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

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. 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 ETA receptor antagonist, induced a significant leftward shift of the ET-1 concentration-response curve (CRC). This leftward shift was abolished after epithelium removal. L-NAME (3×10−3M), 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. In intact preparations, the ETB 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. IRL 1620, a selective ETB 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. 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. British Journal of Pharmacology (1999) 126, 529–535; doi:10.1038/sj.bjp.0702327