicating intravascular trapping in the myocardium. Granulocytes accounted entirely for the differences in leukocyte counts because no significant changes in platelet, lymphocyte, or hematocrit levels were observed. Injection of vehicle alone did not alter any of the monitored variables.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Gastrointestinal Reflexes.
    Date August 1988
    Journal Gastroenterology
    Title Stimulating Intestinal Afferents Reflexly Activates Cardiovascular System in Cats.
    Date March 1988
    Journal The American Journal of Physiology
    Excerpt

    Capsaicin and bradykinin stimulate afferents from certain viscera to reflexly activate the cardiovascular system; however, whether these agents evoke similar reflex responses when applied topically to the intestine is not known. Therefore, in cats anesthetized with methoxyflurane, we applied capsaicin (10 micrograms) or bradykinin (0.5 microgram) to the serosal surface of the jejunum. Additionally, we topically applied bethanechol chloride, a synthetic choline ester with little direct cardiovascular effects, to evoke marked contraction of the smooth muscle of the jejunum. Capsaicin evoked significant (P less than 0.05) increases in mean arterial pressure (105 +/- 4 to 119 +/- 4 mmHg, mean +/- SE), first derivative left ventricular pressure (dP/dt) at 40 mmHg (2,698 +/- 134 to 3,105 +/- 155 mmHg/s), systemic vascular resistance (0.63 +/- 0.15 to 0.68 +/- 0.15 peripheral resistance units), and heart rate (196 +/- 14 to 205 +/- 15 beats/min), whereas aortic flow did not change. In a dose-dependent fashion, bradykinin and bethanechol each caused cardiovascular activation as well as a marked contraction of the smooth muscle in the segment of jejunum to which they were applied. In contrast, capsaicin produced no detectable contraction of visceral smooth muscle. Removal of the celiac and superior mesenteric ganglia abolished the cardiovascular responses evoked by capsaicin and bradykinin. Thus, in cats, stimulating intestinal afferents by topically applying capsaicin or bradykinin reflexly activates the cardiovascular system. Furthermore, although mechanoreceptors may contribute to the responses evoked by bradykinin and bethanechol, the capsaicin-related responses likely are mediated exclusively by chemically sensitive receptors.

    Title Effects of Left Circumflex Ameroid Constrictor Placement on Adrenergic Innervation of Myocardium.
    Date January 1988
    Journal The American Journal of Physiology
    Excerpt

    We evaluated the adrenergic innervation of the swine and canine myocardium after placement of an Ameroid constrictor around the left circumflex coronary artery (LCX). Fluorescent histochemistry was used to identify adrenergic nerve terminals in the myocardium and coronary vasculature. Ameroid occlusion of the proximal LCX in 10 pigs for 3 wk resulted in 6 +/- 1% infarction as well as myocardial ischemia in the left circumflex region of pigs studied during exercise. However, placement of the Ameroid constrictor did not significantly alter the surface density of the nerve terminals in the LCX region of myocardium when compared with innervation of control hearts. Histological examination of the coronary arterial adrenergic innervation in Ameroid-occluded pigs revealed that coronary vessels in the circumflex region of the heart were innervated. Similarly, in seven LCX Ameroid-occluded dogs, no significant decrease in adrenergic innervation of the LCX region of myocardium was observed when compared with control dogs. In contrast LCX Ameroid-occluded pigs demonstrated significant (P less than 0.01) denervation of the left anterior descending (LAD) region of myocardium when compared with control animals. The close proximity of adrenergic nerve bundles in the proximal LAD region indicates that denervation of the myocardium supplied by the LAD may result from the dissection and/or fibrosis associated with placement of the Ameroid constrictor on the proximal LCX. Our results suggest that placement of an Ameroid constrictor on the proximal LCX does not significantly alter the adrenergic innervation of the LCX-perfused myocardium or its associated coronary vasculature. However, denervation of LAD-perfused myocardium and its vasculature may result.

    Title Development of Coronary Collateral Circulation in Left Circumflex Ameroid-occluded Swine Myocardium.
    Date January 1988
    Journal The American Journal of Physiology
    Excerpt

    Coronary collateral development was examined in 34 pigs after gradual occlusion of the left circumflex coronary artery (LCX) with an Ameroid constrictor. Collateral development was assessed by measurements of myocardial blood flow and regional myocardial function at rest and during exercise over a 16-wk period after placement of the constrictor. Coronary collateral development was adequate to prevent severe infarction and restore blood flow to the collateral-dependent LCX region within 3-7 wk. Infarction averaged 5.0 +/- 1.3% of the LCX region. Blood flows at rest were 1.05 +/- 0.14 and 1.13 +/- 0.15 ml.min-1.g-1 in the subendocardium of the collateral and control regions, respectively, 7 wk postoperatively. Concurrently, collateral vessel development supported normal myocardial function at rest as determined by systolic wall thickening in the LCX region. However, collateral development was limited, since blood flows during moderate and severe exercise were reduced in the LCX region compared with control and left anterior descending and right coronary regions. Blood flow ratios (collateral/control flow) during severe exercise 3 wk postoperatively were 0.23 +/- 0.03 and 0.57 +/- 0.05 in the subendocardium and subepicardium and were constant throughout the 16-wk period throughout the study. Myocardial function of the collateral region also was reduced during exercise and a 30-min recovery period. We suggest that this limited coronary collateral circulation, which develops in response to gradual coronary occlusion in swine, serves as a model for the human collateral circulation for the study of protocols to alter growth and development of coronary collateral vessels.

    Title Functional Significance of Alpha-adrenergic Receptors in Mature Coronary Collateral Circulation of Dogs.
    Date October 1987
    Journal The American Journal of Physiology
    Excerpt

    There is little information on the functional significance of alpha-adrenergic receptors in the dog's coronary collateral circulation. Accordingly, we investigated the effects of infusion of either norepinephrine (NE) or B-HT 920 (BHT), an alpha 2-adrenergic agonist, on vascular resistance of coronary collaterals in chloralose-anesthetized dogs 2-3 mo after placement of an Ameroid constrictor around the left circumflex coronary (LCX) artery. To accomplish this, the vagotomized left ventricle was autoperfused through the left main coronary ostium using a servo-controlled constant-pressure pump. Pressures of the left anterior descending (LAD) and peripheral LCX arteries were measured, and regional blood flow in LAD and LCX regions were determined with radioactive microspheres before and during NE infusion in the unblocked condition, following beta-adrenergic and beta + alpha 1-adrenergic blockade with the use of propranolol and prazosin, respectively. The same parameters were also measured before and during BHT infusion following beta-adrenergic and beta + alpha 2-adrenergic blockade with the use of propranolol and idazoxan, respectively. In the unblocked condition, NE reduced LAD, LCX, and collateral resistance by 43, 50, and 31%, respectively. After beta-adrenergic blockade, NE increased LAD resistance (29%) but did not alter LCX or collateral resistance. The increase in LAD resistance was abolished following alpha 1-adrenergic blockade. BHT increased vascular resistance in LAD, LCX, and collateral circulations by 35, 29, and 45%, respectively. Selective alpha 2-adrenergic blockade significantly attenuated the vasoconstrictor response to BHT.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Hypoxia, Bradykinin, and Prostaglandins Stimulate Ischemically Sensitive Visceral Afferents.
    Date October 1987
    Journal The American Journal of Physiology
    Excerpt

    Ischemia of abdominal visceral organs is known to reflexly stimulate the cardiovascular system. The purpose of this study was to determine which of several potential chemical stimuli present during ischemia either directly stimulate or sensitize these afferents to respond to ischemia. Impulse activity was recorded in the right splanchnic nerve of anesthetized cats. First, we determined whether the afferents were ischemically sensitive by subjecting them to 2-6 min of regional ischemia through occlusion of the descending thoracic aorta. We then examined the afferents' response to systemic hypoxia by decreasing the inspired O2 and arterial injection of bradykinin or the prostaglandins (PG) E2, PGF2 alpha, or prostacyclin (PGI2). Sixty-one percent of the rapidly adapting A fibers and 47% of the C fibers were stimulated by ischemia, and of these, 78% of the A fibers and 44% of the C fibers tested were stimulated by hypoxia. The latency of response to hypoxia (60 +/- 12 s) was significantly longer than the chemoreceptor-induced pressor response (45 +/- 11 s). Each afferent stimulated by ischemia and/or hypoxia innervated a receptive field in the pylorus, intestine, porta hepatis, gallbladder or biliary tract, pancreas, or mesentery. Ninety percent of the ischemically sensitive A fibers and 80% of the ischemically sensitive C fibers responded to bradykinin, whereas 40% of the A fibers and 62% of the C fibers responded to PGE2, PGF2 alpha, or PGI2. Several endings responded to ischemia or hypoxia only after bradykinin or PGI2 had been injected. Thus approximately 50% of slowly adapting A and C fiber endings in abdominal visceral organs respond, or can be sensitized by bradykinin or PGI2 to respond, to ischemia and/or hypoxia. However, they are not as sensitive to hypoxia as carotid and aortic body chemoreceptors, since they respond well after the chemoreceptor-induced pressor response.

    Title Association of Decreased Myocardial Beta-receptors and Chronotropic Response to Isoproterenol and Exercise in Pigs Following Chronic Dynamic Exercise.
    Date August 1987
    Journal Circulation Research
    Excerpt

    The effects of chronic dynamic exercise on myocardial beta-adrenergic and muscarinic cholinergic receptors and chronotropic sensitivity to isoproterenol were studied in 5 Yucatan miniswine. Right atrial and left ventricular biopsies, heart rate responses to isoproterenol, and maximal exercise treadmill testing were obtained before and after 10-19 weeks of treadmill running. Radioligand studies using 125I-iodocyanopindolol (ICYP) and 3H-quinuclidinyl benzilate (QNB) were used to determine the number of beta-adrenergic and muscarinic cholinergic receptors. Maximal oxygen consumption increased from 52 +/- 5 to 65 +/- 7 ml/kg/min (mean +/- SD; p less than 0.02), maximal workload from 530 +/- 111 to 1,074 +/- 179 KPM/min (p less than 0.01), resting heart rate decreased from 91 +/- 13 to 62 +/- 4 beats/min (p less than 0.01), heart rate at 75% of pretraining maximal workload decreased from 253 +/- 15 to 196 +/- 12 beats/min (p less than 0.01), and maximal exercise heart rate decreased from 273 +/- 6 to 254 +/- 9 beats/min (p less than 0.01). Decreased heart rate responsiveness to adrenergic stimulation was observed following chronic exercise. Maximal isoproterenol-stimulated heart rate decreased from 225 +/- 13 to 185 +/- 28 beats/min (p less than 0.05) and the slope of the isoproterenol dose-response relation decreased from 63 +/- 16 to 40 +/- 16 (p less than 0.05). Radioligand studies revealed a decrease in beta-receptor number in the right atrium following chronic exercise (61 +/- 9 vs. 34 +/- 8 fmol/mg; p less than 0.02), but receptor number in membranes from the left ventricle did not change (60 +/- 9 vs. 62 +/- 4 fmol/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Training Effects on Regional Blood Flow Response to Maximal Exercise in Foxhounds.
    Date July 1987
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    The effect of training on the regional blood flow response to maximal exercise was investigated in the foxhound. Training consisted of 8-12 wk of treadmill running at 80% of maximal heart rate 1 h/day for 5 days/wk and resulted in a 31% increase in maximal O2 consumption, a 28% increase in maximal cardiac output, and a 23% decrease in systemic vascular resistance during maximal exercise. Blood flow to the heart, diaphragm, brain, skin, and 9 of 10 muscles investigated was similar during maximal exercise pre- and posttraining; however, blood flow to the gastrocnemius muscle was greater posttraining than it was pretraining. Blood flow to the stomach, small intestine, and pancreas decreased during maximal exercise pre- and posttraining; however, blood flow to the large intestine, spleen, liver, adrenal glands, and kidneys decreased during maximal exercise only posttraining. In addition, a larger decrease in blood flow to the stomach during maximal exercise was found posttraining compared with pretraining. These results demonstrate that blood flow to skeletal muscle, the kidneys, and the splanchnic region of the foxhound during maximal exercise can be significantly altered by dynamic exercise training.

    Title Prostaglandins Contribute to Cardiovascular Reflexes Evoked by Static Muscular Contraction.
    Date April 1987
    Journal Circulation Research
    Excerpt

    The purpose of this study was to determine the contribution of prostaglandins to the reflex cardiovascular responses induced by static contraction of the hind limb in cats, i.e., the exercise reflex. To accomplish this, the cardiovascular responses to hind limb contraction induced by electrical stimulation of spinal cord ventral roots L6-7 and S1 were compared before and after inhibition of prostaglandin synthesis (indomethacin, 2-6 mg/kg i.v., n = 5, or sodium meclofenamate, 2-6 mg/kg i.v., n = 5) or after injection of prostaglandin E2 into the hind limb arterial blood supply. Treatment with indomethacin attenuated the contraction-induced increase in mean arterial pressure and left ventricular dP/dt by 76% and 86%, respectively. Heart rate and average developed triceps surae muscle tension were unchanged. After administering sodium meclofenamate, the reflex response was attenuated to a similar degree. In the indomethacin-treated animals, injection of exogenous prostaglandin E2 (PGE2) partially restored the pressor and myocardial contractile responses. In 6 animals, treatment with exogenous PGE2 without prior inhibition of prostaglandin synthesis did not significantly augment the contraction-induced cardiovascular response. Using the radioactive microsphere technique, we measured skeletal muscle blood flow during contraction before and after treatment with indomethacin (n = 6) to determine if an indomethacin-induced alteration in blood flow could account for the attenuated contraction-induced cardiovascular response. Blood flow during static muscle contraction was not significantly altered by indomethacin. We conclude that prostaglandins contribute to the exercise reflex through an action on afferent nerve endings rather than through a regional vascular effect.

    Title Increased Myocardial Beta-receptors and Adrenergic Responses in Hyperthyroid Pigs.
    Date March 1987
    Journal The American Journal of Physiology
    Excerpt

    Controversy exists presently as to whether thyroid hormone potentiates the action of catecholamines on the heart. Therefore, the relationships between adrenergic sensitivity, myocardial beta-receptor number, and the cardiovascular responses associated with excess thyroid hormone were investigated in pigs (Sus scrofa). A hyperthyroid state was induced by the administration of triiodothyronine (T3; 1 mg/kg iv). After 7 days there was a significant increase in resting heart rate, systolic blood pressure, rate-pressure product, and O2 consumption in the hyperthyroid state. At this time echocardiography showed a substantial increase in myocardial cross-sectional size. Pharmacological tests showed an increased intrinsic heart rate (127 +/- 29 to 205 +/- 25 beats/min; P less than 0.001) and an increased chronotropic sensitivity to isoproterenol. The concentration of isoproterenol required for a 50% of maximal response (ED50) was reduced by 33 +/- 30% (2.1 +/- 1.0 to 1.2 +/- 0.3 micrograms/l; P less than 0.025). The slope of the line relating isoproterenol concentration and change in heart rate was increased by 29 +/- 33% (61 +/- 10 to 78 +/- 10; P less than 0.025). Radioligand studies demonstrated an increase in the number of beta-receptors in right atrial membranes from hyperthyroid animals (41 +/- 7 vs. 75 +/- 18 fmol/mg; P less than 0.02). The apparent dissociation constant (KD) of the receptor for l-isoproterenol was similar in membranes from euthyroid and hyperthyroid animals (157 +/- 57 vs. 219 +/- 59 nM, respectively; P = NS). This study demonstrates that hyperthyroidism is associated with an increased chronotropic sensitivity to isoproterenol, consequent to an up-regulation of beta-adrenergic receptors in the right atrium.

    Title Evidence Against High Pressure, Arterial Baroreceptors in the Abdominal Viscera of Cats.
    Date January 1987
    Journal The American Journal of Physiology
    Excerpt

    The abdominal viscera of cats have been postulated to contain a site of cardiovascular regulation. In particular, a baroreceptive function has been ascribed to splanchnic afferent nerves. We wished to determine whether afferents with a cardiac-rhythmic discharge functioned as arterial baroreceptors. Nineteen afferents with a cardiac rhythmic discharge were studied. All afferents were A fibers, whose endings were located in either the pancreas, mesentery, or porta hepatis region. We examined their characteristics of discharge with regard to changes in mean pressure, pulse pressure, and dP/dt of the arterial pulse. Hemodynamic alterations were achieved by intravenous administration of isoproterenol, norepinephrine, or phenylephrine and by occlusion of the descending thoracic aorta. After isoproterenol, increases in nerve activity occurred when pulse pressure and dP/dt were increased but while mean pressure was decreasing, indicating that mean pressure was not the stimulus for discharge of these afferents. Additionally, under similar hemodynamic conditions, afferents did not demonstrate reproducible patterns of activity. The afferents generally discharged with one impulse per cardiac cycle, rarely with two to three impulses per cycle. None demonstrated a bursting pattern even when arterial blood pressure was quite elevated. The spontaneous pattern of discharge changed frequently, often after the viscera were repositioned, and sometimes remained even after complete occlusion of the aorta. The data indicate that these visceral afferents do not respond as high pressure, arterial baroreceptors. All afferents adapted extremely rapidly and exhibited a low gain (0.02 +/- 0.00 impulses X s-1 X mmHg-1), indicating that these fibers would be ineffective in signaling physiologically significant changes in hemodynamic variables. The data from this study do not support the existence of baroreceptors in the abdominal viscera of cats.

    Title Validation of a Respiratory Mask for Measuring Gas Exchange in Exercising Swine.
    Date November 1986
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    A respiratory mask was developed for resting and exercising swine. The lightweight, low-dead-space design fits airtight against the animals' snouts to provide breath-by-breath measurements of respiration and metabolism. Validation of the mask was carried out using the Fick principle with dye-dilution cardiac outputs and arterial and mixed venous O2 content measurements. Linear regression analysis of O2 consumption (VO2) measurements by the two techniques revealed a slope of 1.07 and a Y-intercept of -1.06 ml X kg-1 X min-1. The standard error of the estimate of VO2 was 3.5 ml X kg-1 X min-1. The mask design permits rapid measurements of ventilation and metabolism in response to acute and chronic exercise.

    Title O2 Consumption During Exercise in Dogs--roles of Splenic Contraction and Alpha-adrenergic Vasoconstriction.
    Date October 1986
    Journal The American Journal of Physiology
    Excerpt

    To examine the influence of alpha-adrenergic vasoconstriction on the aerobic capacity of dogs, we calculated O2 consumption (VO2) by the Fick method during submaximal and maximal exertion before and during alpha-adrenergic blockade with phentolamine. Regional blood flow was measured with radioactive microspheres. alpha-Adrenergic receptor blockade reduced VO2 by 12.9% during submaximal and 17.9% during maximal exercise. Arterial and venous lactic acid approximately doubled during both levels of stress in the presence of alpha-adrenergic receptor blockade. Calculated VO2 decreased because arteriovenous O2 (A-V)O2 extraction was reduced by 11.6% during submaximal exercise. During maximal exercise a 16.7% decrease in (A-V)O2 extraction and a 5.7% decrease in cardiac output contributed to the decrease in maximal VO2. During both levels of stress, (A-V)O2 extraction was reduced because arterial O2 content was decreased. Since circulating hematocrits during exercise were reduced by alpha-adrenergic receptor blockade (43-38%), we postulate that splenic contraction likely was inhibited. Additionally, distribution of blood flow to skeletal muscle and visceral organs was unaltered by alpha-blockade. To examine the importance of splenic contraction during maximal exercise, we examined hemodynamic and metabolic responses before and after splenectomy. Compared with the spleen-intact condition, splenectomized dogs demonstrated a 12.6% reduction in VO2 as a result of 7.7 and 5.5% reductions in (A-V)O2 extraction and cardiac output, respectively. (A-V)O2 extraction was reduced because arterial O2 content and circulating hematocrit during exercise were decreased. Therefore, in the exercising dog, alpha-adrenergic receptor blockade reduces O2 consumption and causes a shift to anaerobic metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Bradykinin in Reflex Cardiovascular Responses to Static Muscular Contraction.
    Date September 1986
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    We examined the contribution of bradykinin to the reflex hemodynamic response evoked by static contraction of the hindlimb of anesthetized cats. During electrical stimulation of ventral roots L7 and S1, we compared the cardiovascular responses to hindlimb contraction before and after the following interventions: inhibition of converting enzyme (kininase II) with captopril (3-4 mg/kg, n = 6); inhibition of kallikrein activity with aprotinin (Trasylol, 20,000-30,000 KIU/kg, n = 8); and injection of carboxypeptidase B (500-750 U/kg, n = 7). Treatment with captopril augmented the rise in mean arterial blood pressure and maximal time derivative of pressure (dP/dt) caused by static contraction from 21 +/- 3 to 39 +/- 7 mmHg and 1,405 +/- 362 to 2,285 +/- 564 mmHg/s, respectively. Aprotinin attenuated the contraction-induced rise in mean arterial blood pressure (28 +/- 4 to 9 +/- 2 mmHg) and maximal dP/dt (1,284 +/- 261 to 469 +/- 158 mmHg/s). Carboxypeptidase B reduced the cardiovascular response to static contraction. Thus the mean arterial blood pressure response was decreased from 36 +/- 12 to 24 +/- 11 mmHg, maximal dP/dt from 1,618 +/- 652 to 957 +/- 392 mmHg/s, and heart rate from 12 +/- 2 to 7 +/- 1 beats/min. These data suggest that stimulation of muscle afferents by bradykinin contributes to a portion of the reflex cardiovascular response to static contraction.

    Title Substance P, 5-hydroxytryptamine, and Bradykinin Stimulate Abdominal Visceral Afferents.
    Date April 1986
    Journal The American Journal of Physiology
    Excerpt

    To determine if chemicals produced endogenously within the gastrointestinal system stimulate abdominal visceral sensory endings, we recorded the response of 42 A- and 25 C-fibers in the splanchnic nerve of cats as substance P (10-20 micrograms), 5-hydroxytryptamine (5-HT, 100-200 micrograms), or bradykinin (10 micrograms) was injected into the descending thoracic aorta. Approximately half of the sensory endings responded to each chemical. However, significantly more C- than A-fiber endings responded to 5-HT (64 vs. 39%) and bradykinin (76 vs. 41%). Most C-fiber endings were insensitive to external mechanical stimuli, supporting the concept that these endings are primarily chemosensitive. In contrast, most A-fiber endings were quite sensitive to external mechanical stimuli. Additionally, more A-fiber endings located in contractile (gut or vasculature) than in noncontractile (pancreas, liver, or spleen) regions responded to 5-HT (58 vs. 19%), bradykinin (67 vs. 15%), and substance P (57 vs. 29%), a response that frequently occurred coincident with the development of chemically induced gut contractions. Thus many A-fiber endings are primarily sensitive to mechanical stimuli. However, 15-30% of the A-fiber endings located in noncontractile regions responded to chemicals, although the endings likely were removed from the mechanical effects of these chemicals. Since these A-fiber endings are also quite sensitive to external mechanical stimuli, they may be polymodal in their function. We conclude that abdominal visceral sensory endings are not homogeneous in function and are stimulated by several chemicals produced endogenously within the gastrointestinal system, including substance P, 5-HT, and bradykinin.

    Title Function of Mature Coronary Collateral Vessels and Cardiac Performance in the Exercising Dog.
    Date October 1985
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Formation of extensive collateral vessels after chronic constriction of a coronary artery in dogs can provide for similar increases in blood flow to native and collateralized regions of myocardium during exertion. Previous investigations have not compared myocardial blood flow and cardiac functional responses during exercise in constricted and nonconstricted (sham) animals. Thus we evaluated left ventricular performance and myocardial blood flow at rest and during mild, moderate, and severe exertion in sham-operated dogs and in dogs 2-3 mo after placement of an Ameroid occluder around the proximal left circumflex artery. Changes in double product, maximal left ventricular dP/dt, and pressure-work index were similar in both groups for each level of exertion. Despite similar increases in estimated myocardial O2 demand and similar diastolic perfusion pressures, average transmural myocardial blood flow increased less in the constrictor animals, particularly during severe exercise (2.74 +/- 0.22 vs. 1.45 +/- 0.29 ml X min-1 X g-1). The smaller increases in blood flow occurred equally in native and collateralized regions as well as in the papillary muscles and boundary areas between the native and collateralized regions. The differences in flow in the native and collateralized regions were uniform across the wall of the myocardium. We also observed smaller increases in stroke volume and cardiac output in the constrictor group, disparities which increased with increasing exertion (stroke volume, severe exercise = 0.92 +/- 0.13 vs. 0.53 +/- 0.09 ml/kg). We postulate that myocardial active hyperemia is limited either because the coronary vessels remaining after chronic circumflex occlusion cannot dilate sufficiently or that there is inappropriate active vasoconstriction during severe exertion.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Bradykinin-induced Chemoreflexes from Skeletal Muscle: Implications for the Exercise Reflex.
    Date October 1985
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    We examined the cardiovascular response to bradykinin stimulation of skeletal muscle afferents and the effect of prostaglandins on this response. Intra-arterial injection of 1 microgram bradykinin into the gracilis muscle of cats reflexly increased mean arterial pressure by 16 +/- 2 mmHg, left ventricular end-diastolic pressure by 1.6 +/- 0.6 mmHg, maximal dP/dt by 785 +/- 136 mmHg/s, heart rate by 11 +/- 2 beats/min, and mean aortic flow by 22 +/- 3 ml/min. The hemodynamic responses were abolished following denervation of the gracilis muscle. The increases in mean arterial pressure and maximal dP/dt were reduced by 68 and 45%, respectively, following inhibition of prostaglandin synthesis with indomethacin (2-8 mg/kg iv). Treatment with prostaglandin E2 (PGE2, 15-25 micrograms ia) restored the initial increase in mean arterial pressure, but not dP/dt, caused by bradykinin stimulation. Injection of PGE2 (15-30 micrograms ia) into the gracilis, without prior treatment with indomethacin, augmented the bradykinin-induced increases in mean arterial pressure and dP/dt. We conclude that small doses of bradykinin injected into skeletal muscle are capable of reflexly activating the cardiovascular system and that prostaglandins are necessary for the full manifestation of the corresponding hemodynamic response. The pattern of hemodynamic adjustment following bradykinin injection into skeletal muscle is very similar to that induced by static exercise. Therefore, it is possible that intense exercise provides a stimulus for this bradykinin-induced reflex in vivo.

    Title Dynamic Exercise Training in Foxhounds. I. Oxygen Consumption and Hemodynamic Responses.
    Date October 1985
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Ten foxhounds were studied during maximal and submaximal exercise on a motor-driven treadmill before and after 8-12 wk of training. Training consisted of working at 80% of maximal heart rate 1 h/day, 5 days/wk. Maximal O2 consumption (VO2max) increased 28% from 113.7 +/- 5.5 to 146.1 +/- 5.4 ml O2 X min-1 X kg-1, pre- to posttraining. This increase in VO2max was due primarily to a 27% increase in maximal cardiac output, since maximal arteriovenous O2 difference increased only 4% above pretraining values. Mean arterial pressure during maximal exercise did not change from pre- to posttraining, with the result that calculated systemic vascular resistance (SVR) decreased 20%. There were no training-induced changes in O2 consumption, cardiac output, arteriovenous O2 difference, mean arterial pressure, or SVR at any level of submaximal exercise. However, if post- and pretraining values are compared, heart rate was lower and stroke volume was greater at any level of submaximal exercise. Venous lactate concentrations during a given level of submaximal exercise were significantly lower during posttraining compared with pretraining, but venous lactate concentrations during maximal exercise did not change as a result of exercise training. These results indicate that a program of endurance training will produce a significant increase in VO2max in the foxhound. This increase in VO2max is similar to that reported previously for humans and rats but is derived primarily from central (stroke volume) changes rather than a combination of central and peripheral (O2 extraction) changes.

    Title Effect of Prostaglandins on Bradykinin-induced Visceral-cardiac Reflexes.
    Date August 1985
    Journal The American Journal of Physiology
    Excerpt

    We examined the effect of prostaglandins on the reflex cardiovascular response to bradykinin applied to the abdominal organs of anesthetized cats. Bradykinin (10 micrograms/ml) was applied to the serosal surface of the stomach, gallbladder, or jejunum before and after injection of indomethacin (2-10 micrograms/ml iv) and after application of 1 microgram/ml of prostaglandins E1, E2, or F2 alpha (PGE1, PGE2, PGF2 alpha) or prostacyclin (PGI2). In six cats, stimulation of the stomach with bradykinin significantly increased mean arterial pressure (MAP) by 37 +/- 5 (SE) mmHg and maximal dP/dt by 633 +/- 101 mmHg/s. Following indomethacin the bradykinin-induced increases in MAP and dP/dt were significantly reduced to 19 +/- 4 mmHg and 191 +/- 58 mmHg/s, respectively. Treatment with PGE1, PGE2, or PGI2, but not PGF2 alpha, restored the initial bradykinin response. The gallbladder and jejunum responded similarly. Also application of exogenous prostaglandins, PGE2 or PGI2, to the stomach, gallbladder, or jejunum significantly augmented the cardiovascular response to bradykinin. Finally, PGE2 restored a portion of the cardiovascular response to bradykinin following the development of tachyphylaxis. We conclude that prostaglandins are necessary for the full manifestation of the cardiovascular response to bradykinin.

    Title Extracardiac and Coronary Vascular Effects of Digitalis.
    Date June 1985
    Journal Journal of the American College of Cardiology
    Excerpt

    The administration of digitalis glycosides causes a variety of extracardiac effects. In both normal human subjects and in other species, digitalis increases smooth muscle tone of resistance and capacitance vessels. The vasoconstriction is mediated, in part, by a direct action of these glycosides on smooth muscle and, in part, by an increase in alpha-adrenergic tone. Constriction of coronary and splanchnic vessels may lead to myocardial or mesenteric ischemia. In contrast to normal subjects, patients with congestive heart failure demonstrate arteriolar and venodilation in response to these glycosides, possibly because the myocardial effect, to increase cardiac output and peripheral blood flow, overcomes the vasoconstrictor properties of these drugs. Other important actions of digitalis glycosides occur in the central and peripheral nervous systems. Their effects on the area postrema of the medulla oblongata are largely responsible for the alpha-adrenergic-mediated peripheral vasoconstriction, as well as the nausea and vomiting that frequently accompany digitalis intoxication. Actions of glycosides on the cerebral cortex are responsible for the wide range of neurotoxic effects that range from visual disturbances and headaches to seizures and coma. Finally, peripheral neurologic effects of digitalis glycosides on baroreceptor and cardiac afferent fibers may: improve the depressed function of these receptors in the situation of heart failure, and reflexly lower peripheral vascular resistance, thereby partially preventing the vascular constrictor action of these glycosides.

    Title Cardiovascular Effects of Haemorrhagic Shock in Spleen Intact and in Splenectomized Dogs.
    Date February 1985
    Journal Clinical Physiology (oxford, England)
    Excerpt

    Cardiac performance was evaluated during haemorrhagic shock in 27 dogs with spleens intact, 24 splenectomized, and 23 splenectomized transfused dogs that were given a volume of packed red blood cells simulating splenic contraction. Contractile changes were evaluated by calculating dP/dt at 20 mmHg developed pressure (dP/dt DP20), and by relating stroke work to left ventricular end-diastolic volume measured by biplane cinefluorography. Although heart rate increased comparably during early shock, cardiac output, stroke volume, maximal dP/dt, dP/dt DP20, and arterial blood pressure decreased more in splenectomized and splenectomized transfused dogs than in those with spleens intact. During shock dP/dt DP20 was more depressed in the splenectomized and splenectomized transfused dogs than in those with spleens intact. In addition, an increase in left ventricular end-diastolic volume was accompanied by an increase in left ventricular stroke work in dogs with spleens intact. In contrast, stroke work remained depressed in both splenectomized groups despite increased left ventricular volume. Progressive acidosis and decreased left ventricular blood flow were similar in all dogs during haemorrhage. The greater reduction in left ventricular performance during haemorrhagic shock in the splenectomized and splenectomized transfused dogs was not related to excess lactate, changes in plasma volume, or red blood cell mass. Decreased left ventricular performance, despite improved ventricular filling, indicates greater cardiac dysfunction during haemorrhagic shock. This study suggests that, in dogs, the spleen maintains left ventricular performance during haemorrhage by mechanisms other than autotransfusion.

    Title Cardiac Receptors: Their Function in Health and Disease.
    Date December 1984
    Journal Progress in Cardiovascular Diseases
    Excerpt

    Cardiac receptors include both mechanically and chemically sensitive receptors located in atria and in ventricles. Atrial receptors innervated by myelinated vagal afferent fibers reflexly regulate heart rate and intravascular volume. On the other hand, stimulation of ventricular receptors can cause either reflex bradycardia and hypotension or, alternatively, excitation of the cardiovascular system. The former response is mediated by vagal afferents, whereas the latter is mediated by sympathetic (spinal) afferents. Under normal circumstances, cardiac receptors sense changes in wall motion or diastolic pressure and perhaps provide a fine tuning of the cardiovascular system. However, under certain pathological conditions such as coronary ischemia, which cause release of substances such as bradykinin and prostaglandins, there is an exaggerated response of the ventricular receptors. Because these receptors cause a reflex depression of the cardiovascular system and, in particular, induce renal vasodilation, they may protect the heart and kidney by lessening myocardial oxygen requirements and by increasing renal blood flow. In the situation of heart failure both atrial and ventricular receptors are reset and therefore provide for an exaggerated neurohumoral discharge. Finally, patients with aortic stenosis may demonstrate a paradoxical vasodilation and syncope during exercise when there likely is excessive stimulation of left ventricular receptors by the high transmural pressure.

    Title Static Contraction of Hindlimb Muscles in Cats Reflexly Relaxes Tracheal Smooth Muscle.
    Date October 1984
    Journal Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology
    Excerpt

    Static contraction of skeletal muscle is associated with increased ventilation. Although chemical stimulation of afferents from skeletal muscle causes relaxation of tracheal smooth muscle, it is not known if skeletal muscle contraction also causes tracheal relaxation. Therefore, in 10 chloralose-anesthetized cats, I examined the hemodynamic and tracheal smooth muscle responses to hindlimb skeletal muscle contraction induced by stimulating the L7 and S1 ventral roots. Isometric tension was measured in the transverse cervical trachea. During contraction average gastrocnemius tension increased from 0.7 +/- 0.1 to 4.9 +/- 0.6 kg, blood pressure and heart rate increased from 100 +/- 8 to 128 +/- 9 mmHg and from 192 +/- 11 to 202 +/- 13 beats/min, respectively, whereas tracheal tension decreased from 19.7 +/- 0.4 to 17.5 +/- 0.7 g (all P less than 0.02). There were significant (P less than 0.01) linear correlations between change in tracheal tension and maximal developed tension (r = -0.65), tension time (r = -0.68), and average developed tension (r = -0.76). Transection of the L7 and S1 dorsal roots in six cats reduced the tracheal relaxation associated with muscle contraction (pre: 19.9 +/- 0.3 to 17.5 +/- 0.3 g vs. post: 20.3 +/- 0.4 to 20.3 +/- 0.6 g) while average developed gastrocnemius muscle tension was not altered (pre: 1.1 +/- 0.1 to 6.4 +/- 1.1 kg vs. post: 1.2 +/- 0.2 to 6.8 +/- 1.2 kg). Thus static contraction of hindlimb muscles in cats reflexly lowers tracheal tension. This response is related to muscle mass and total tension generated by the contracting skeletal muscle.

    Title Oxygen Consumption and Hemodynamic Responses During Graded Treadmill Exercise in the Dog.
    Date October 1984
    Journal Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology
    Excerpt

    A description is given of a technique that provides a relatively simple means by which O2 consumption and hemodynamic variables can be measured in exercising dogs. We used a multistage submaximal treadmill test to study the responses of 10 foxhounds to dynamic exercise. They were also studied during maximal treadmill exercise. O2 consumption increased from 16.3 +/- 1.7 ml O2 X min-1 X kg-1 at rest to 92.9 +/- 9.7 ml O2 X min-1 X kg-1 at a work load of 6.4 km/h, 20% grade and to 111.9 +/- 9.6 ml O2 X min-1 X kg-1 during maximal exercise. Cardiac output (CO) increased from 6.11 +/- 0.45 l/min at rest to 16.91 +/- 1.46 and 17.66 +/- 0.60 l/min at 6.4 km/h, 20% grade and maximal exercise, respectively. Arteriovenous O2 difference increased from 5.8 +/- 0.3 vol% at rest to 12.0 +/- 0.4 and 13.2 +/- 0.7 vol% at 6.4 km/h, 20% grade and maximal exercise, respectively. Heart rate (HR) increased from 116 +/- 7 beats/min at rest to 250 +/- 8 beats/min at 6.4 km/h, 20% grade and to 278 +/- 6 beats/min during maximal exercise. O2 uptake, CO, and arteriovenous O2 difference increased with the onset of exercise, appeared to level at lower work intensities (6.4 km/h, 4 and 8% grade), and increased significantly at each of the higher work intensities (6.4 km/h, 12, 16, and 20% grade). Additionally, we observed linear relationships between O2 consumption and HR (HR = 1.35 X VO2 + 120.5; r = 0.87; P less than 0.001) and between O2 consumption and CO (CO = 5.91 X VO2 + 216.6; r = 0.96; P less than 0.001). Further, the linear relationship between O2 consumption and CO demonstrated in the present study is similar to that observed in humans.

    Title Chemically Induced Cardiovascular Reflexes Arising from the Stomach of the Cat.
    Date October 1984
    Journal The American Journal of Physiology
    Excerpt

    We examined the potential for cardiovascular reflexes caused by the application of either bradykinin or capsaicin to the serosal or mucosal surface of the stomach. After application to the serosa, bradykinin (10 micrograms/ml) evoked increases in mean arterial pressure of 12 +/- 2 mmHg, heart rate of 5 +/- 1 beats/min, left ventricular dP/dt (at 40 mmHg developed pressure) of 305 +/- 54 mmHg/s and systemic vascular resistance of 0.04 +/- 0.01 PRU. Capsaicin (200 microgram/ml) caused similar cardiovascular responses. There were no cardiovascular responses when either substance was applied to the gastric mucosa. The responses to both chemicals were abolished by celiac ganglionectomy but not by bilateral vagotomy. To determine whether the cardiovascular responses evoked by bradykinin were caused by smooth muscle contraction, we compared the increases in gastric smooth muscle tension and blood pressure elicited by bradykinin, bethanechol, or acetylcholine. Bethanechol and acetylcholine caused greater increases in tension than bradykinin, whereas bradykinin evoked greater increases in blood pressure than either bethanechol or acetylcholine. We conclude that stimulation of gastric afferents by capsaicin or bradykinin causes cardiovascular reflexes, primarily through activation of chemosensitive receptors.

    Title Effects of Bradykinin and Capsaicin on Endings of Afferent Fibers from Abdominal Visceral Organs.
    Date October 1984
    Journal The American Journal of Physiology
    Excerpt

    Stimulation of sensory endings in abdominal visceral organs with capsaicin or bradykinin reflexly increases heart rate, blood pressure, and myocardial contractility through afferent pathways in splanchnic nerves. To determine the afferent fiber types stimulated, we recorded impulses in the right splanchnic nerve in 12 anesthetized cats after either injecting capsaicin (50-200 micrograms) or bradykinin (6.5-20 micrograms) into the descending thoracic aorta or applying pledgets soaked with these chemicals to a visceral organ. We studied 26 A- and 23 C-fibers, each with one receptive field in the mesentery, stomach, duodenum, jejunum, ileum, pancreas, liver, gallbladder, or porta hepatis. Endings of C-fibers generally were mechanically insensitive, whereas endings of A-fibers were mechanically sensitive. After a latency of 10.7 +/- 3.3 s, capsaicin increased the activity of 10 of 26 A-fibers from 2.0 +/- 0.9 to 9.9 +/- 2.6 impulses/s and 23 of 23 C-fibers from 0.2 +/- 0.1 to 13.0 +/- 1.6 impulses/s after a latency of 3.3 +/- 0.9 s. Bradykinin increased the activity of 15 of 26 A-fibers from 2.6 +/- 0.9 to 7.4 +/- 1.5 impulses/s after a latency of 17.0 +/- 1.7 s and 16 of 22 C-fibers from 0.4 +/- 0.2 to 4.7 +/- 1.2 impulses/s after a latency of 19.0 +/- 1.9 s. Capsaicin stimulated significantly more C- than A-fibers (P less than 0.001) and a significantly greater fraction of C-fibers than did bradykinin (P less than 0.007). We conclude that stimulation of splanchnic C-fiber afferents by capsaicin and both A- and C-fiber afferents by bradykinin is primarily responsible for the reflex cardiovascular responses caused by these chemicals.

    Title Reflex Regional Vascular Responses During Passive Gastric Distension in Cats.
    Date September 1984
    Journal The American Journal of Physiology
    Excerpt

    The increase in systemic vascular resistance during gastric distension in cats may result from variable vasomotor responses in several parallel regional vascular beds. Accordingly, in 23 anesthetized cats the stomach was passively distended with a balloon while systemic hemo-dynamics were monitored. Regional vascular responses were determined during control periods and during gastric distension either by injection of radioactive microspheres (15 cats) or by constant perfusion of vascularly isolated organs (8 cats). During distension, mean arterial pressure and systemic vascular resistance increased by 32 and 28%, respectively. Regional flow measurements indicated no significant alterations in any of the organs examined. Calculated regional vascular resistances indicated vasoconstriction in the kidneys (53%), small intestine (31%), and large intestine (37%) that was reversed by alpha-adrenergic blockade with phentolamine. Constant-flow perfusion studies confirmed the regional vasoconstriction in the renal, superior mesenteric, and hindlimb circulations. These studies suggest a regional heterogeneity of vasomotor response during passive gastric distension in cats that includes no change in vascular resistance in some organs and alpha-adrenergic vasoconstriction in others.

    Title Localization of the Cells of Origin for Primary Afferent Fibers Supplying the Gallbladder of the Cat.
    Date July 1984
    Journal Experimental Neurology
    Excerpt

    Horseradish peroxidase was utilized to study the distribution of afferent fibers from the gallbladder in cats. The afferent cell bodies were found in the nodose ganglion and T4 to L1 dorsal root ganglia.

    Title Stimulation of Pancreatic Afferents Reflexly Activates the Cardiovascular System in Cats.
    Date February 1984
    Journal The American Journal of Physiology
    Excerpt

    Chemical stimulation of afferents from the stomach and gallbladder has been shown reflexly to activate the cardiovascular system. It is not known, however, whether stimulating afferents from the pancreas evoke similar reflex activity. Therefore we recorded the cardiovascular responses in cats anesthetized with methoxyflurane, while we applied capsaicin (200 micrograms/ml) and bradykinin (0.001-1,000 micrograms/ml) to the surface of the pancreas. Topically applying these algesic substances evoked cardiovascular responses that included increases in systemic arterial pressure, heart rate, left ventricular dP/dt at 40-mmHg developed pressure and systemic vascular resistance. Bilateral vagotomy at the level of the diaphragm did not diminish the cardiovascular responses evoked by capsaicin or bradykinin. In contrast, removal of the celiac and superior mesenteric ganglia abolished the cardiovascular responses demonstrated previously when capsaicin or bradykinin was applied to the pancreas. We conclude that afferent endings in the pancreas can be stimulated reflexly to increase cardiovascular function in cats. This reflex activation represents a potential mechanism for eliciting the cardiovascular changes observed during acute pancreatitis, particularly the marked vasoconstriction that may lead to renal failure.

    Title Stimulation of Splanchnic Afferents Reflexly Relaxes Tracheal Smooth Muscle in Dogs.
    Date November 1983
    Journal Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology
    Excerpt

    Although chemical stimulation of abdominal visceral afferents has been shown to reflexly increase cardiovascular and ventilatory function, the effect of stimulating these afferents on airway smooth muscle is unknown. Therefore, we recorded transverse smooth muscle tension from an innervated segment of trachea in chloralose-anesthetized dogs while we topically applied capsaicin (200 micrograms/ml) and bradykinin (0.01-10 micrograms/ml) to the serosal surfaces of the stomach, small intestine, and gallbladder. Application of these irritant substances to the stomach and small intestine decreased tracheal tension and increased mean arterial pressure. However, application of capsaicin and bradykinin to the gallbladder had only small effects on both of these variables. Cutting the splanchnic nerves abolished or greatly attenuated the decreases in tension and increases in mean arterial pressure, whereas cutting the vagi had no effect on them. We conclude that stimulation of splanchnic afferent endings in the stomach and small intestine reflexly relaxes tracheal smooth muscle in dogs. This effect may be one component of the constellation of autonomic responses reflexly evoked by abdominal visceral pain and inflammation.

    Title Effects of Static Muscular Contraction on Impulse Activity of Groups Iii and Iv Afferents in Cats.
    Date October 1983
    Journal Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology
    Excerpt

    Static contraction of the hindlimb muscles, induced by electrical stimulation of the ventral roots, reflexly increases arterial blood pressure and heart rate. Although stimulation of groups III and IV muscle afferents is believed to cause these reflex increases, the responses of these afferents to a level of static contraction that increases arterial pressure have not yet been determined. Therefore, in barbiturate-anesthetized cats, afferent impulses arising from endings in the gastrocnemius muscle were recorded from the L7 or S1 dorsal roots, while the cut peripheral end of the L7 ventral root was stimulated. In addition, the effects of capsaicin (100-200 micrograms) and bradykinin (25 micrograms) on the activity of the groups III and IV afferents stimulated by contraction were examined. Contraction of the gastrocnemius muscle to a level equal to or greater than that needed to cause a pressor response stimulated 12 of 19 (63%) group III afferents and 13 of 19 (68%) group IV afferents. However, the discharge patterns of the group III afferents stimulated by contraction were very different from those of the group IV fibers. No relationship was found between those fibers stimulated by contraction and those stimulated by chemicals. Our results suggest that although both groups III and IV muscle afferents contribute to the reflex cardiovascular increases evoked by static exercise, group III fibers were likely to be stimulated by the mechanical effects of muscular contraction, whereas at least some group IV fibers were likely to be stimulated by the metabolic products of muscular contraction.

    Title Bradykinin Stimulates Pancreatic Afferents to Activate the Cardiovascular System.
    Date July 1983
    Journal Transactions of the Association of American Physicians
    Title Cardiovascular Reflexes Arising from the Gallbladder of the Cat. Effects of Capsaicin, Bradykinin, and Distension.
    Date February 1983
    Journal Circulation Research
    Excerpt

    We have studied the cardiovascular responses which can be evoked when the gallbladder is stimulated pharmacologically or mechanically. To determine the potential for reflex cardiovascular activation, we applied capsaicin, a selective thin-fiber agonist, to the serosal surface of the gallbladder. This algesic substance evoked cardiovascular responses which included increases in mean arterial pressure (MAP) by 14%, heart rate (HR) by 3%, left ventricular dP/dt at 40 mm Hg developed pressure (dP/dt DP40) by 14%, and systemic vascular resistance (SVR) by 19%. There were no demonstrable effects on the cardiovascular system when this same substance was applied to the surface of the liver. Bilateral vagotomy at the level of the diaphragm did not alter the responses to capsaicin. Right atrial overdrive pacing did not reduce the positive inotropic effect elicited when the gallbladder was stimulated. Removal of the celiac and superior mesenteric ganglia, or selective denervation of the gallbladder, abolished the cardiovascular responses which were evoked previously. beta-Adrenergic blockade, however, abolished only the reflex chronotropic and intropic responses. Thus, the potential for eliciting reflex cardiovascular alterations by stimulating gallbladder afferents with capsaicin was established. In subsequent studies, stimulating the gallbladder with bradykinin, an endogenous polypeptide, evoked a reflex activation of the cardiovascular system similar to that seen with capsaicin (MAP = 14%; HR = 4%; dP/dt DP40 = 18%; SVR = 14%). These reflex responses were dose dependent, were produced by mucosal as well as serosal application of this substance, and were eliminated by bilateral splanchnic nerve action. In contrast to capsaicin and bradykinin, distension of the gallbladder did not cause any cardiovascular alterations. We conclude that stimulation of gallbladder afferents by the algesic substance capsaicin or by bradykinin, an endogenous substance that under certain conditions may be formed in bile, can induce significant reflex activation of the cardiovascular system.

    Title Sympathoadrenal Mechanisms in Hemodynamic Responses to Gastric Distension in Cats.
    Date December 1982
    Journal The American Journal of Physiology
    Excerpt

    There is presently little information on the efferent mechanisms responsible for the reflex cardiovascular activation during passive gastric distension. Therefore, 40 cats anesthetized with alpha-chloralose were studied with passive gastric balloon distention before and during 1) two repeated gastric distensions, 2) beta-adrenergic blockade with propranolol, 3) alpha-adrenergic blockade with phentolamine, or 4) bilateral adrenalectomy. Before and during each distension mean arterial pressure, heart rate, cardiac output, rate of rise of left ventricular pressure (dP/dt) at 40 mmHg developed pressure and calculated systemic vascular resistance were determined. Repeated gastric distension caused similar hemodynamic responses without tachyphylaxis. beta-Blockade significantly reduced the increase in dP/dt from 893 +/- 362 to 150 +/- 63 mmHg/s. alpha-Blockade significantly altered the changes in mean arterial pressure from 33 +/- 5.0 to -2 +/- 4.7 mmHg and systemic vascular resistance from 0.114 +/- 0.019 to 0.004 +/- 0.031 peripheral resistance units. Bilateral adrenalectomy significantly diminished the contractile response from 525 +/- 107 to 50 +/- 85 mmHg/s but did not significantly alter the pressor and vasoconstrictor responses. We conclude that, during passive gastric distension in cats, the increase in myocardial contractility is mediated by beta-adrenergic-receptor stimulation, whereas the arterial vasoconstrictor and pressor responses are mediated by alpha-adrenergic receptor stimulation. Additionally, during gastric distension a substantial portion of the contractile response is dependent on the integrity of the adrenal glands.

    Title Reflex Relaxation of Tracheal Smooth Muscle by Thin-fiber Muscle Afferents in Dogs.
    Date October 1982
    Journal The American Journal of Physiology
    Excerpt

    Although the reflex cardiovascular and ventilatory responses evoked by stimulation of groups III and IV muscle afferents have been extensively investigated, less is known about the effects of stimulation of these afferents on airway caliber. Therefore, in 11 chloralose-anesthetized dogs, we recorded transverse smooth muscle tension from an innervated segment of the trachea, while we stimulated groups III and IV muscle afferents with capsaicin and bradykinin. Injection of both substances into the arterial supply of the skinned hindlimb evoked dose-dependent decreases in tracheal tension, whereas injection into the femoral vein either increased tension or had no effect on it. Injection of capsaicin and bradykinin into the arterial supply of the gracilis muscle also decreased tracheal tension. In addition, cutting the sciatic, gracilis, and femoral nerves abolished the decreases in tracheal tension caused by injection of capsaicin and bradykinin into the arterial supply of the hindlimb. We conclude that chemical stimulation of groups III and IV muscle afferents causes reflux relaxation of tracheal smooth muscle in dogs.

    Title Reflex Cardiovascular Depression Induced by Capsaicin Injection into Canine Liver.
    Date August 1982
    Journal The American Journal of Physiology
    Excerpt

    Capsaicin was injected into the portal circulation of 29 dogs after a blood delay pathway was constructed between the liver and right heart, through which capsaicin-contaminated blood could be replaced while systemic hemodynamics were maintained constant. Capsaicin (500 micrograms) rapidly decreased left ventricular systolic pressure (-10%), mean arterial pressure (-12%), heart rate (-4%), renal vascular resistance (-7%), maximal rate of left ventricular pressure rise (dP/dtmax) (-12%), and dP/dt at 25 mmHg developed left ventricular pressure (-15%) in animals with paced hearts. Left ventricular end-diastolic pressure did not change. Vagus nerve interruption at the level of the diaphragm did not alter hemodynamic changes occurring during capsaicin injections, but anterior hepatic nerve interruption eliminated the changes, suggesting that the cardiovascular responses were reflex in origin and that the principal afferent pathway traverses the hepatic nerve. This study demonstrates that activation of afferent fiber receptors within the liver tissue can contribute to neural regulation of the cardiovascular system, but the natural stimulus for these receptors is not known.

    Title Total Plasma Creatinine: an Accurate Measure of Total Striated Muscle Mass.
    Date April 1982
    Journal Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology
    Excerpt

    Creatinine is a metabolite unique to striated muscle. Measurement of 24-h urinary creatinine excretion is an established method for estimating striated muscle mass. However, accurate assessment of urinary creatinine excretion is often impractical. We investigated the hypothesis that total plasma creatinine could be used instead of urinary creatinine excretion to estimate body composition. In 24 men, plasma volume and plasma creatinine concentration were measured, and total plasma creatinine was calculated as the product of these two measurements. Other measurements included urinary creatinine excretion, total body water, and anthropometry. Total plasma creatinine correlated strongly with urinary creatinine excretion (r = 0.82) and with weight, total body water, and anthropometrically estimated lean body mass. Muscle mass could be predicted by the equation: 0.88 x total plasma creatinine (mg). To verify this relationship, total plasma creatinine was prospectively measured in four dogs, then their total striated muscle was removed and weighed. Predicted muscle mass was within +/- 3.9% (range = 0.5-10.8%) of observed muscle mass. The ability to estimate muscle mass conveniently and accurately from total plasma creatinine should prove valuable for future studies in physiology and body composition.

    Title Effects of Capsaicin and Bradykinin on Afferent Fibers with Ending in Skeletal Muscle.
    Date March 1982
    Journal Circulation Research
    Excerpt

    Capsaicin, injected into the arterial supply of the skinned hindlimb of dogs, evokes reflex increases in cardiovascular function. Moreover, the cardiovascular reflexes evoked by capsaicin are very similar to those evoked by static exercise. The afferent fibers initiating these reflex increases have not been identified electrophysiologically, although their endings are believed to be located in skeletal muscle. We have, therefore, attempted to determine which afferent fibers are stimulated by capsaicin. In anesthetized dogs, we recorded impulses from afferent fibers with endings in either the gastrocnemius or gracilis muscles and injected capsaicin (10-30 microgram/kg) into the abdominal aorta. Capsaicin stimulated 24 of 34 group IV (C fiber) endings, but only 5 of 19 group III (A delta fiber) endings. By contrast, bradykinin (0.5-1.5 microgram/kg) stimulated 17 of 33 group IV endings and 9 of 19 group III endings. Impulse activity for the 24 group IV afferents stimulated by capsaicin increased from 0.7 +/- 0.1 to a peak of 9.3 +/- 1.4 imp/sec. Firing started 6 +/- 1 seconds after injection and remained above control levels for 24 +/- 5 seconds. Capsaicin had no significant effect on the firing rate of 30 group I and II muscle afferents. Our results suggest that group IV muscle afferents are primarily responsible for causing the reflex increases in cardiovascular function evoked by injecting capsaicin into the arterial supply of the skinned hindlimb of dogs. Moreover, capsaicin is likely to be a useful pharmacological tool with which to determine the reflex autonomic effects caused by stimulation of group IV muscle afferents.

    Title Static Exercise in Anesthetized Dogs, a Cause of Reflex Alpha-adrenergic Coronary Vasoconstriction.
    Date January 1982
    Journal Basic Research in Cardiology
    Excerpt

    The coronary blood flow and vascular resistance responses to static hindlimb exercise were studied in 11 anesthetized dogs after beta- and combined alpha- and beta-adrenergic blockade to determine if this stress causes coronary vasoconstriction. After beta-blockade static exercise increased the blood pressure and double product, but decreased the right and left ventricular (LV) coronary blood flow and increased the coronary vascular resistance. These vascular changes primarily occurred in the epicardial and mid-myocardial but not the endocardial layers of the LV. Following combined alpha- and beta-adrenergic blockade, the systemic hemodynamic and coronary flow and resistance changes were abolished. These data suggest that alpha-adrenergic mediated coronary vasoconstriction occurs during static hindlimb exercise in dogs.

    Title Chronic Training with Static and Dynamic Exercise: Cardiovascular Adaptation, and Response to Exercise.
    Date July 1981
    Journal Circulation Research
    Excerpt

    To determine the acute and chronic effects of static and dynamic exercise upon the cardiovascular system, two groups of athletes were studied and compared to untrained control individuals. Thus, 12 long distance runners (LDR) and 17 competitive weight lifters (CWL) were compared to 10 light controls (LC) and 14 heavy controls (HC). The echocardiographically measured left ventricular mass (LVM) was shown to be increased in both groups of athletes. When this mass was related to lean body mass, the LDR demonstrated a significantly increased LVM, whereas the CWL had a LVM similar to that of the HC. During static handgrip exercise, the LDR maintained a relative bradycardia and, consequently, a lower calculated double product when compared to the LC, whereas the CWL reacted similarly to the HC. Further, the LDR demonstrated higher end-diastolic and higher end-systolic volume indices than the LC during static exercise. The exercising stroke volume index and the cardiac index were, however, not significantly different in the LDR compared to the LC. In contrast to the LDR, the cardiovascular dynamics of the CWL changed in a manner very similar to that of the HC during static exercise. This information suggests, therefore, that endurance training alters both the absolute and relative left ventricular mass and the response of the cardiovascular system to static exercise. On the other hand, static exercise training increases the absolute but not the relative left ventricular mass. Also, the immediate hemodynamic response to static exercise is similar in athletes who train with this form of exercise compared to untrained control subjects.

    Title Cardiovascular Reflexes Elicited by Passive Gastric Distension in Anesthetized Cats.
    Date June 1981
    Journal The American Journal of Physiology
    Excerpt

    Hemodynamic responses to passive gastric distension were examined in alpha-chloralose anesthetized cats. Gastric balloons were distended with 37 degrees C fluid at slow (50 ml/min) and rapid (250 ml/min) infusion rates before and after laparotomy. Passive gastric distension at the slow infusion rate significantly (P less than 0.05) increased mean arterial pressure (MAP) by 28%, dP/dt at 40 mmHg developed pressure by 29%, and systemic vascular resistance (SVR) by 35%. Likewise, the rapid distension rate significantly (P less than 0.05) increased MAP (20%), dP/dt (16%), and SVR (23%). Heart rate, aortic flow, and left ventricular end-diastolic pressure remained unchanged at both distension rates. Cardiovascular responses to passive gastric distension were similar before and after laparotomy. Section of the vagus nerve at the diaphragm did not alter the responses, whereas abdominal splanchnic nerve section significantly (P less than 0.05) reduced the changes in mean arterial pressure and dP/dt. These results indicate that passive gastric distension in the cat elicits cardiovascular reflexes sufficient to increase myocardial oxygen demand. Such a reflex response could potentially contribute to postprandial angina in humans.

    Title Reflex Alpha-adrenergic Coronary Vasoconstriction During Hindlimb Static Exercise in Dogs.
    Date April 1981
    Journal Circulation Research
    Excerpt

    We studied 18 alpha-chloralose-anesthetized dogs to determine if alpha-adrenergic coronary vasoconstriction occurs with hindlimb static exercise. Exercise was elicited by spinal cord ventral nerve root stimulation. Regional coronary blood flow was determined by the radioactive microsphere method. Animals were studied under four experimental conditions: control rest and static exercise, rest and static exercise after beta-adrenergic blockade with propranolol (2 mg/kg), rest and exercise after alpha-adrenergic blockade with phentolamine (.35 mg/kg), and rest and exercise after combined alpha- and beta-adrenergic blockade. Myocardial oxygen consumption during exercise was determined during control and during alpha-adrenergic blockade conditions. Control hindlimb static exercise resulted in significant increases in systolic (10.6%) and diastolic (12.5%) arterial pressures, heart rate (12.2%), and double product (24.6%). Associated with the increased demand for oxygen, myocardial oxygen consumption increased (33.6%) as did left ventricular myocardial flow (29.6%). However, left ventricular coronary vascular resistance was unchanged during static exercise. After beta-adrenergic blockade, systolic (12.2%) and diastolic (11.6%) arterial pressures and double product (10.7%) still increased significantly, but heart rate did not change with static exercise. In contrast, alpha-adrenergic vasoconstriction was unmasked as left (LV) and right (RV) ventricular myocardial blood flow decreased (LV: -30.0%, RV: -25.0%) and coronary vascular resistance increased (LV: 52.5%, RV: 45.3%) with static exercise. Combined alpha- and beta-adrenergic blockade abolished the reduction in myocardial blood flow and the increase in coronary vascular resistance which occurred with static exercise after beta-adrenergic blockade. These data suggest that, during static exercise, reflexes from skeletal muscles can cause alpha-adrenergic coronary artery vasoconstriction.

    Title Cardiovascular Responses to Static Exercise in Distance Runners and Weight Lifters.
    Date February 1981
    Journal Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology
    Excerpt

    Sixty individuals including 17 competitive weight lifters (CWL), 12 competitive long-distance runners (LDR), 7 amateur (noncompetitive) weight lifters (AWL), 14 heavy controls (HC), and 10 light controls (LC) were studied at supine rest and during static exercise at 40% of maximal voluntary contraction. Blood pressures were similar in all groups at rest (R) and exercise (EX), but the heart rate (HR) and calculated double product (DP) of the LDR were lower at rest (HR: 53 +/- 2.9 beats/min, DP: 6,346 +/- 402) and at fatigue (HR: 78 +/- 5.4 beats/min. DP: 12,739 +/- 1,011) compared to the control group (R-HR: 69 +/- 2.2 beats/min, DP: 8,553 +/- 372; EX-HR: 97 +/- 3.5 beats/min, DP: 16,345 +/- 836). The LDR demonstrated higher end-diastolic volume index (EDVI) and higher end-systolic volume index (ESVI) at rest (EDVI: 84 +/- 3.7, ESVI: 31 +/- 2.7 ml/m2) and at the time of fatigue (EDVI: 90 +/- 5, ESVI: 37 +/- 2.7 ml/m2) compared to the LC group (R-EDVI: 61 +/- 4.4, ESVI: 22 +/- 2.2; EX-EDVI: 75 +/- 3.4, ESVI: 27 +/- 3.2 ml/m2). The CWL, AWL, and control groups had similar HR, DP, and cardiac volumes at rest and during exercise. These data suggest that competitive endurance (dynamic exercise) training alters the cardiovascular response to static exercise. On the other hand, weight lifting (static exercise) training does not alter the cardiovascular response to static exercise.

    Title The Spinal Cord Ventral Root: an Afferent Pathway of the Hind-limb Pressor Reflex in Cats.
    Date November 1980
    Journal The Journal of Physiology
    Excerpt

    1. In anaesthetized cats the sciatic nerve was cut and the central end was stimulated at a high frequency and voltage. This caused an increase in arterial blood pressure and a rise in heart rate. The pressure response was diminished by dorsal root section but not completely eliminated until ventral root section (L4-S3). The tachycardia response was abolished by dorsal root section alone. 2. In other cats capsaicin was injected intra-arterially into the hind limb, causing elevations in both blood pressure and heart rate. Similar to the sciatic nerve stimulation experiments, the pressor response was principally reduced by dorsal root section but was further significantly decreased by ventral root section (L1-S3). The rise in heart rate was prevented by dorsal root section alone. 3. It is concluded that, in cats, the afferent pathway of the pressor response to sciatic nerve stimulation and to hind-limb capsaicin injection are conducted principally in the dorsal roots but also to a small extent in the ventral roots of the spinal cord. Although the tachycardia response appears to be conducted only through the dorsal roots, it is possible that at lower resting heart rates and by stimulation of a large population of the unmyelinated skeletal muscle afferents, the ventral root is a functional pathway.

    Title Exercise-induced St Elevation in Patients Without Myocardial Infarction.
    Date September 1979
    Journal Circulation
    Excerpt

    A review of 6040 consecutive exercise tests yielded 106 patients without previous myocardial infarction (MI) who had exercise-induced ST elevation (greater than or equal to 0.5 mm in a 15-lead ECG system). In 46, ST elevation was correlated with left ventriculography and coronary angiography. Coronary artery disease (CAD) (greater than or equal to 70% narrowing) was detected in 40 of 46 patients: 12 patients had one-vessel disease, 13 had two-vessel disease, and 15 had three-vessel disease. Resting ventriculograms were normal in 36 of 40 patients. Of 21 patients with anterior (V1-V3) ST elevation, 86% had a left anterior descending (LAD) obstruction and 78% had obstruction proximal to the first diagonal branch. LAD disease occurred significantly more frequently than right and circumflex CAD. There was no anatomic correlation of three persons with lateral (leads V4--6, I or aVL) or 27 patients with inferior-posterior (leads II, III, aVF, Y or Z) exercise-induced ST elevation. Therefore, exercise-induced ST elevation is strongly correlated with CAD but not resting wall motion abnormalities. Further, anterior exercise-induced ST elevation in patients without a previous MI often predicts a significant proximal LAD obstruction.

    Title Reflex Control of the Circulation by Afferents from Skeletal Muscle.
    Date January 1979
    Journal International Review of Physiology
    Excerpt

    Functionally, the pressor reflex, rather than the depressor reflex, appears to be the normal physiologic response to exercise. Available data indicate that chemoreceptors, probably in the form of free nerve endings, are stimulated by local factors, e.g., hypoxia or hyperkalemia. Impulses from these receptors are mediated by group IV afferent nerves to the central nervous system. Then, through efferent sympathetic and parasympathetic nerves, systemic blood pressure, cardiac output, heart rate, and myocardial contractility all increase. The baroreceptors tend to modify the reflex increase in heart rate. The potential significance of local control of the systemic circulation by neural reflexes from skeletal muscle is apparent when one considers that during exercise local control allows both rapid and precise control of the circulation from the metabolically active region of the body. However, the exact role of neural reflexes from skeletal muscle during voluntary exercise still remains to be defined. Clearly, more studies are necessary to elucidate fully their function in the overall control of the circulation in conscious animals and man.

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