Modulation of ET-1-induced contraction of human bronchi by airway epithelium-dependent nitric oxide release via ETA receptor activation

Citation
E. Naline et al., Modulation of ET-1-induced contraction of human bronchi by airway epithelium-dependent nitric oxide release via ETA receptor activation, BR J PHARM, 126(2), 1999, pp. 529-535
Citations number
39
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
00071188 → ACNP
Volume
126
Issue
2
Year of publication
1999
Pages
529 - 535
Database
ISI
SICI code
0007-1188(199901)126:2<529:MOECOH>2.0.ZU;2-H
Abstract
1 The purpose of this work was to investigate whether endothelin-1 (ET-1) w as able to induce the release of an inhibitory factor from the airway epith elium in isolated human bronchi and to identify this mediator as well as th e endothelin receptor involved in this phenomenon. 2 In intact bronchi, ET-1 induced a concentration-dependent contraction (-l ogEC(50) = 7.92 +/- 0.09, n = 18) which was potentiated by epithelium remov al (-logEC(50) = 8.65 +/- 0.11, n = 17). BQ-123, an ETA receptor antagonist , induced a significant leftward shift of the ET-1 concentration-response c urve (CRC). This leftward shift was abolished after epithelium removal. 3 L-NAME (3 x 10(-3) M), an inhibitor of nitric oxide (NO) synthase, induce d a significant leftward shift of the ET-1 CRC, and abolished the potentiat ion by BQ-123 (10(-8) M) of ET-1-induced contraction. 4 In intact preparations, the ETB receptor antagonist BQ-788 induced only a t 10(-5) M a slight rightward shift of the ET-1 CRC. In contrast, in epithe lium-denuded bronchi or in intact preparations in the presence of L-NAME, B Q-788 displayed a non-competitive antagonism toward ET-1-induced contractio n. 5 IRL 1620, a selective ETB receptor agonist, induced a contraction of the isolated bronchus (-logEC(50) = 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 air way smooth muscle. One is contractile via ETB-receptor activation, the othe r is inhibitory and responsible of NO release which counteracts via ETA-rec eptor activation the contraction.