Activation Of Cardiac Vagal Afferents Research Articles

Cardiac Vagal Afferent Response in Rats during Cardiac Contractility Modulation (CCM)

Congestive heart failure (CHF) is responsible for substantial cardiac morbidity and mortality. Cardiac Contractility Modulation (CCM) delivers non‐excitatory endocardial electrical pulses during the refractory period. CCM enhances cardiac contractility, ejection fraction, and quality of life in patients. The underlying mechanism of action for these benefits is not fully understood. Since similar impulses delivered to the gut increase muscle contraction leading to activation of vagal afferents, we tested the effect of CCM on vagal afferent activity in the heart.HypothesisCCM results in an increase in activity of cardiac vagal afferent nerves. Since CCM is non‐excitatory, we speculate that CCM reflexly activates vagal afferents via increases in contractility, reducing excessive efferent sympathetic tone in CHF.MethodsAdult male Sprague‐Dawley rats under pentobarbital anesthesia were instrumented for extracellular recordings of cardiac vagal afferent firing during CCM stimulation of the left ventricle (4V or 7.5V for 60s).ResultsIn 18 vagal nerve fibers with cardiac receptive fields, CCM produced an intensity dependent increase (p<0.05) in firing frequency of 10 fibers (4.2 ± 1.2 Hz at 7.5V vs. 1.4 ± 0.66 Hz at baseline). 6 neurons were not affected by CCM. In two neurons, 4V stimulation increased while 7.5V had no effect on single fiber firing.ConclusionCCM, a new therapy for CHF elicits activation of cardiac vagal afferents. This likely results from a reflex increase in regional contractility, contributing to the clinical benefit of CCM via an increase in vagal afferent and reduced sympathetic tone. Supported by Impulse Dynamics, Inc.

Activation of cardiac afferents by arachidonic acid: relative contributions of metabolic pathways.

Arachidonic acid (AA) is metabolized via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 (CP450) pathways to a variety of bioactive products. The sensitivity of cardiac afferent endings to AA and its metabolites, especially those derived from LOX and CP450 pathways, is currently unclear. We examined AA-induced activation of cardiac vagal chemosensitive afferents in non- and postischemic hearts in rats and evaluated the relative contributions of the three metabolic pathways to the effects. Epicardial application of AA activated the cardiac afferents dose dependently in both nonischemic and postischemic hearts, with afferent responses greater in the latter condition. In nonischemic hearts, the afferent response to AA was abolished only after simultaneous administration of indomethacin and 17-octadecynoic acid (COX and CP450 inhibitors, respectively). Nordihydroguaiaretic acid (a LOX inhibitor) had no effect on the afferent response to AA. In postischemic hearts, abolition of the afferent response to AA required simultaneous blockade of all three pathways. None of the AA metabolic inhibitors affected resting activity of cardiac afferents in nonischemic hearts, but each suppressed afferent activity during ischemia-reperfusion. Most COX metabolites, CP450 metabolites, and 5-LOX metabolites tested were capable of activating cardiac afferents. The 12-LOX metabolites and 15-LOX metabolites had no effect on afferent activity. These data indicate that in the nonischemic heart, basal AA metabolism does not contribute to resting afferent activity, but AA is capable of activating cardiac afferents via COX and CP450 but not LOX pathways. During ischemia-reperfusion, all three metabolic pathways contribute to activation of cardiac vagal afferents with an enhanced responsiveness to AA. Our results suggest that induction of the 5-LOX pathway contributes to the enhanced sensitivity of cardiac vagal afferents to AA in the ischemic condition.

Cardiac sympathetic afferent activation provoked by myocardial ischemia and reperfusion. Mechanisms and reflexes.

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.

Intrapericardiac injections of algogenic chemicals excite primate C1-C2 spinothalamic tract neurons.

Extracellular potentials of 38 C1-C2 spinothalamic tract (STT) neurons in anesthetized monkeys (Macaca fascicularis) were examined for responses to intrapericardiac injections of an algogenic chemical mixture (adenosine, 10(-3) M; bradykinin, prostaglandin E(2), serotonin, histamine, each 10(-5) M). Chemical stimulation of cardiac/pericardiac receptors increased activity of 21 cells, decreased activity of 5 cells, and did not change activity of 12 cells. Cells excited by chemical stimuli received input from noxious mechanical stimulation of somatic fields; most receptive fields included the neck, inferior jaw, or head areas. Nerve ablations in 11 cells excited by intrapericardiac chemicals showed that cardiac input activated by algogenic chemicals traveled primarily in vagal afferent fibers to C1-C2 segments; phrenic or cardiopulmonary sympathetic inputs were predominant in 2 of 11 cells. These results supported the concept that activation of cardiac vagal afferents might lead to the production of referred pain sensation in somatic fields innervated from high cervical segments.

Activation of cardiac vagal afferents facilitates late vagal inhibition in neurones of the rostral ventrolateral medulla oblongata bilaterally

A reduced activity of cardiac vagal afferent fibres is considered as one of the pathophysiological causes of post-infarction complications [A. Head, Baroreflexes and cardiovascular regulation in hypertension. J. Cardiovasc. Pharmacol. 26 (1995) S7–S16]. The mechanism of how a reduction of cardiac vagal activity leads to enhanced sympathetic drive and systemic hypertension is however not yet clear. Experimental data have shown that the rostral ventrolateral medulla oblongata (RVLM) plays an important role in tonic blood pressure regulation, the control of sympathetic vasoconstriction and cardiac performance. The aim of the study was to determine whether activation of cardiac vagal afferents contributes to eliciting the long-lasting late inhibition that we have previously shown to occur in neurones of the RVLM [A. Zagon, K. Ishizuka, I. Rocha, K.M. Spyer, Late vagal inhibition in neurones of the ventrolateral medulla oblongata in the rat. Neurosci. 92 (1999) 877–888]. The experiments were carried out in terminally anaesthetised and artificially ventilated rats using in vivo intracellular recordings. The data confirmed that late vagal inhibition is elicited by cumulative activation of functionally different vagal afferents, including those that originate from cardiac receptors. It was also demonstrated that activation of cardiac afferents could lead to a significant increase in the duration of this long-lasting late response component. Facilitation of late vagal inhibition was observed in RVLM neurones both ipsi- and contralateral to the stimulated nerve. It is suggested that such facilitation of late vagal inhibition may be a mechanism of how pulse-synchronous activation of cardiac afferents leads to a tonic modulation of the activity of RVLM neurones. An attenuation of late vagal inhibition during reduced activity of cardiac vagal afferents could lead to enhanced excitability in these neurones which in turn can lead to an increase in medullary sympathetic outflows towards the heart and peripheral blood vessels.

Activation of cardiac vagal afferents in ischemia and reperfusion. Prostaglandins versus oxygen-derived free radicals.

Myocardial ischemia and reperfusion can evoke excitation of cardiac vagal nerve endings and activation of a cardiogenic depressor reflex (Bezold-Jarisch effect). We postulate that oxygen-derived free radicals, which are known to be produced during prolonged ischemia and reperfusion, contribute to this afferent excitation. We recorded activity from 47 chemosensitive vagal afferent fibers in 31 rats; the endings of these fibers were located in the left ventricle. Chemosensitive endings were identified with topical applications of capsaicin (10 micrograms) to the surface of the heart. Reactivity of the endings to oxygen-derived free radicals was assessed by topical application of H2O2 (3 to 9 mumol). Activity of the vagal fibers was recorded during 30 minutes of occlusion of the left anterior descending coronary artery (LAD) and 10 minutes of subsequent reperfusion. The activity of chemosensitive endings within the ischemic zone increased in the first 2 minutes of LAD occlusion from 2.2 +/- 0.4 to 4.3 +/- 0.9 impulses per second (107 +/- 30% increase, P < .05). This increased activity waned after 3 to 5 minutes of occlusion. Endings outside the ischemic zone did not increase, their activity at the beginning of ischemia. Reperfusion caused a rapid elevation of activity only in chemosensitive fibers whose endings were found to respond to topical H2O2. The reperfusion-sensitive endings were located both within and outside the ischemic zone of the left ventricle. Indomethacin (5 mg/kg i.v., 20 minutes before occlusion) effectively prevented activation of chemosensitive afferent endings at the beginning of LAD occlusion regardless of their sensitivity to H2O2 but had no effect on the activation at reperfusion.

Activation of cardiac vagal afferents by oxygen-derived free radicals in rats.

Myocardial ischemia and reperfusion can evoke excitation of cardiac vagal afferent nerve endings and activation of a cardiogenic depressor reflex (Bezold-Jarisch effect). We postulate that oxygen-derived free radicals, which are well known to be produced during prolonged ischemia and reperfusion, contribute to this excitation. Hydroxyl radicals derived from hydrogen peroxide (H2O2) activate abdominal sympathetic afferents and produce reflex excitation of the cardiovascular system. However, it is not known whether inhibitory vagal cardiac afferents are activated by oxygen-derived free radicals. We recorded activity from 52 single vagal afferent fibers in 29 rats; the endings of these fibers were located in the walls of all four chambers of the heart. Thirty-three (63%) of these fibers were classified as chemosensitive C-fiber endings because of their irregular discharge under resting conditions, their activation in response to the topical application of capsaicin (1 to 10 micrograms) to the surface of the heart encompassing the receptive field, and their conduction velocities. Fourteen (27%) of the remaining fibers were found to be mechanoreceptors. Topical application of H2O2 to the heart activated 50% of the chemosensitive endings and did not directly affect cardiac mechanoreceptors. Activity increased by 498% at a dose of 3 mumol (P < .001). This effect was reproducible and dose dependent and was not due to [H+]. Topical application of xanthine/xanthine oxidase (20 mmol/0.03 mU) activated 8 of the 12 chemosensitive fibers tested and had no direct effect on mechanosensitive fibers. Activity increased by 287% (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of Reflex Vasoconstriction after Experimental Coronary Embolization in the Dog

The possibility that failure of vascular resistance to increase contributes to hypotension after myocardial infarction was examined in the hindlimbs of dogs following embolization of the coronary arteries. Vascular resistance did not change significantly during sustained severe hypotension after embolization in either the intact hindlimb or in simultaneously autoperfused innervated and denervated hindlimbs using constant flow. In nonembolized animals, an immediate large increase in hindlimb vascular resistance occurred when equivalent hypotension was produced by stimulation of the distal end of the sectioned vagus nerve. Lack of such response during hypotension after embolization suggested that inhibition of reflex vasoconstriction had occcurred. Bilateral cervical vagotomy allowed normal reflex vasoconstriction to proceed during hypotension after infarction. These data indicate that (1) since vascular resistance is unchanged in both innervated and denervated hindlimbs, normal neurogenic vascular tone is sustained during hypotension after myocardial infarction and (2) the baroreceptor reflex, which normally promotes vasoconstriction during hypotension, is inhibited reflexly following myocardial infarction, probably by activation of cardiac vagal afferents.