Abstract
The signal transduction system in cardiac myocytes has been studied extensively, such as cAMP-dependent protein kinase, Ca2+- and protein kinase C pathways. Classical second messengers are cAMP and Ca2+. Here we studied the positive inotropic action and cAMP system and the mechanism of down-regulation of β-adrenoceptors. we have developed the most potent β1-adrenoceptor full agonist T-0509. The positive inotropic effect of isoproterenol, T-0509 and procatelol are correlated closely with a particulate fraction of cAMP. This shows a compartmentalized increase in cAMP levels are important for positive inotropic effects of β-adrenoceptor agonists. Prolonged infusion of T-0509 decreased the number of β-adrenoceptors and the isoproterenol-stimulated adenylyl cyclase activity. However, blockade of β-adrenoceptor binding sites by an irreversible β-adrenoceptor antagonist could not mimic the desensitization state induced by chronic administration of T-0509. This result suggested that mechanism other than down-regulation can play a significant role in the loss of responsiveness. Fundamental studies on physiological responses of β1receptor mediated transduction system in cardiac myocytes will be important for undestanding disease state such as heart failure and also discovery of novel drugs.
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