内皮素-1在人体皮肤中的血管收缩作用：ETA和ETB受体的作用

Vasoconstrictor effect of endothelin-1 in human skin: role of ETA and ETB receptors.

作者信息

Lipa J E, Neligan P C, Perreault T M, Baribeau J, Levine R H, Knowlton R J, Pang C Y

机构信息

Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, H3H 1P3 Canada.

出版信息

Am J Physiol. 1999 Feb;276(2):H359-67. doi: 10.1152/ajpheart.1999.276.2.H359.

DOI:10.1152/ajpheart.1999.276.2.H359

PMID:9950834

Abstract

The aim of this project was to investigate the role of ETA and ETB receptors in the mediation of endothelin (ET)-1-induced vasoconstriction in human skin. This information should provide important insights into the design of pharmacological intervention against skin vasospasm induced by ET-1 in peripheral vascular disease or surgical trauma. Vasoconstriction in response to intra-arterial drug infusion in isolated perfused human skin flaps (8 x 18 cm) derived from dermolipectomy specimens was assessed by studying changes in skin perfusion and perfusion pressure under constant flow rate in each drug treatment (n = 4). It was observed that ET-1 (10(-10) to 10(-8) M) and norepinephrine (NE, 10(-8) to 10(-5) M) caused skin vasoconstriction in a concentration-dependent manner, with the vasoconstrictor potency of ET-1 approximately 200-fold higher than NE. The ETA-receptor antagonist BQ-123 but not the ETB-receptor antagonist BQ-788 blocked the vasoconstrictor effect of ET-1. This observation was confirmed by studying skin perfusion using the dermofluorometry technique. In addition, ETB-receptor agonists BQ-3020 and sarafotoxin S6c (10(-9) to 10(-6) M) did not evoke skin vasoconstriction. BQ-3020 also did not elicit skin vasoconstriction even in the presence of 10(-5) M of Nomega-nitro-L-arginine methyl ester and indomethacin. Furthermore, results from saturable and competitive ET-1 radioligand membrane receptor binding assays revealed that high-affinity and capacity binding sites are predominantly the ETA receptor subtype in endothelium-denuded skin arteries and veins of 0.5-1.5 mm diameter, with an ETA-to-ETB receptor ratio of 83:17 in arteries (n = 5) and 78:22 in veins (n = 7). Results from the present functional and radioligand receptor binding studies clearly indicate that ET-1 is a very potent vasoconstrictor in human skin and its vasoconstrictor effect is primarily mediated by ETA receptors, with no significant participation from ETB receptors.

摘要

本项目的目的是研究内皮素 A（ETA）和内皮素 B（ETB）受体在介导内皮素（ET）-1 诱导的人体皮肤血管收缩中的作用。这些信息应为设计针对外周血管疾病或手术创伤中 ET-1 诱导的皮肤血管痉挛的药物干预提供重要见解。通过研究每种药物处理（n = 4）下恒定流速时皮肤灌注和灌注压力的变化，评估源自皮肤切除术标本的离体灌注人体皮瓣（8×18 厘米）中动脉内药物输注引起的血管收缩。观察到 ET-1（10⁻¹⁰ 至 10⁻⁸ M）和去甲肾上腺素（NE，10⁻⁸ 至 10⁻⁵ M）以浓度依赖性方式引起皮肤血管收缩，ET-1 的血管收缩效力比 NE 高约 200 倍。ETA 受体拮抗剂 BQ-123 而非 ETB 受体拮抗剂 BQ-788 阻断了 ET-1 的血管收缩作用。使用皮肤荧光测定技术研究皮肤灌注证实了这一观察结果。此外，ETB 受体激动剂 BQ-3020 和铃蟾毒素 S6c（10⁻⁹ 至 10⁻⁶ M）未引起皮肤血管收缩。即使存在 10⁻⁵ M 的 Nω-硝基-L-精氨酸甲酯和吲哚美辛，BQ-3020 也未引起皮肤血管收缩。此外，饱和和竞争性 ET-1 放射性配体膜受体结合试验结果显示，在直径为 0.5 - 1.5 毫米的去内皮皮肤动脉和静脉中，高亲和力和容量结合位点主要是 ETA 受体亚型，动脉中 ETA 与 ETB 受体的比例为 83:17（n = 5），静脉中为 78:22（n = 7）。目前的功能和放射性配体受体结合研究结果清楚地表明，ET-1 是人体皮肤中一种非常有效的血管收缩剂，其血管收缩作用主要由 ETA 受体介导，ETB 受体无显著参与。