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

本研究旨在建立地诺帕明的儿茶酚衍生物T-0509作为选择性β_1全激动剂，并利用选择性β受体激动剂研究心脏肌肉中β-肾上腺素能受体亚型的功能意义。与异丙肾上腺素相比，T-0509对β_1肾上腺素受体的选择性几乎与异丙肾上腺素相当，对β_2肾上腺素受体的选择性是β_2肾上腺素受体的150倍。(1)在豚鼠心脏中，我们发现了cAMP的亚细胞部分，它与多种cAMP依赖药的正性变力作用(PIE)密切相关。在这一组分中，A激酶活性也与PIE密切相关。(2)在豚鼠心室肌中，β-受体激动剂的PIE可通过β_1-肾上腺素能受体的钙电流增加来解释。(3)β-全激动剂可引起大鼠慢性给药脱敏，但以往研究中使用的剂量极高，用来研究β-受体亚型在体内的影响。我们正在研究选择性β_1激动剂与非选择性β_1激动剂相比导致弱脱敏的可能性。(4)犬冠状动脉有β-肾上腺素能受体。我们发现，即使在生理条件下，β_1全激动剂也可能通过β_1肾上腺素能受体引起微小但显著的冠状动脉扩张。

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.