CHARACTERIZATION OF POSITIVE INOTROPIC EFFECT OF ENDOTHELIN ON MAMMALIAN VENTRICULAR MYOCARDIUM

Endothelin-1 elicited a positive inotropic effect (PIE) on isolated rabbit, guinea pig, and rat but not on dog ventricular myocardium. Specific high-affinity binding of I-125-labeled endothelin-1 was detected in the ventricular membrane fraction of these species. Maximal binding capacity was the highest in the rabbit, lowest in the dog, and in between in the guinea pig and rat; this rank order corresponds roughly to the effectiveness of endothelin-1 in producing a PIE. There was no difference in the potency or efficacy for the PIE of the endothelin isoforms endothelin-1, -2, and -3 in the rabbit papillary muscle. A tumor-promoting phorbol ester, phorbol 12,13-dibutyrate, inhibited selectively the PIE and the accumulation of [H-3]inositol monophosphate induced by endothelin-1 as well as those of myocardial alpha-1-adrenoceptor stimulation in a concentration that did not (10(-8) M) or only slightly (10(-7) M) reduced the PIE of BAY K 8644. Phorbol 12,13-dibutyrate did not affect the specific binding of I-125-labeled endothelin-1 in the ventricular membrane fraction of the rabbit. The present findings indicate that the characteristics of the endothelin-induced PIE in mammalian ventricular myocardium are similar to those of myocardial alpha-1-adrenoceptor activation that may involve phosphoinositide hydrolysis. The receptor density and the PIE of endothelin on mammalian cardiac muscle show a wide range of variation among species.