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Role of Muscarinic K Channels in Parasympthetic Regulation of Heart Beat

毒蕈碱 K 通道在副交感心率调节中的作用

基本信息

批准号：
12670715
负责人：
YAMADA Mitsuhiko
金额：
$ 2.18万
依托单位：
Osaka University (2002)National Cardiovascular Center Research Institute (2000-2001)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

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.

我发现蜜蜂毒素，Tertiapin选择性地阻断心肌细胞上的M碱钾通道(KACH)。因此，我分析了Tertiapin如何在灌流了朗宁多夫装置的离体兔心脏中调节卡巴胆碱的负变时效应。心得安(100 NM)、卡巴胆碱(1 nM-10μM)呈浓度依赖性地诱发窦性心动过缓。Tertiapin(300 NM)部分抑制氨基甲胆碱的作用。1 0 0 nM和~gt；1 nM氨基甲胆碱分别以浓度依赖方式诱导Tertiapin敏感组分和不敏感组分，分别占10μM氨基甲胆碱作用的75%和2 5%。由于压力感受性反射是由KACH通道介导的，因此，目前的资料表明，副交感神经末梢在压力感受性反射中分泌较多的乙酰胆碱。Tertiapin不敏感成分似乎是由于氨基甲胆碱降低基础cAMP水平而引起的对超极化激活的非选择性阳离子电流的抑制。在异丙肾上腺素(100 NM)存在下，10 nM和~gt；1 nM氨基甲胆碱分别以浓度依赖的方式诱导Tertiapin敏感成分和不敏感成分，两者均占10μM氨基甲胆碱作用的50%左右。因此，腺苷环化酶抑制对M受体刺激的负变时效应的贡献变大，而Kach电流在有β-肾上腺素能刺激时的负变时效应变小。Tertiapin敏感成分在存在异丙肾上腺素时对卡巴胆碱的敏感性高于不存在异丙肾上腺素的事实，这表明β肾上腺素能刺激增加了KACH通道对卡巴胆碱的敏感性或窦房结动作电位对卡巴胆碱的敏感性。需要进一步的研究来区分这两种可能性。