Abstract

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 μM 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 ≥300 nM but not ≤100 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 ∼75% 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 ∼25% of the maximum effect of CCh. The sinus rate in the presence of 1 μM CCh and 300 nM tertiapin was similar to that in the presence of 2 mM CsCl, a blocker of the hyperpolarization-activatedI_f current. Furthermore, no tertiapin-insensitive component existed in the presence of 2 mM CsCl. Therefore, the negative chronotropic effect of ≥300 nM CCh is mainly mediated by K_ACh channels, whereas that of ≤100 nM CCh may result from suppression of the I_f current.