Endothelin-1 increases susceptibility of isolated rat hearts to ischemia/reperfusion injury by reducing coronary flow

Endothelin-1 (ET-1) is the most potent vasoconstrictor known to date, and i t was proposed that this peptide plays a major role in myocardial ischemia/ reperfusion injury. ET-1 could increase myocardial susceptibility to ischem ia by two mechanisms:via coronary flow reduction and/or via direct, metabol ic effects on the heart. In isolated, buffer-perfused rat hearts, function was measured with a left ventricular balloon, and energy metabolism (ATP, phosphocreatine, inorganic phosphate, intracellular pH) was estimated by (NMR)-N-31-spectroscopy. Und er constant pressure perfusion, hearts were subjected to 15 min of control perfusion, 15 ("moderate injury") or 30 ("severe injury") min of global isc hemia, followed by 30 min of reperfusion. Hearts were pre-treated with ET-1 (boluses of 0, 0.4, 4, 40 of 400 pmol) 5 min prior to ischemia. In the control period, ET-1 reduced coronary flow ventricular function, pho sphocreatine and intracellular pH dose-dependently; during ischemia/reperfu sion, coronary now, functional recovery and high-energy phosphate metabolis m were adversely affected by ET-1 in a dose-related manner. To study effect s of ET-1 not related to coronary now reduction, additional hearts were per fused under constant flow conditions (ET-1 0 or 400 pmol) during 15 min of control, 15 min of ischemia and 30 min of reperfusion. When coronary flow w as held constant, functional and energetic parameters were similar for untr eated and ET-1 treated hearts during the entire protocol, i.e, the adverse effects of ET-1 on function and energy metabolism during ischemia/reperfusi on were completely abolished. In both constant pressure and constant flow p rotocols, 400 pmol ET-1 reduced the extent of ischemic intracellular acidos is, The authors conclude that ET-1 increases the susceptibility of isolated hearts to ischemia/reperfusion injury via reduction of coronary flow. (C) 1998 Academic Press.