Role of Muscarinic K Channels in Parasympthetic Regulation of Heart Beat

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I found that honey bee toxin, tertiapin selectively blocks muscarinic K+ (KACh) channels in cardiac myocytes. Thus, I analyzed how tertiapin modulates the negative chronotropic effect of carbachol in isolated rabbit hearts perfused with Langendorff apparatus. In the presence of propranolol (100 nM), carbachol (1 nM - 10 μM) induced sinus bradycardia in a concentration-dependent manner. Tertiapin (300 nM) partially inhibited the effect of carbachol. The tertiapin-sensitive and -insensitive components were respectively induced by * 100 nM and > 1 nM carbachol in a concentration-dependent manner, and accounted for 〜75 and 〜25 % of the effect of 10 μM carbachol. Because the baroreflex is mediated by KACh channels, the present data indicate that the parasympathetic nerve termini secrete a relatively large quantity of acetylcholine in the baroreflex. The tertiapin-insensitive component seemed to arise from inhibition of a hyperpolarization-activated nonselective cation current caused by a decrease in a basal cAMP level by carbachol. In the presence of isoproterenol (100 nM), the tertiapin-sensitive and -insensitive components were respectively induced by * 10 nM and > 1 nM carbachol in a concentration-dependent manner, and both accounted for 〜50 % of the effect of 10 μM carbachol. Therefore, the contribution of inhibition of adenylate cyclase to the negative chronotropic effect of muscarinic receptor stimulation became larger, while that of KACh currents became smaller in the presence than absence of β-adrenergic stimulation. The fact that the tertiapin-sensitive component became more sensitive to carbachol in the presence than absence of isoproterenol indicates that β-adrenergic stimulation increases the sensitivity of either KACh channels to carbachol or sinoatrial action potential to KACh currents. Further studies are needed to discreminate these two possibilities.