Concentration- and time-dependence of phosphoinositide hydrolysis induced by endothelin-1 in relation to the positive inotropic effect in the rabbit ventricular myocardium.

The effects of endothelin-1 on phosphoinositide hydrolysis in relation to the positive inotropic effect of the compound were studied in the rabbit ventricular myocardium. Endothelin-1 elicited a concentration- and time-dependent accumulation of [3H]inositol monophosphate (IP1) in ventricular muscle slices prelabeled with myo-[3H]inositol in concentrations similar to those that caused a positive inotropic effect. The EC50 value of endothelin-1, both for the induction of [3H]IP1 accumulation and for the positive inotropic effect was 6 x 10(-9) M. The endothelin-induced positive inotropic effect was linearly related to [3H]IP1 accumulation. Endothelin-1 induced a small transient negative inotropic effect before the onset of a gradually developing and sustained positive inotropic effect which reached a steady level at 30 min. After administration of endothelin-1, [3H]IP3 accumulated rapidly and transiently before the development of the positive inotropic effect. [3H]IP2 accumulated slowly and peaked at 20 min. [3H]IP1 accumulation occurred more slowly and of the inositol phosphates its time course coincided best with that of the positive inotropic effect. Phorbol 12,13-dibutyrate inhibited both the [3H] IP1 accumulation and positive inotropic effect induced by endothelin-1. The present results indicate that an acceleration of phosphoinositide hydrolysis induced by activation of endothelin-1 receptors may be responsible for induction of the positive inotropic effect of endothelin-1 on rabbit ventricular myocardium.