POSITIVE CHRONOTROPIC AND INOTROPIC RESPONSES TO NOVEL CARDIOTONICS, NKH-477 AND MCI-154 IN ISOLATED, PERFUSED CANINE HEART PREPARATIONS

The chronotropic and inotropic effects of recently developed cardioton ics, NKH 477 (a direct adenylate cyclase activator) and MCI-154 (a Ca2 + senisitizer) and norepinephrine (an adrenoceptor agonist, NE) were i nvestigated in the isolated, blood-perfused canine right atrial or lef t ventricular preparations. Each of the substances (0.3-30 nmol of NKH 477, 0.3-300 nmol of MCI-154 and 0.1-1 nmol of NE) induced positive c hrono- and inotropic responses in a dose-related manner. While each su bstance produced similar positive inotropic effects in the isolated ri ght atria, the positive chronotropic effect of NKH 477 was greater tha n those of MCI-154 and NE. Positive cardiac effects of NKH 477 and MCI -154 were not inhibited by propranolol which suppressed NE-induced pos itive cardiac effects. Parasympathetic nerve stimulation depressed pos itive chronotropic and inotropic effects of NKH 477, MCI-154 and NE. T hese results suggest than the direct activation of adenylate cyclase b y NKH 477 causes more prominent positive chronotropic than positive in otropic effects as compared with the chronotropic and inotropic effect s of either NE, a beta-adrenoceptor agonist or MCI-154, a Ca2+ sensiti zer. The neurally released acetylcholine was also shown to attenuate t he positive chronotropic and inotropic effects of these cardiotonics a t distal as well as proximal sites of increase in tissue cAMP in the i solated canine heart.