Dual constrictor and dilator actions of ET_B receptors in the rat renal microcirculation: interactions with ET_A receptors

Abstract

The vascular actions of endothelin-1 (ET-1) reflect the combination of vasoconstrictor ETA and ETB receptors on smooth muscle cells and vasodilator ETB receptors on endothelial cells. The present study investigated the contribution of ET receptor subtypes using a comprehensive battery of agonists and antagonists infused directly into the renal artery of anesthetized rats to evaluate the actions of each receptor class alone and their interactions. ET-1 (5 pmol) reduced renal blood flow (RBF) 25 Ϯ 1%. ETA antagonist BQ-123 attenuated this response to a 15 Ϯ 1% decrease in RBF (P Ͻ 0.01), indicating net constriction by ETB receptors. Combined receptor blockade (BQ-123ϩBQ-788) resulted in a renal vasoconstriction of 7 Ϯ 1% (P ϭ 0.001 vs. BQ-123), supporting a constrictor action of ET B receptors. In marked contrast, the ETB antagonist BQ-788 enhanced the ET-1 RBF response to 60 Ϯ 5% (P Ͻ 0.001), suggesting ET B-mediated net dilation. Consistent with ET A blockade, the ETB agonist sarafotoxin 6C (S6C) produced vasoconstriction, reducing RBF by 23 Ϯ 5%. Dose-response curves for ET-1 and S6C showed similar degrees of constriction between 0.2 and 100 pmol. Both antagonists (BQ-123, BQ-788) were equally effective at threefold lower than the standard doses, suggesting complete inhibition. We conclude that ET B receptors alone exert a net constrictor effect but cause a net dilator influence when costimulated with ET A receptors. Such opposing actions indicate more complex than additive interaction between receptor subtypes. Model analysis suggests ET A-mediated constriction is appreciably greater without than with costimulation of ET B receptors. Possible explanations include ET-1 clearance by ET B receptors and/or a dilator ETB receptor function that counteracts constriction. vascular smooth muscle cells; endothelial cells; renal vascular resistance; nitric oxide ENDOTHELIN-1 (ET-1) PLAYS an important role in the regulation of renal hemodynamics and salt and water excretion (38). Under physiological conditions the vascular endothelium constitutively produces ET-1. Although endogenous ET-1 normally has a minor influence on renal hemodynamics (37), it gains more importance in disease states such as hypertension, acute and chronic renal failure, and congestive heart failure (38). ET-1 is capable of constricting or dilating the renal vasculature depending on the relative distribution and influence of ET A and ET B receptors. In the vascular wall, ET A receptors are limited to smooth muscle cells, whereas ET B receptors are expressed in both endothelial and smooth muscle cells (38). Both receptor types are coupled to Gq proteins, thereby activating several signaling pathways including phospholipase C and intracellular calcium concentration (38), which leads to constriction of smooth muscle cells. Activation of endothelial ET B receptors by the same signaling pathways produces vasodilation mediated by nitric oxide and possibly eicosanoids (14).There is general agreement that administration of ET-1 produces renal vasoconstrictio...

The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification

“…In the current study, kidney blood flow was reduced to a similar level as that in tumours (despite a somewhat different time course), suggesting that vasoconstriction in kidney is mediated primarily through the ET B receptor. This was also suggested by Just et al (2004), although there is also evidence for some involvement of ET A receptors (Matsuura et al 1996;Ozawa et al 2003). In the present study, the response of small intestine to IRL 1620 was also vasoconstrictive, again indicating that the predominant responsive ET B receptors in this tissue are on contractile elements of the blood vessels.…”

Adverse effects of pneumoperitoneum on renal function: involvement of the endothelin and nitric oxide systems

“…Activation of ET B receptor with selective agonists such as sarafotoxin 6c produced transient depressor response followed by a longer pressor phase (7). Similarly, BQ3020, an ET B agonist, is a potent constrictor of renal and mesenteric vasculature beds (21). Based on these contradictory results, it is widely believed that the endothelial ET B receptor mediates dilatation and the smooth muscle cell ET B receptor mediates constriction (6,19,37).…”

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.…”