ROLE OF ENDOGENOUS ENDOTHELIN IN EXTENSION OF RABBIT MYOCARDIAL-INFARCTION

The role of endogenous endothelin-1 (ET-1) in myocardial infarction wa s investigated in a rabbit ischemia-reperfusion model and in rabbit La ngendorff hearts. AwETN40, a monoclonal antibody against ET-1, at 10 m g/kg i.v. inhibited hypertension and hypotension induced by ET-1 (0.3 nmol/kg i.v.): about 70-100% inhibition lasted for 24 h. In a coronary occlusion (30 min)-reperfusion (24 h) model, AwETN40 (10 mg/kg i.v.) reduced the infarct size from 60.9 +/- 4.6% (infarct region/ischemic r egion in weight, IgG1kappa control; n = 5) to 37.1 +/- 5.2% (n = 5, p < 0.05). Plasma ET-1 levels were increased significantly by coronary o cclusion-reperfusion and returned to control level 24 h after reperfus ion. Effects of ET-1 on the coronary vessels and cardiac contractility were studied in the Langendorff heart. ET-1 increased the perfusion p ressure from concentrations as low as 10 pM, whereas the developed lef t ventricular pressure was not altered. These results suggest that ET- 1 decreases oxygen supply to the cardiac muscles by constricting coron ary vessels and that this, in turn, worsens the ischemic condition of the heart to extend the infarct size.