Effect of endothelin-1 and its combination with adenosine on myocardial contractility and myocardial energy metabolism in vivo

Abstract

Contradictory results have been reported about the isotropic effects of the vasoconstrictive peptide endothelia-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 isotropic 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 isotropic 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%, + 1361%. + 60%). While the maximum of the isovolumic LVSP (peak LVSP) and the corresponding dP/d t max (peak dP/d t max) were unchanged with sole ET-1 (peak LVSP: + 5%, peak dP/d t max −2%). these indexes of myocardial contractility were increased after pretreatment with ADO (peak LVSP: + 11%, + 13%, + 4%; peak dP/d t max: +9%, + 20%, + 10%) indicating a positive isotropic 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 isotropic effect of the peptide. ADO antagonizes the vasoconstriction, normalizes the energy metabolism and unmasks the positive inotropy of ET-1.