Pharmacological modulation of endothelin‐induced contraction of guinea‐pig isolated airways and thromboxane release

Abstract

1 The aim of the present experiments was to study the possible involvement of known bronchoconstrictor substances in mediating the myotropic action of endothelin-1 (ET-1, human-porcine endothelin) in guinea-pig isolated airways. 2 ET-1 (1–100 nm) caused a dose-dependent contraction of guinea-pig trachea, upper bronchus and parenchyma. The contractions developed slowly, reaching maximal values 4–6 min after addition of the peptide. 3 The contractile action of ET-1 was significantly attenuated by indomethacin (10 μm), a cyclo-oxygenase blocker, BM 13505 (5 μm), a thromboxane receptor antagonist, FPL 55712 (19 μm) and YM 16638 (1 μm), antagonists of the sulphidopeptide leukotrienes, BN 52021 (10 μm) and WEB 2086 (1 μm), platelet-activating factor receptor antagonists in all three tissue preparations studied. 4 Pretreatment of the airway tissues with compound U 75302 (3 μm), a selective leukotriene B₄ receptor antagonist, or with a mixture of antagonists containing methysergide (0.75 μm), phentolamine (0.4 μm), propranolol (13 μm), atropine (0.4 μm) and diphenhydramine (0.45 μm) did not modify the myotropic action of ET-1. 5 ET-1, 10 and 100 nm induced three, and nine fold increases in thromboxane A₂ release from lung parenchymal strips. 6 ET-1-induced thromboxane A₂ release was completely abolished by indomethacin, and was significantly attenuated by BN 52021, WEB 2086 and FPL 55712. Neither BM 13505 nor YM 16638 exerted a significant effect on thromboxane release. 7 The present findings show that contraction of guinea-pig airway smooth muscle by ET-1 is mediated, in part, by the release of thromboxane A₂, sulphidopeptide leukotrienes and platelet-activating factor, and suggest that the increased thromboxane A₂ release following ET-1 is partly a consequence of enhanced synthesis of sulphidopeptide leukotrienes and platelet-activating factor.