Evidence for the existence of endothelin-b receptor subtypes and
their physiological roles in the rat.
Gellai, Miklos, Tracey Fletcher, Mark Pullen, and Ponnal Nambi.
Department of Renal Pharmacology, SmithKline Beecham
Pharmaceuticals, King of Prussia, PA
APStracts 3:0069R, 1996.
The physiological roles of endothelinB (ETB) receptor subtypes in
systemic and renal hemodynamics were assessed in conscious Sprague
-Dawley rats. Mean arterial pressure (MAP), hindlimb flow (HLF) and
renal blood flow (RBF) were measured via an implanted catheter and
pulsed Doppler flow probes. Bolus, i.v. injections of sarafotoxin 6c
(S6c), a selective ETB 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 ETB antagonist, blocked the dilator and potentiated the
constrictor effect; SB 209670, a mixed ET receptor antagonist,
attenuated both responses to S6s . In follow-up studies, the role of
endogenous ET was assessed by administration of the antagonists
alone: RES-701-1, SB 209670 and the ETA-selective antagonist, BQ123.
RES-701-1 unmasked a significant systemic and renal vasoconstriction,
which was attenuated by SB 209670, but not by BQ123. SB 209670 and
BQ123 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 ETB receptor but poorly to the ETB
receptor predominant in the rat kidney. Collectively, The results
indicate that 1) the vascular effects of ET in the rat are mediated
by two ETB receptor subtypes; an RES-701-1-sensitive, mediating
vasodilation and an RES-701-1-insensitive subtype mediating
vasoconstriction; 2) the predominant role of endogenous ET is
vasodilation; and 3) the ETA receptor plays a negligible role in the
control of vascular tone in the rat.
Received 11 November 1995; accepted in final form 14 February
1996.
APS Manuscript Number R25-5.
Article publication pending Am. J. Physiol. (Regulatory Integrative
Comp. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 13 March 96