Evidence for the existence of endothelin-B receptor subtypes and their physiological roles in the rat

The physiological roles of endothelin-B (ET(B)) receptor subtypes in systemic and renal hemodynamics were assessed in conscious Sprague-Dawley rats. Mean arterial pressure, hindlimb flow, and renal blood flow were measured via an implanted catheter and pulsed Doppler flow probes. Bolus intravenous injections of sarafotoxin 6c (S6c), a selective ET(B) agonist, elicited transient dose-dependent vasodilation, followed by sustained vasoconstriction in the systemic bed, but only vasoconstriction in the renal bed. RES-701-1, a selective ET(B) antagonist, blocked the dilator and potentiated the constrictor effect; SB-209670, a mixed ET receptor antagonist, attenuated both responses to S6c. In follow-up studies, the role of endogenous ET was assessed by administration of the antagonists alone: RES-701-1, SB-209670, and the ET(A)-selective antagonist BQ-123. RES-701-1 unmasked a significant systemic and renal vasoconstriction, which was attenuated by SB-209670 but not by BQ-123. SB-209670 and BQ-123 had no effect on basal hemodynamic parameters. Data from radioligand binding experiments showed that RES-701-1 binds with high affinity to the cloned human ET(B) receptor but poorly to the ET(B) receptor predominant in the rat kidney. Collectively, the results indicate that 1) the vascular effects of ET in the rat are mediated by two ET(B) receptor subtypes: an RES-701-1-sensitive subtype, mediating vasodilation, and an RES-701-1-insensitive subtype, mediating vasoconstriction; 2) the predominant role of endogenous ET is vasodilation; and 3) the ET(A) receptor plays a negligible role in the control of vascular tone in the rat.