Inhibition of ETB receptors limits the efficacy of nonselective endothelin antagonists in vivo.

Endothelin-1 (ET-1) produces vasoconstriction via activation of ETA and ETB receptors on vascular smooth muscle, and vasodilatation via ETB receptors on endothelial cells. Here we have used the selective ETA receptor antagonist BQ-123, the selective ETB receptor antagonist BQ-788 and the nonselective ETA/ETB receptor antagonist PD 145065 to study the role of these receptors in mediating the hemodynamic changes induced by an infusion of ET-1 to the anesthetised, ganglion-blocked rat. ET-1 (10 pmol/kg/min) infused for 70 min induced an increase in the mean arterial pressure (MAP) and total peripheral resistance (TPR), as well as a fall in cardiac output (CO). ET-1 also induced a fall in the blood flow to all of the tissues studied except the heart and stomach. BQ-123 (10 nmol/kg/min) attenuated, whereas BQ-788 (10 nmol/kg/min) potentiated, most of these effects of ET-1. PD 145065 (10 nmol/kg/min), a potent antagonist in vitro, was largely without effect in vivo, even though the dose infused was 1,000 times that of ET-1. Therefore, BQ-123 inhibits the vasoconstrictor effects of ET-1 more actively than PD 145065. Because BQ-788 potentiates the effects of ET-1 on TPR and generally increases ET-1-induced regional vasoconstriction, this weaker effect of PD 145065 compared to BQ-123 is most likely due to its additional effect on ETB receptors. Therefore, nonselective receptor antagonists may well prove less efficacious in vivo than predicted from in vitro assays because they will reduce the ET-1-limiting processes on vasoconstriction mediated by ETB receptors.