ENDOTHELIN(A) RECEPTOR ANTAGONISM BY PD-156707 DOES NOT REDUCE INFARCT SIZE AFTER CORONARY-ARTERY OCCLUSION REPERFUSION IN PIGS/

Episodes of myocardial ischemia are associated with increases in cardi ac venous plasma endothelin (ET) concentrations, suggesting that FT ma y play a role in the development of myocardial infarction. The purpose of this study was to determine if selective blockade of ET(A) recepto rs by PD 156707 reduces infarct size caused by coronary artery occlusi on and reperfusion in pentobarbital-anesthetized micropigs. A PD 15670 7 dose which selectively blocks the ET(A)-mediated vasopressor respons e, but not the ET(B)-mediated vasodepressor response to i.v. ET-1 chal lenges (0.3 nmol/kg), was established in dose ranging studies in anest hetized micropigs. In myocardial infarction studies, micropigs receive d either saline vehicle (n = 7) or PD 156707 (n = 8) at a loading dose of 10 mg/kg/1 hr, followed by a maintenance dose of 7 mg/kg/hr. Coinc iding with the start of the maintenance dose, the left anterior descen ding coronary artery was occluded for 1 hr followed by 3 hr of reperfu sion. PD 156707 caused a significant (29 mm Hg) decrease in arterial b lood pressure before occlusion. PD 156707 had no effect on infarct siz e (61.1 +/- 5.6% of the region at risk in the PD 156707 treatment grou p vs. 70.1 +/- 3.9% in the control group). These results suggest that ET(A) receptor activation does not substantially contribute to coronar y artery occlusion/reperfusion-induced myocardial infarction.