The effects of the endothelin ETA receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion

Abstract

1. The effects were investigated of the ETA receptor antagonist, FR 139317, on endothelin-1 (ET-1)-induced coronary vasoconstriction in the isolated perfused heart of the rabbit. In addition, this study examined whether FR 139317 reduced infarct size in a rabbit model of coronary artery occlusion and reperfusion. 2. In the rabbit isolated perfused heart, ET-1 (1-100 pmol) elicited a dose-dependent increase in coronary perfusion pressure (CPP). For example, 30 pmol ET-1 caused CPP to rise by 22 +/- 8 mmHg and 100 pmol ET-1 by 47 +/- 10 mmHg (n = 8). Infusion of FR 139317 (1 microM) significantly attenuated the increase in CPP caused by ET-1 (30 pmol: 3 +/- 1 mmHg, 100 pmol: 8 +/- 2 mmHg; n = 8). 3. In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 45 or 60 min of coronary artery occlusion followed by 2 h of reperfusion was 47 +/- 6% (n = 6) and 55 +/- 7% (n = 5), respectively. A continuous infusion of FR 139317 (0.2 mg kg-1 min-1 preceded by a loading dose of 1.0 mg kg-1, i.v.; n = 5-6) had no effect on the extent of the myocardial infarct size (45 min: 47 +/- 6%; 60 min: 49 +/- 7%). Even a three-times higher dose (0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1, i.v.; n = 4) of FR 139317 had no effect on myocardial infarct size (48 +/- 5%) after 45 min occlusion of the antero-lateral branch of the left coronary artery (LAL) and 2 h reperfusion.4. In a separate group of experiments, the LAL was occluded for 60 min and subsequently reperfused for 6 h. FR 139317 (0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1, i.v.; n =4) had no significant effect on infarct size even in this long reperfusion model (control: 48 +/- 3%, FR 139317:61 +/- 6%).5. Thus, the vasoconstrictor effects elicited by ET-1 in the coronary vasculature of the rabbit are primarily mediated via the ETA receptor, for they were inhibited by the ETA receptor antagonist, FR 139317. However, an enhanced formation of endogenous ET-1 does not play a major role in ischaemia/reperfusion injury of the rabbit heart, for FR 139317 had no effect on infarct size.