EFFECT OF ENDOTHELIN ANTAGONISTS WITH OR WITHOUT BQ-788 ON ET-1 RESPONSES IN PITHED RATS

The overall effects of endothelin-1 (ET-1) on blood pressure are cause d by a composite activation of constrictor ET(A) and ET(B) receptors a nd dilator ET(B) receptors. Therefore, it is difficult to accurately c ompare the ET(A) activity of selective ET(A) receptor antagonists (BQ 123 and BMS 182874) with mixed ET(A)/ET(B) antagonists (SB 209670 and bosentan) on the cumulative dose-response curve to ET-1. The developme nt of a selective ET(B) antagonist (BQ 788), which inhibits both the d ilator and constrictor ET(B) receptors, offered the opportunity to inv estigate the role of ET(B) receptors in the response to exogenous ET-1 in the pithed rat. BQ 788 (3 mg/kg) re suited in an eightfold leftwar d shift in the ET-1 dose-response curve, suggesting a significant invo lvement of ET(B) dilator receptors. In the absence or presence of BQ 7 88, each ET antagonist evoked a rightward shift from vehicle. With the exception of BMS 182874, BQ 788 increased the magnitude of the shifts . Furthermore, the profile of the shifts changed from nonparallel to p arallel in the presence of BQ 788. The inclusion of BQ 788 also altere d the rank order of the ET antagonists tested. The results presented d escribe an in vivo system that accurately characterizes the ET(A) acti vity of ET antagonists.