PROTECTIVE EFFECTS OF NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONIST BOSENTAN ON MYOCARDIAL ISCHEMIC AND REPERFUSION INJURY IN THE PIG

Objective: The aim was to investigate the effects of the non-peptide e ndothelin receptor antagonist bosentan (Ro 47-0203) on haemodynamic va riables, infarct size, myocardial overflow, and tissue content of endo thelin-like immunoreactivity (ET-LI) during ischaemia and reperfusion in anaesthetised pigs, and to study the inhibitory effect of bosentan on ET-1 induced coronary constriction in vitro. Methods: Ischaemia was induced by ligation of the left anterior descending coronary artery f or 45 min, followed by 4 h of reperfusion. Bosentan was given either i ntravenously (5 mg . kg(-1)) 15 min before ischaemia or as a 25 min lo cal coronary venous retroinfusion (10(-4) M) starting at 30 min of isc haemia. ET-LI was analysed in myocardial tissue and in plasma from the anterior interventricular coronary vein and aorta. The effect of bose ntan on endothelin-l induced vasoconstriction was evaluated in isolate d diagonal branches of left anterior descending coronary artery. Resul ts: Intravenous bosentan slightly reduced arterial blood pressure (P < 0.05) but did not affect basal coronary vascular resistance. Local re troinfusion of bosentan did not change blood pressure. Intravenous and retroinfused bosentan significantly reduced infarct size by 58% and 4 8% respectively (P < 0.01) and enhanced the recovery of coronary blood flow by 65-90% compared to vehicle treated controls at the end of 4 h reperfusion. The basal plasma levels of ET-LI and the myocardial over flow of ET-LI during reperfusion increased twofold after bosentan. A t hreefold increase in the concentration of ET-LI was observed in the is chaemic/reperfused myocardium and this enhancement was significantly a ttenuated by bosentan. Bosentan effectively antagonised the endothelin -1 induced but not the serotonin induced, contractions of isolated cor onary arteries and reversed the established contraction induced by end othelin-1. Conclusions: The non-peptide endothelin receptor antagonist bosentan markedly protects the myocardium from ischaemia/reperfusion injury and improves blood flow to the reperfused area, indicating the involvement of endogenous endothelin-1 and the therapeutic value of bo sentan in the treatment of ischaemia/reperfusion injury.