Effects of the spatial dispersion of acetylcholine release on the chronotropic responses to vagal stimulation in dogs.

Abstract

We determined the effects of changing the spatial dispersion of acetylcholine release on the phase-dependent chronotropic responses to vagal stimulation in anesthetized dogs. We stimulated the vagus nerves with one brief burst of electrical pulses each cardiac cycle, and we changed the timing of the stimulus by a small, constant amount each cardiac cycle to scan the entire cycle. To vary the heterogeneity of acetylcholine release, we changed the voltage of the stimulus pulses over a range of submaximal values. To achieve the maximum homogeneity of acetylcholine release, we used supramaximal voltages, and we varied the level of acetylcholine release from each excited fiber by changing the number of pulses per burst. We used the average cardiac cycle length of the phase-response curve to assess the overall vagal effect, independent of its timing within the cardiac cycle. We found that the amplitude of the phase-response curve varied directly and the minimum-to-maximum phase difference varied inversely with the overall efficacy of vagal activity. However, for any given alteration in the overall efficacy, the specific changes in the characteristics of the phase-response curve did not depend on whether the alteration was achieved by varying the number of pulses per burst or by varying the stimulus voltage. Therefore, we conclude that although the cardiac chronotropic response is very sensitive to changes in the timing of vagal stimulation, it is not influenced appreciably by the spatial dispersion of acetylcholine release from the vagal nerve endings over a wide range of stimulation strengths.

Subtype-selective blockade of cardiac muscarinic receptors inhibits vagal chronotropic responses in cats

“…Previous studies have reported on considerable reductions in the responsiveness of the cardiac pacemaker to vagal chronotropic effects after small changes in the timing of vagal stimulation over a certain specific phase of the cardiac cycle [25,[43][44]. In the present study, when a vagal burst of six pulses was delivered at 180-200 ms before the next P wave of the ECG, a small (∼25 ms; Fig.…”

“…First, changes in the timing of vagal stimulation throughout the cardiac cycle produce variations in effective concentrations of acetylcholine at the sinoatrial node due to rapid hydrolysis by acetylcholinesterase [10][11]. Because of the short half-life of neurally released acetylcholine in the cardiac neuroeffector junction [10,27,35], a vagal burst delivered at a short P-Stimulus interval over the initial portion of the cardiac cycle produces a chronotropic response that is of a lower magnitude as compared to those elicited by vagal bursts applied at progressively later periods [25,20,[43][44]. This is consistent with results of the present study (Fig.…”

“…*P<0.05 vs corresponding basal value pacemaker discharge, the conductance changes induced by neurally released acetylcholine could not overcome the already activated inward current responsible for depolarization of pacemaker cells. This explains the considerable reduction in a chronotropic response in a given P-P interval of the ECG when the moment of vagal stimulation is changed over a certain critical time in the cardiac cycle [25,[43][44]. This critical time precedes the next P wave of the ECG by an interval equal to the latency of the vagal chronotropic effect, which is determined by the duration of a number of processes such as vagal impulse transmission, the diffusion of neurally released acetylcholine at the cardiac neuroeffector junction, and acetylcholine-induced changes in the conductance of pacemaker cells [24].…”

“…2a) reduction in elicited lengthening of the cardiac cycle. The increment in P-Stimulus interval which is necessary to produce a change of the vagal chronotropic response from its maximal to minimal values (the maximum-to-minimum phase difference) is thought to reflect the degree of synchronization of electrical activity of pacemaker cells [43][44]. If the upstroke of the action potential is generated almost simultaneously in various pacemaker cells (tight synchronization), then even very small (just a few milliseconds) increments in P-Stimulus interval over a specific phase of the cardiac cycle result in delivery of the vagal burst at a time point at which the majority of pacemaker cells are already depolarized, and hence, no longer responsive to vagal stimulation during that cardiac cycle.…”

“…Vagal stimulation with brief bursts of pulses elicits varying degree of cardiac slowing depending on the time at which the vagal burst is delivered throughout the cardiac cycle [24][25][43][44]. Importantly, in previous studies utilizing subtype-selective muscarinic cholinoreceptor antagonists [1,3,14,19,28,33], long trains of pulses rather than brief, phase-coupled stimulation bursts were used for vagal stimulation, and the average magnitude of vagally induced bradycardia rather than beat-to-beat changes in cardiac cycle length was assessed.…”