EFFECT OF ENDOTHELIN-1 AND ITS COMBINATION WITH ADENOSINE ON MYOCARDIAL-CONTRACTILITY AND MYOCARDIAL ENERGY-METABOLISM IN-VIVO

Contradictory results have been reported about the inotropic effects of the vasoconstrictive peptide endothelin-1 (ET-1), In contrast to in vitro experiments, in vivo studies could not demonstrate a positive inotropy of ET-1, It may be possible, that the direct positive inotropic effect of ET-1 observed in in vitro studies is counterbalanced in vivo by an indirect negative inotropy due to its coronar-constrictive effect. This study examined the hemodynamic and inotropic effects of 2500 ng ET-1/kg without and after pretreatment with the vasodilating nucleoside adenosine (0.5, 2.0, 5.0 mg ADO/kg/min). Data were compared with NaCl controls in open-chest rats during and after a 7-min infusion, Besides measurements in the intact circulation isovolumic measurements were carried out for quantification of myocardial contractility independently of peripheral vascular effects, We further examined the effect of ET-1 and its combination with 2.0 mg ADO/kg/min on myocardial high-energy phosphates (ATP, AMP, ADP, creatine phosphate), ET-1 causes a strong and longlasting vasoconstriction (+186% v preinfusion values), which is dose-dependently antagonized in part by ADO (+109%, + 136%, +60%). While the maximum of the isovolumic LVSP (peak LVSP) and the corresponding dP/dt(max) (peak dP/dt(max)) were unchanged with sole ET-1 (peak LVSP: +5%, peak dP/dt(max): -2%), these indexes of myocardial contractility were increased after pretreatment with ADO (peak LVSP: +11%, +13%, +4%; peak dP/dt(max): +9%, +20%, +10%) indicating a positive inotropic effect of ET-1, ET-1 causes a reduction of the high energy-phosphates (ATP: -19%, P<0.01; creatine phosphate: -23%, P<0.05; v controls) that can be prevented by ADO (ATP: -7%, creatine phosphate: -5%, both N.S.). The vasoconstrictive-induced ischaemia of ET-1 counteracts the direct positive inotropic effect of the peptide. ADO antagonizes the vasoconstriction, normalizes the energy metabolism and unmasks the positive inotropy of ET-1. (C) 1995 Academic Press Limited