Role of ET(B) receptors in local clearance of endothelin-1 in rat heart: studies with the antagonists PD 155080 and BQ-788.

The effects of two endothelin (ET) receptor antagonists, PD 155080 (ET(A) selective) and BQ-788 (ET(B) selective), on cardiac function and ET-1 release were studied in isolated rat hearts. In normoxic hearts, infusion of PD 155080 (50 nM-5 microM) 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 microM) increased it approximately 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) ET(A) receptors mediate coronary constriction, whereas ET(B) receptors bind and sequester ET-1, and (2) ET-1 displaced by ET(B) antagonist accesses ET(A) receptors resulting in coronary constriction.