气道上皮依赖性一氧化氮通过激活ET(A)受体释放来调节ET-1诱导的人支气管收缩。

Modulation of ET-1-induced contraction of human bronchi by airway epithelium-dependent nitric oxide release via ET(A) receptor activation.

作者信息

Naline E, Bertrand C, Biyah K, Fujitani Y, Okada T, Bisson A, Advenier C

机构信息

Laboratoire de Pharmacologie, Faculté de Médecine Paris-Ouest, France.

出版信息

Br J Pharmacol. 1999 Jan;126(2):529-35. doi: 10.1038/sj.bjp.0702327.

DOI:10.1038/sj.bjp.0702327

PMID:10077248

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565829/

Abstract

The purpose of this work was to investigate whether endothelin-1 (ET-1) was able to induce the release of an inhibitory factor from the airway epithelium in isolated human bronchi and to identify this mediator as well as the endothelin receptor involved in this phenomenon. 2. In intact bronchi, ET-1 induced a concentration-dependent contraction (-logEC50 = 7.92+/-0.09, n = 18) which was potentiated by epithelium removal (-logEC50 = 8.65+/-0.11, n = 17). BQ-123 , an ET(A) receptor antagonist, induced a significant leftward shift of the ET-1 concentration-response curve (CRC). This leftward shift was abolished after epithelium removal. 3. L-NAME (3 x 10(-3) M), an inhibitor of nitric oxide (NO) synthase, induced a significant leftward shift of the ET-1 CRC, and abolished the potentiation by BQ-123 (10(-8) M) of ET-1-induced contraction. 4. In intact preparations, the ET(B) receptor antagonist BQ-788 induced only at 10(-5) M a slight rightward shift of the ET-1 CRC. In contrast, in epithelium-denuded bronchi or in intact preparations in the presence of L-NAME, BQ-788 displayed a non-competitive antagonism toward ET-1-induced contraction. 5. IRL 1620, a selective ET(B) receptor agonist, induced a contraction of the isolated bronchus (-logEC50=7.94+/-0.11, n= 19). This effect was not modified by epithelium removal or by BQ-123. BQ-788 exerted a competitive antagonism against IRL 1620 which was similar in the presence or absence of epithelium. 6. These results show that ET-1 exerts two opposite effects on the human airway smooth muscle. One is contractile via ETB-receptor activation, the other is inhibitory and responsible of NO release which counteracts via ETA-receptor activation the contraction.

摘要

本研究的目的是探究内皮素 -1（ET-1）是否能够诱导分离的人支气管气道上皮释放一种抑制因子，并鉴定该介质以及参与此现象的内皮素受体。2. 在完整的支气管中，ET-1 诱导浓度依赖性收缩（-logEC50 = 7.92±0.09，n = 18），去除上皮后收缩增强（-logEC50 = 8.65±0.11，n = 17）。ET(A)受体拮抗剂 BQ-123 使 ET-1 浓度 - 反应曲线（CRC）显著左移。去除上皮后，这种左移消失。3. 一氧化氮（NO）合酶抑制剂 L-NAME（3×10⁻³ M）使 ET-1 的 CRC 显著左移，并消除了 BQ-123（10⁻⁸ M）对 ET-1 诱导收缩的增强作用。4. 在完整标本中，ET(B)受体拮抗剂 BQ-788 仅在 10⁻⁵ M 时使 ET-1 的 CRC 轻微右移。相比之下，在去上皮支气管或存在 L-NAME 的完整标本中，BQ-788 对 ET-1 诱导的收缩表现出非竞争性拮抗作用。5. 选择性 ET(B)受体激动剂 IRL 1620 诱导分离支气管收缩（-logEC50 = 7.94±0.11，n = 19）。去除上皮或使用 BQ-123 均未改变此效应。BQ-788 对 IRL 1620 发挥竞争性拮抗作用，无论有无上皮存在情况均相似。6. 这些结果表明，ET-1 对人气道平滑肌发挥两种相反的作用。一种是通过激活 ETB 受体产生收缩作用，另一种是抑制作用，负责释放 NO，通过激活 ETA 受体抵消收缩作用。