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

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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.