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 s ystemic and renal hemodynamics were assessed in conscious Sprague-Dawl ey rats. Mean arterial pressure, hindlimb flow, and renal blood flow w ere 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 b y sustained vasoconstriction in the systemic bed, but only vasoconstri ction in the renal bed. RES-701-1, a selective ET(B) antagonist, block ed the dilator and potentiated the constrictor effect; SB-209670, a mi xed ET receptor antagonist, attenuated both responses to S6c. In follo w-up studies, the role of endogenous ET was assessed by administration of the antagonists alone: RES-701-1, SB-209670, and the ET(A)-selecti ve antagonist BQ-123. RES-701-1 unmasked a significant systemic and re nal vasoconstriction, which was attenuated by SB-209670 but not by BQ- 123. SB-209670 and BQ-123 had no effect on basal hemodynamic parameter s. Data from radioligand binding experiments showed that RES-701-1 bin ds with high affinity to the cloned human ET(B) receptor but poorly to the ET(B) receptor predominant in the rat kidney. Collectively, the r esults indicate that 1) the vascular effects of ET in the rat are medi ated by two ET(B) receptor subtypes: an RES-701-1-sensitive subtype, m ediating vasodilation, and an RES-701-1-insensitive subtype, mediating vasoconstriction; 2) the predominant role of endogenous ET is vasodil ation; and 3) the ET(A) receptor plays a negligible role in the contro l of vascular tone in the rat.