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Electropharmacological study of receptor-mediated regulation of cardiac Na^+-activated K^+ channels

受体介导的心脏Na^激活K^通道调节的电药理学研究

基本信息

批准号：
08670102
负责人：
NAKAYA Haruaki
金额：
$ 1.41万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670102/
关键词：
Na^+-activated K^+ channel endothelin-1 beta_1-adrenoceptor ET_A receptor protein kinase A 心筋細胞 Na^+活性化 K^+チャネル ET_A エンドセリン β受容体

项目摘要

The Na<@D1+@>D1-activated K<@D1+@>D1 (K<@D2Na@>D2) channel has a large unitary conductance and is activated by an increase in the Na<@D1+@>D1 concentration at the inner side of the sarcolemma. It has been postulated that the K<@D2Na@>D2 channels may be activated not only in pathological conditions such as myocardial ischemia and digitalis toxicity but also in physiological conditions. However, it has not been determined whether cardiac K<@D2Na@>D2 channels are regulated by some receptor mechanisms. In this study I examined the effects of beta-adrenoceptor and endothelin (ET) receptor stimulation on the K<@D2Na@>D2 current in guinea pig ventricular cells by using patch clamp techniques. The K<@D2Na@>D2 current was activated by intracellular loading of 50 mM Na<@D1+@>D1 and extracellular application of 10 muM ouabain. Endothelin-1 (ET-1) at a concentration of 10 nM inhibited the K<@D2Na@>D2 current by 21(]SY.+-。[)4% (n=5), which was blocked by the selective ET<@D2A@>D2 receptor antagonis … More t BQ-485 (100 nM).Endothelin-3 (ET-3,30 nM) failed to inhibit the K<@D2Na@>D2 current. Neither protein kinase C inhibitor (staurosporine, calphostin C) nor intracellular loading of inositol 1,4,5-trisphosphate (IP<@D23@>D2) affected the K<@D2Na@>D2 current inhibition by ET-1. Isoproterenol (ISO,1-1000 nM) also inhibited the K<@D2Na@>D2 current in a concentration-dependent manner. The ISO (100 nM) -induced decrease of the K<@D2Na@>D2 current was abolished by 10 muM atenolol but not by 100 nM ICI 118,551, indicating the involvement of beta<@D21@>D2-adrenoceptors. Forskolin (10 muM) also inhibited the K<@D2Na@>D2 current and the ISO-induced K<@D2Na@>D2 current inhibition was attenuated by the intracellular loading of protein kinase inhibitor peptide. Therefore, cAMP-protein kinase A pathway plays an important role in the beta<@D21@>D2-adrenoceptor-mediated inhibition of the K<@D2Na@>D2 current. Thus, both ET<@D2A@>D2 receptor an beta<@D21@>D2-adrenoceptor stimulation inhibit the cardiac K<@D2Na@>D2 current and modulate the action potential repolarization in pathological as well as physiological conditions. Less

Na<@D1+@>D1激活的K<@D1+@>D1（K<@D2Na@>D2）通道具有大的单位电导，并通过肌膜内侧Na<@D1+@>D1浓度的增加而激活。据推测，K<@D2Na@>D2通道不仅可以在病理条件如心肌缺血和洋地黄中毒中被激活，而且可以在生理条件下被激活。然而，尚未确定心脏K<@D2Na@>D2通道是否受某些受体机制调节。本实验用膜片钳技术观察了β-肾上腺素受体和内皮素受体对豚鼠心室肌细胞K<@D2Na@>D2电流的影响。通过细胞内加载50 mM Na D1 + D1和细胞外应用10 μ M哇巴因来激活K D2 Na D2电流。浓度为10 nM的内皮素-1（ET-1）抑制K<@D2Na@>D2电流21 μ M ±。[)4%（n=5），可被选择性ET<@D2A@>D2受体拮抗剂阻断 ...更多信息内皮素-3（ET-3，30 nM）不能抑制K<@D2Na@>D2电流。蛋白激酶C抑制剂（staurosporine，calphostin C）和细胞内负载1，4，5-三磷酸肌醇（IP<@D23@>D2）均不影响ET-1对K<@D2Na@>D2电流的抑制作用。异丙肾上腺素（ISO，1-1000 nM）也以浓度依赖性方式抑制K<@D2Na@>D2电流。ISO（100 nM）诱导的K<@D2Na@>D2电流的降低被10 μ M阿替洛尔消除，但不被100 nM ICI 118，551消除，表明β <@D21@>D2-肾上腺素受体参与。毛喉素（10 μ M）也抑制K<@D2Na@>D2电流，而ISO诱导的K<@D2Na@>D2电流抑制作用被细胞内蛋白激酶抑制肽的负载减弱。因此，cAMP-蛋白激酶A通路在β <@D21@>D2-肾上腺素受体介导的K<@D2Na@>D2电流抑制中起重要作用。因此，ET D2受体和β D2-肾上腺素受体刺激抑制心脏KD 2Na D2电流并调节病理和生理条件下的动作电位复极。少