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 ischaemi c and reperfusion injury were investigated in the Langendorff perfused rat isolated heart. Endothelin-l (0.012-0.4 nmol) evoked dose-depende nt reduction in coronary flow, which was attenuated by bosentan (1.0-1 0 mu M) in a concentration-related fashion. The inhibitory effect of b osentan lasted more than 30 min. The endothelin ET(B) receptor agonist Suc-[Glu(9),Ala(11,15)]endothelin-1-(8-21) (IRL 1620) increased coron ary 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 reperfu sion, the recoveries of the left ventricular developed pressure, dP/dt (max), and coronary flow were significantly larger in a group given bo sentan 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 perio d. During the reperfusion period, left ventricular end diastolic press ure 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 lef t ventricle compared to 21 +/- 2% in the vehicle group (P < 0.01). Ace tylcholine-induced endothelium-dependent vasodilatation was significan tly reduced after ischaemia and reperfusion in the vehicle group but n ot in the bosentan group. It is concluded that bosentan attenuates the coronary vasoconstrictor effect elicited by endothelin and reduces is chaemia/reperfusion-induced myocardial and endothelial injury in the r at isolated heart. The results suggest that endogenous endothelin may be involved in the pathogenesis of myocardial ischaemic and reperfusio n damage and a beneficial effect of bosentan in preventing myocardial and endothelial injury following ischaemia and reperfusion.