心筋細胞情報伝達と創薬 Signal transduction system in cardiac myoctes and discovery of novel drugs
The signal transduction system in cardiac myocytes has been studied extensively, such as cAMP-dependent protein kinase, Ca<SUP>2+</SUP>- and protein kinase C pathways. Classical second messengers are cAMP and Ca<SUP>2+</SUP>. 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 β<SUB>1</SUB>-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 β<SUB>1</SUB>receptor mediated transduction system in cardiac myocytes will be important for undestanding disease state such as heart failure and also discovery of novel drugs.
日本薬理学雑誌 106, 35-40, 1995-09-01