MORECULAR PHARMACOLOGICAL STUDY OF SIGNAL TRANSDUCTION

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Signal transduction processes triggered by activation of endothelin (ET) and angiotensin II (Ang II) play a crucial role in a number of cardiovascular diseases, namely in congestive heart failure, for the pathophysiological regulation of myocardial cell function and progression of the disease at the level of gene expression. Activation of α-adrenoceptors shares signal transduction triggered by these receptors. They may regulate the process of cardiac hypertrophy and remodeling. Therefore the study on the signal transduction subsequent to activation of these classes of receptor is of extreme importance for understanding of pathophysiology of cardiac diseases and for constitution of therapeutic strategies. Although activation of protein kinase C (PKC) induced by diacylglycerol (DAG), the product of stimulation of PI hydrolysis resulting from receptor activation, may be primarily involved in the regulation, phorbol esters that activate PKC and PKC inhibitors, such as calphostin C and chel … More erythrine, do not mimic the regulatory effect of receptor stimulation in intact myocardial cells.The study was carried out to elucidate the role of signal transduction, namely PI hydrolysis, in regulation of myocardial contractility in intact myocardium and myocytes. ET-1 and Ang II elicit an increase in intracellular Ca^<2+> mobilization and an increase in myofilament Ca^<2+> sensitivity. It has been postulated that the activation of PKC and subsequent activation of Na^+/H^+ exchanger that leads to intracellular alkalinization and secondary increase in intracellular Ca^<2+> ions may play a crucial role, but compelling pieces of evidence have not yet been obtained because of lack of pharmacological tools, ion exchange inhibitors, with sufficiently high selectivity, in intact myocardium.In the present study, it was clarified that selective inhibitors of Na^+/H^+ exchanger HOE642 and KB-R9032 inhibited the positive inotropic effect (the increase in shortening) of ET-1 without affecting the effect of isoproterenol in rabbit single myocytes loaded with indo-1. On the other hand, the increase in Ca^<2+> transients induced by ET-1 was inhibited by the Na^+/Ca^<2+> inhibitor KB-R7943. It became evident that ET-1 did not cause a prominent effect on L-type Ca^<2+> current by means of whole cell patch clamp in rabbit myocytes. Similar results have been obtained also with Ang II. These results indicate that stimulation of ion exchangers mediated by receptor activation with ET-1 and Ang II plays a crucial role in regulation of Ca^<2+> signaling in intact myocardial cells. Less