| Abstrakt: |
Endothelin‐1 (ET‐1) produces constriction of the rat mesenteric vascular bed in vivovia ETAand ETBreceptor 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 ETAreceptor antagonist, BQ‐123; the ETBreceptor selective agonist, sarafotoxin S6c (SRTX S6c); the ETBreceptor selective antagonist, BQ‐788; and the ETA/ETBantagonist, TAK‐044.In 3rd generation mesenteric arteries, ET‐1 (10−1310−7m) produced concentration‐dependent contractions (pD29.86). SRTX S6c (10−1210−7m) also induced concentration‐dependent contractions in 53% of arteries studied, although the Emaxwas much less than that obtained with ET‐1 (10.7±2.9% vs 101.9±2.6% of the 60 mmKCl‐induced contraction).Neither ETBreceptor desensitization, by a supra‐maximal concentration of SRTX S6c (10−7m), nor incubation with BQ‐788 (3×10−8m), had any significant effect on the ET‐1 concentration‐response curve, although both treatments tended to enhance rather than inhibit responses to ET‐1.In the presence of BQ‐123 (10−6m), responses to low concentrations of ET‐1 (up to 10−10m) were unaffected but responses to concentrations of ET‐1 above 10−10mwere significantly inhibited.SRTX S6c desensitization followed by incubation with BQ‐123 (10−6m) or co‐incubation with BQ‐788 (3×10−8m) 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 effect was obtained by incubation with TAK‐044 (10−8mand 3×10−7m).Thus, responses of rat small mesenteric arteries to ET‐1 are mediated by both ETAand ETBreceptors. The relative role of ETBreceptors is greater than that predicted by the small responses to SRTX S6c or by resistance of ET‐1‐induced contraction to ETBreceptor desensitization or BQ‐788. The effect of ETBreceptor desensitization or blockade is only revealed in the presence of ETAreceptor 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. |
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