Activation of endothelin ET_A receptors masks the constrictor role of endothelin ET_B receptors in rat isolated small mesenteric arteries

Abstract

1 Endothelin-1 (ET-1) produces constriction of the rat mesenteric vascular bed in vivo via ET A and ET B receptor subtypes. The aim of this study was to investigate the relative roles of these receptor subtypes in rat isolated, endothelium-denuded, small mesenteric arteries, under pressure, by use of ET-1; the ET A receptor antagonist, BQ-123; the ET B receptor selective agonist, sarafotoxin S6c (SRTX S6c); the ET B receptor selective antagonist, BQ-788; and the ET A /ET B antagonist, TAK-044. 2 In 3rd generation mesenteric arteries, ET-1 (10 713 ± 10 77 M) produced concentration-dependent contractions (pD 2 9.86). SRTX S6c (10 712 ± 10 77 M) also induced concentration-dependent contractions in 53% of arteries studied, although the E max was much less than that obtained with ET-1 (10.7+2.9% vs 101.9+2.6% of the 60 mM KCl-induced contraction). 3 Neither ET B receptor desensitization, by a supra-maximal concentration of SRTX S6c (10 77 M), nor incubation with BQ-788 (3610 78 M), had any signi®cant e ect on the ET-1 concentration-response curve, although both treatments tended to enhance rather than inhibit responses to ET-1. 4 In the presence of BQ-123 (10 76 M), responses to low concentrations of ET-1 (up to 10 710 M) were una ected but responses to concentrations of ET-1 above 10 710 M were signi®cantly inhibited. 5 SRTX S6c desensitization followed by incubation with BQ-123 (10 76 M) or co-incubation with BQ-788 (3610 78 M) and BQ-123 caused inhibition of responses to all concentrations of ET-1, resulting in a rightward shift of the ET-1 concentration-response curve. The same e ect was obtained by incubation with TAK-044 (10 78 M and 3610 77 M). 6 Thus, responses of rat small mesenteric arteries to ET-1 are mediated by both ET A and ET B receptors. The relative role of ET B receptors is greater than that predicted by the small responses to SRTX S6c or by resistance of ET-1-induced contraction to ET B receptor desensitization or BQ-788. The e ect of ET B receptor desensitization or blockade is only revealed in the presence of ET A receptor blockade, suggesting the presence of a`crosstalk' mechanism between the receptors. These results support the concept that dual receptor antagonists, like TAK-044, may be required to inhibit completely constrictor responses to ET-1.

Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels

“…By blocking both receptor subtypes, bosentan may preserve the inter-play, while selective ET A receptor inhibition unbalances it. Previous investigators such as Mickley [29] and Adner [30] have previously reported the existence of an interaction between the two receptor subtypes in small mesenteric arteries. We have also recently demonstrated the existence of an interaction between the ET A and ET B receptor to induce the ET-1 vasoconstriction in pulmonary resistance arteries [17].…”

Combined Endothelin Receptor Blockade Evokes Enhanced Vasodilatation in Patients With Atherosclerosis

“…Another possibility is that cross talk exists between the 2 receptors, such that if only 1 receptor is blocked, the other receptor can compensate for the loss of activity. 23,24 Blockade of 1 of the receptors may attenuate an inhibitory action on the other receptor. 25 Such a mechanism may explain the potentiated effect of combined ET A and ET B receptor blockade in the atherosclerotic patients in the present study.…”

Pharmacological endothelin receptor interaction does not occur in veins from ETB receptor deficient rats

“…Venous ET A receptor blockade inhibited ET-1-induced contraction to a larger degree when ET B receptors were blocked, desensitized or non-functional (because of genetic disruption). Functional ET A and ET B receptor cross-talk occurs in other vessels including rat mesenteric veins (Claing et al 2002), rat isolated small mesenteric resistance arteries (Mickley et al 1997), mouse mesenteric veins (Perez-Rivera et al 2005), hamster saphenous and jugular veins (Lodge et al 1995), pulmonary arteries (Sauvageau et al 2006), and renal afferent arteries (Inscho et al 2006). All of these vessels, like the vena cava from wild-type rats, possess contractile ET A and ET B receptors, suggesting that pharmacological ET A and ET B receptor interaction may require the presence of contractile ET B receptors.…”