The effects of two endothelin (ET) receptor antagonists, PD 155080 (ETA selective) and BQ-788 (ETB selective), on cardiac function and ET-1 release were studied in isolated rat hearts. In normoxic hearts, infusion of PD 155080 (50 nM-5 μM) reduced coronary resistance, but had no effect on ET-1 release. Low concentrations of BQ-788 (2 and 20 nM) had no effect on coronary resistance; high concentrations (0.2 and 2 μM) increased it ∼ 2-fold; all concentrations increased ET-1 release (up to 24-fold). Similar results were obtained in reperfused hearts. Although concentrations of ET-1 were higher in interstitial fluid than coronary effluent, levels never exceeded the low pg/ml range. These results indicate that (1) ETA receptors mediate coronary constriction, whereas ETB receptors bind and sequester ET-1, and (2) ET-1 displaced by ETB antagonist accesses ETA receptors resulting in coronary constriction.
