Regulation by beta-adrenoceptor subtypes of cardiac function : Analysis by selective beta agonists

β-肾上腺素受体亚型对心脏功能的调节：选择性β激动剂的分析

基本信息

批准号：
02454485
负责人：
NAGAO Taku
金额：
$ 4.03万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-02454485/
关键词：
beta-adrenoceptor subtypes beta_1 full agonist T-0509 Cyclic AMP compartment A Kinase tolerance L-type CA^<2+> channel coronary vasodilation β受容体イソプロテレノ-ル β_1選択性環状AMP Ca^<2+>電流コンパ-トメント心収縮心拍数

项目摘要

This study was aimed to establish T-0509, the catechol derivative of denopamine, as selective beta_1 full agonist and to study functional significance of beta-adrenoceptor subtypes in the ventricular muscle of the heart using selective beta agonists.First we established the catechol derivative of denopamine (T-0509) as a selective beta_1 full agonist using isolated tissues and radioligand binding assay. T-0509 is almost as potent as isoproterenol and 150 times more selective to beta_1-adrenoceptors than beta_2- adrenoceptors as compared with isoproterenol.Following results were obtained using T-0509. (1) In the guinea pig heart, we found a subcellular fraction of cAMP which closely relates to the positive inotropic effects (PIE) of various cAMP-dependent agents. In this fraction, A kinase activity also closely related to PIE. (2) In the guinea pig ventricular muscle, PIE of beta full agonists can be explained by an increase in Ca^<2+> current via beta_1-adrenoceptors. (3) The beta full agonist causes desensitization by chronic administration to rats, but the doses used in previous studies were found to be extremely high to study the influence of beta-adrenoceptor subtypes in vivo. We are studying the possibility that selective beta_1 agonist causes weak desensitization as compared with non-selective beta agonists. (4) The beta-adrenoceptor has been shown in canine coronary artery. Wefound the possibility that beta_1 full agonist causes small but significant coronary vasodilation via beta_1-adrenoceptors even in the physiological condition.

这项研究的目的是建立T-0509，即beta_1的beta_1完全激动剂，并研究β-肾上腺素受体亚型在心脏的心室肌肉中的功能意义，使用选择性β激动剂。首先，我们建立了denopitivate denopitivate denopitivate denopitivate denoptivative denopitive denopativate denopativate denopativate t-10509）和放射性结合测定法。与异丙肾上腺素相比，T-0509几乎与异丙肾上腺素一样有效，对β_1-肾上腺素受体的选择性高150倍，对β_2-肾上腺素受体的选择性高出150倍。使用T-0509获得了遵循的结果。（1）在豚鼠心脏中，我们发现了cAMP的亚细胞分数，与各种cAMP依赖性剂的阳性肌力作用（PIE）紧密相关。在此部分，激酶活性也与PIE密切相关。（2）在豚鼠的心室肌肉中，可以通过通过beta_1- adenrenoceptors的Ca^<2+>电流增加来解释Beta全动力学家的馅饼。（3）Beta完全激动剂会导致慢性给药对大鼠的脱敏，但发现先前研究中使用的剂量非常高，以研究β-肾上腺素粘膜亚型在体内的影响。我们正在研究与非选择性β激动剂相比，选择性β_1激动剂会导致弱脱敏的可能性。（4）β-肾上腺素受体已显示在犬冠状动脉中。 beta_1完全激动剂也可能通过beta_1-肾上腺素受体引起小但显着的冠状动脉血管舒张的可能性，即使在生理状态下也是如此。