The role of muscarinic K+ channels in the negative chronotropic effect of a muscarinic agonist

Acetylcholine causes bradycardia through M2 muscarinic receptors in sinoatrial node cells. I examined with electrocardiogram how the muscarinic K+ (K-ACh) channel participates in the sinus bradycardia induced by a muscarinic agonist in the Langendorff preparation of rabbit hearts. In the presence of 100 nM propranolol, 1 nM to 10 muM carbachol (CCh) induced sinus bradycardia in a concentration-dependent manner. Tertiapin (100 or 300 nM), which selectively blocks K-ACh channels in cardiac myocytes, significantly inhibited the effect of greater than or equal to300 nM but not less than or equal to100 nM CCh. The effect of CCh was divided into tertiapin-sensitive and -insensitive components. The former component was induced by > 100 nM CCh in a concentration-dependent manner and accounted for similar to75% of the maximum effect of CCh. The K-ACh channel in atrial myocytes was also activated by this range of concentrations of CCh as measured with the patch-clamp method. The tertiapin-insensitive component was induced by 1 to 300 nM CCh in a concentration-dependent manner and accounted for similar to25% of the maximum effect of CCh. The sinus rate in the presence of 1 muM CCh and 300 nM tertiapin was similar to that in the presence of 2 mM CsCl, a blocker of the hyperpolarization-activated If current. Furthermore, no tertiapin-insensitive component existed in the presence of 2 mM CsCl. Therefore, the negative chronotropic effect of greater than or equal to300 nM CCh is mainly mediated by K-ACh channels, whereas that of less than or equal to100 nM CCh may result from suppression of the I-f current.