Role of Muscarinic K Channels in Parasympthetic Regulation of Heart Beat

我发现蜜蜂毒素，特硫平选择性阻断心肌细胞中的毒蕈碱K+（KACh）通道。因此，我分析了特硫平如何调节卡巴胆碱在离体兔心脏灌注Langendorff装置的负性变时作用。在普萘洛尔（100 nM）存在下，卡巴胆碱（1 nM - 10 μM）以浓度依赖性方式诱导窦性心动过缓。Tertiapin（300 nM）部分抑制卡巴胆碱的作用。100 nM和> 1 nM卡巴胆碱分别以浓度依赖性方式诱导对特硫平敏感和不敏感的组分，分别占10 μM卡巴胆碱作用的75%和25%。由于压力感受器反射是由KACh通道介导的，因此，本数据表明，副交感神经末梢在压力感受器反射中分泌相对大量的乙酰胆碱。对特硫平不敏感的组分似乎是由卡巴胆碱引起的基础cAMP水平下降引起的超极化激活的非选择性阳离子电流抑制引起的。在异丙肾上腺素（100 nM）存在下，10 nM和> 1 nM卡巴胆碱分别以浓度依赖方式诱导对特硫平敏感和不敏感的成分，两者均占10 μM卡巴胆碱作用的约50%。因此，在β-肾上腺素能刺激存在时，腺苷酸环化酶抑制对M受体负性变时效应的贡献增大，而KACh电流的贡献减小。与不存在异丙肾上腺素相比，在存在异丙肾上腺素的情况下，特硫平敏感组分对卡巴胆碱变得更敏感，这一事实表明β-肾上腺素能刺激增加了KACh通道对卡巴胆碱或窦房动作电位对KACh电流的敏感性。需要进一步的研究来区分这两种可能性。

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.