BENEFICIAL-EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST BOSENTAN ON MYOCARDIAL AND ENDOTHELIAL INJURY FOLLOWING ISCHEMIA-REPERFUSION IN THE RAT

The effects of bosentan, a nonpeptide endothelin receptor antagonist, on endothelin-induced changes in coronary flow and myocardial ischaemic and reperfusion injury were investigated in the Langendorff perfused rat isolated heart. Endothelin-l (0.012-0.4 nmol) evoked dose-dependent reduction in coronary flow, which was attenuated by bosentan (1.0-10 mu M) in a concentration-related fashion. The inhibitory effect of bosentan lasted more than 30 min. The endothelin ET(B) receptor agonist Suc-[Glu(9),Ala(11,15)]endothelin-1-(8-21) (IRL 1620) increased coronary flow in the absence but not in the presence of bosentan. In hearts subjected to 30 min of global ischaemia followed by 30 min of reperfusion, the recoveries of the left ventricular developed pressure, dP/dt(max), and coronary flow were significantly larger in a group given bosentan 10 mu M at the start of ischaemia (92 +/- 7%, 98 +/- 8% and 83 +/- 5%, respectively) than in a vehicle-treated group (70 +/- 4%, 70 +/- 6% and 42 +/- 2%, respectively);at the end of the reperfusion period. During the reperfusion period, left ventricular end diastolic pressure was significantly lower in the bosentan group than in the vehicle group. The area of no-reflow in the bosentan group was 7 +/- 3% of left ventricle compared to 21 +/- 2% in the vehicle group (P < 0.01). Acetylcholine-induced endothelium-dependent vasodilatation was significantly reduced after ischaemia and reperfusion in the vehicle group but not in the bosentan group. It is concluded that bosentan attenuates the coronary vasoconstrictor effect elicited by endothelin and reduces ischaemia/reperfusion-induced myocardial and endothelial injury in the rat isolated heart. The results suggest that endogenous endothelin may be involved in the pathogenesis of myocardial ischaemic and reperfusion damage and a beneficial effect of bosentan in preventing myocardial and endothelial injury following ischaemia and reperfusion.