ROLE OF ENDOGENOUS ENDOTHELIN IN MYOCARDIAL AND CORONARY ENDOTHELIAL INJURY AFTER ISCHEMIA AND REPERFUSION IN RATS - STUDIES WITH BOSENTAN, A MIXED ET(A)-ET(B) ANTAGONIST

1 Previous studies suggested that endothelin-1 (ET-1) may play a role in myocardial ischaemia and reperfusion. This study was designed to test the effect of a new nonpeptide antagonist of endothelin ET(A) and ET(B) receptors, bosentan, on myocardial infarct size, ventricular arrhythmias, and coronary endothelial dysfunction after ischaemia and reperfusion. 2 Anaesthetized male Wistar rats were subjected to 20 min ischaemia (left coronary artery occlusion) followed by 1 h (for the evaluation of coronary endothelial dysfunction) or 2 h (for the evaluation of infarct size) reperfusion, or 5 min ischaemia followed by 15 min reperfusion (for the evaluation of reperfusion arrhythmias). Vascular studies were performed on 1.5-2 mm coronary segments (internal diameter 250-300 mu m) removed distal to the site of occlusion and mounted in wire myographs for isometric tension recording. Area at risk and infarct size were determined by Indian ink injection and triphenyl tetrazolium staining, using computerized analysis of enlarged sections after colour video acquisition. 3 Bosentan, administered at a dose which virtually abolished the presser response to big ET-1 (3 mg kg(-1), i.v. before ischaemia) did not affect heart rate, arterial pressure or the rate pressure product before ischaemia, during ischaemia and during reperfusion. Bosentan did not affect the incidence of reperfusion-induced ventricular fibrillation (controls: 86%, n = 14; bosentan: 93%, n = 15), and did not modify infarct size (% of area at risk: controls: 63 +/- 4, n = 10; bosentan: 60 +/- 6, n = 8). Ischaemia followed by reperfusion markedly reduced the endothelium-dependent relaxations to acetylcholine (maximal response: sham: 59 +/- 4%, n = 9; ischaemia-reperfusion: 26 +/- 6%, n = 8; P<0.01), characteristic of reperfusion-induced endothelial dysfunction, and this dysfunction was not prevented by bosentan (maximal response to acetylcholine: 25 +/- 5%, n = 9; P<0.01 vs sham; P = NS vs ischaemia/ reperfusion). 4 These experiments suggest that endogenous endothelin does not contribute to myocyte or coronary endothelial injury in this rat model of ischaemia and reperfusion.