Muscarinic activation causes biphasic inotropic response and decreases cellular Na+ activity in canine cardiac Purkinje fibers.

In this study, the effects of carbachol (CCh) on twitch tension, intracellular Na+ activity (aiNa), and action potential were simultaneously measured in canine cardiac Purkinje fibers in order to examine the regulation of inotropy through muscarinic receptors and its relation to aiNa. In fibers driven at 1 Hz, CCh (10 microM) initially and transiently decreased and then increased the twitch tension by 36 +/- 8%. The action potential showed a significant elevation of the plateau and a significant shortening of the duration at 90% repolarization (APD90), from 403 +/- 7 to 389 +/- 7 ms. The aiNa decreased from 7.4 +/- 0.4 to 6.7 +/- 0.3 mM (n = 23, p < 0.05). Atropine (1 microM) decreased the twitch tension by 21 +/- 6% (n = 7, p < 0.05) without significant effects on the action potential and aiNa, and inhibited the effects of CCh. Cs+ (20 mM) increased the plateau height and APD90, enhanced the twitch tension by 66 +/- 24%, but decreased aiNa from 7.3 +/- 0.3 to 6.3 +/- 0.4 mM (n = 6, p < 0.05). In the presence of 20 mM Cs+, some fibers generated slow responses. The addition of 10 microM CCh further increased the twitch tension and APD90, and decreased aiNa from 6.3 +/- 0.4 to 5.3 +/- 0.3 mM. Ouabain (0.3 microM) increased the twitch tension and aiNa, and inhibited the CCh-induced decrease of aiNa. In the presence of ouabain, 20 mM Cs+ depolarized the fiber and generated slow responses with a decreased aiNa. The addition of 10 microM CCh enhanced the slow action potential, and increased aiNa although there was a transient decrease during early exposure. These results suggest that activation of muscarinic receptors in canine Purkinje fibers results in an enhancement of the Na+-K+ pump activity and a biphasic inotropic response, probably via different receptor subtypes. The inhibitory effect, most likely through M2 receptors, is associated with the activation of K+ channels. The stimulatory effect, on the other hand, is probably due to the action on the M1 receptors, resulting in increases in Ca2+ currents.