Cardiac contractile and metabolic effects mediated via the myocardial H2-receptor adenylate cyclase system. Characterization of two new specific H2-receptor agonists, impromidine and dimaprit, in the guinea pig and human myocardium

Abstract

The present study chartacterizes myocardial effects of two new histaminergic H2-receptor specific compounds, impromidine, and dimaprit, on cardiac contractile and metabolic parameters of the guinea pig heart and human papillary muscle in comparison to the well-known effects of catecholamines. Impromidine and dimaprit produced a dose-dependent stimulation of the right and left ventricular contractile force in the isolated perfused biventricular catheterized guinea pig heart with maximal stimulation rates equal to those of isoproterenol. Hemodynamic equieffective doses of isoproterenol (2.8X10(-9) mol/l), histamine (1.1X10(-5) mol/l), impromidine (4.6X10(-7) mol/l, and dimaprit (8.5X10(-6) mol/l) induced nearly identical increases in tissue concentrations of c-AMP. All compounds dose-dependently enhanced the activity of the myocardial adenylate cyclase with very similar KA-values in a particulate sarcolemmal membrane preparation of both guinea pig ventricles and human papillary muscles. No effect of either compound was seen on cardiac phosphodiesterase activity. Selective administration of the beta1-blocking agent metoprolol and the H2-receptor antagonist cimetidine clearly discriminates two independent receptors linked to the sarcolemmal adenylate cyclase system in the guinea pig and human myocardium. This is further supported by results obtained from beta-receptor-binding studies in which an interference of impromidine and dimaprit with the stereospecific binding of (-)[3H]-dihydroalprenolol to cardiac beta-receptors could be definitely excluded. The possible therapeutic role of both H2-agonists on the non-ischemic, surviving myocardium, which is transiently refractory to beta-adrenergic stimulation by catecholamines after myocardial infarction, will be discussed.