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

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.