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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&lt；@d1+@>d1激活的K&d1；d1(K&lt；@D2Na@&gt；D2)通道具有较大的单位电导，并被肌膜内侧Na&lt；@d1+@&gt；d1浓度的增加所激活。已经推测，K&lt；@D2Na@&gt；D2通道不仅在心肌缺血和洋地黄毒性等病理条件下被激活，而且在生理条件下也可能被激活。然而，目前还没有确定心脏K&lt；@D2Na@&Gt；D2通道是否受某些受体机制的调节。在本研究中，我用膜片钳技术研究了β-肾上腺素受体和内皮素(ET)受体刺激对豚鼠心室肌细胞K&D2Na和D2电流的影响。细胞内负载50 mM Na~(2+)和细胞外施加10微米哇巴因可激活K&D2Na~(2+)~(D2)~(D2)电流。内皮素-1(ET-1)在浓度为10 nM时，对K&D2Na@&Gt；D2电流的抑制作用为21(+)。[)4%(n=5)，被选择性ET&lt；@D2a@&gt；D2受体拮抗剂…阻断更多的tBQ-485(100 NM)、内皮素-3(ET-3，30 nM)不能抑制K&lt；@D2Na@&Gt；D2电流。蛋白激酶C抑制剂(Stauroporine、Calphostin C)和细胞内三磷酸肌醇负荷(IP&lt；@D23@&gt；D2)均不影响ET-1对K&d2Na@&gt；D2电流的抑制作用。异丙肾上腺素(ISO，1-1000 nM)也以浓度依赖的方式抑制K&lt；@D2Na@&D2电流。ISO(100 NM)引起的K&lt；@D2Na@&gt；D2电流的降低可被10 mU的阿替洛尔所阻断，但不能被100 nM的ICI 118,551所阻断，这表明β&lt；@D21@&gt；D2-肾上腺素能受体参与其中。福司可林(10 MU)也抑制K&lt；@D2Na@&gt；D2电流，而ISO诱导的K&lt；@D2Na@&gt；D2电流抑制作用可被细胞内蛋白激酶抑制肽减弱。因此，cAMP-蛋白激酶A通路在β-肾上腺素受体介导的抑制K&lt；@D2Na@&gt；D2电流中起重要作用。因此，在病理和生理条件下，ET&lt；@D2a@&gt；D2受体和β&d21；&gt；D2-肾上腺素能受体都抑制心肌K&lt；@D2Na@&gt；D2电流，并调节动作电位复极。较少