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.
1 To characterize the receptors mediating the effects of the endothelin/sarafotoxin family of peptides on the responses to electrical stimulation of the rat vas deferens (RVD) and guinea-pig ileum (GPI) we have used endothelin-I (ET-1), ET-3, sarafotoxin 6b (SX6b) and SX6c as agonists and the endothelinreceptor antagonists BQ-123 (ETA receptor selective) and PD 142893 (non-selective). 2 In the RVD, ET-1 and SX6b increased the twitches induced by field stimulation starting at a threshold concentration of 10-`' M while the threshold concentration for ET-3 was 3 x 10-9 M. SX6c (up to 3 x 10-8M) did not potentiate the twitches. SX6b produced significantly (P<0.05) greater potentiations than ET-1 at concentrations of 3 x 10-9 M and higher, and I0-7 M ET-3 also produced a significantly greater effect than ET-1 at the same concentration. Thus, at threshold the rank order of peptides was ET-1 = SX6b>ET-3>>>SX6c, and at concentrations of 3 x 108 M and higher, SX6b> ET-3> ET-1 >>> SX6c.3 In the presence of BQ-123 or PD 142893 (10-' M) the threshold concentrations for ET-1 to augment the twitches were increased 30 fold. In the same conditions neither SX6b nor ET-3 potentiated the responses. The relative activities of the endothelin/sarafotoxin peptides and the effectiveness of the endothelin receptor antagonists are consistent with postjunctional ETA receptors mediating these effects. 4 In the transmurally stimulated GPI the endothelin/sarafotoxin peptides produced two effects; an increase in the basal tension of the tissues and an inhibition of the twitch responses. To increase the basal tension the peptides had the order of potency ET-1 > SX6b >> ET-3 = SX6c. These direct effects of ET-1 or SX6b were strongly antagonized (100 fold) by either BQ-123 (10-'M) or PD 142893 (10-' M). Thus, ETA receptors mediate contractions of the GPI induced by these peptides.5 The endothelin/sarafotoxin peptides were approximately equipotent at depressing twitches of the GPI in response to transmural stimulation (EC,0s, 4 x 10 -to 1.5 x 10-10 M). The depressions induced by ET-1 were unaffected by either BQ-123 (10-' M) or PD 142893 (10-5 M). BQ-123 produced a small (three fold) antagonism of the inhibitory effects of ET-3 or SX6c. These results indicate that a receptor of the ETB type mediates the inhibitory effects of the endothelin/sarafotoxin peptides on neurotransmission in the GPI.6 Thus, both ETA receptors and ETB receptors mediate the effects of the endothelin/sarafotoxin peptides on neurotransmission.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.