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

Abstract

The physiological roles of endothelin-B (ETB) 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 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 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 ETA-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 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 subtype, 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.

Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats

“…Also, it is possible to assume that nonselective blockade not only reduces deleterious effects of ET A receptor blockade but is detrimental due to blockade of beneficial vasorelaxant actions of ET B receptors, which is mediated through the release of nitric oxide and prostaglandins. 39 The question is even more complicated because, first, 2 distinct ET B receptors were identified 40,41 (ET B1 present on vascular endothelium cause vasodilation whereas ET B2 on vascular smooth muscle cells mediate vasoconstriction) and, second, different actions of these receptors are reported in various species 40,42,43 (in contrary to other species, Brooks found no ET B2 -mediated vasoconstriction in dogs). Moreover, Just et al 41 speculated that not only dual (constrictor and dilator) actions of ET B receptors have to be considered but also interactions with ET A receptors evaluating their physiological function.…”

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

“…In the endothelium, signaling by the ET B receptor involves NO synthase and other vasodilatory pathways (88,89,192). Previous work revealed an important role for the endothelial ET B receptor in maintaining the physiologically low vascular resistance of the renal circulation in conscious male rats (77,78). Short-term administration of an ET B or mixed ET B /ET A receptor antagonist in conscious midterm pregnant rats or in nonpregnant rats chronically treated with RLN inhibited renal vasodilation and hyperfiltration (36,47) (comparable with NO synthase blockade, vide supra).…”

Emerging role of relaxin in renal and cardiovascular function

“…Although ET is widely known as a potent vasoconstrictor by interacting with ET A and ET B receptor subtypes on vascular smooth muscle (44), the peptide has also been shown to raise intracellular calcium in endothelial cells, thereby stimulating prostacyclin, NO, and possibly other relaxing factors through the endothelial ET B receptor subtype (45,46,104,111). In view of the reputation of ET as a potent vasoconstrictor, it was surprising to find that disruption of the ET-1 gene in heterozygous mice elevated blood pressure (60), and specific blockade of the ET B receptor subtype in chronically instrumented conscious male rats with the pharmacological antagonist RES-701-1 produced marked renal vasoconstriction (41). These unexpected findings are consistent with a major role for endogenous ET in maintaining low renal vascular tone via an RES-701-1-sensitive endothelial ET B receptor subtype either by tonic stimulation of endothelium-derived relaxing factors and/or restraint of ET production (45,46,59,104,111).…”

“…Moreover, renal vasoconstriction elicited by sarafatoxin 6C (S6C), a selective ET B agonist, was potentiated by RES-701-1 and nitro-L-arginine (Ref. 41 and personal communication from M. Gellai). Thus the RES-701-1-sensitive ET B receptor subtype located on the endothelium maintains low renal vascular tone in conscious rats most likely by tonic stimulation of NO.…”