Endothelin-1 (1-31) induces a thiorphan-sensitive release of eicosanoids via ET_B receptors in the guinea pig perfused lung

Maturation of big endothelin-1 (big ET-1) commonly produces the 21 amino acid vasoactive ET-1, which binds two ET receptors (ET_A and ET_B) to produce its effects. In the guinea pig, the systemic administration of ET-1 produces a bronchoconstrictor response that is mediated indirectly via the release of thromboxane A₂ through ET_B receptor activation. A new potent metabolite of big ET-1, ET-1 (1–31), has been reported to act as an ET_A receptor selective agonist. In this study we investigated the effects of ET-1 (1–31), compared with ET-1, on the release of eicosanoids in the isolated and perfused guinea pig lung. We also clarified the implication of ET receptors in these effects using selective ET_A or ET_B receptor antagonists, BQ-123 and BQ-788 respectively. Finally, using the neutral endopeptidase 24.11 (NEP 24.11) inhibitor, thiorphan, we determined the involvement of this enzyme on ET-1 (1–31) effects. Infusion of ET-1 (1–31) (50nM) stimulates a marked release of thromboxane A₂ and prostacyclin equivalent to that observed with a ten times lower concentration of ET-1 (5nM). BQ-788 (5nM and 10nM), but not BQ-123 (1µM), decreases the release of thromboxane A₂ and prostacyclin triggered by both agonists. Interestingly, thiorphan (25µM) abolishes the eicosanoid-releasing properties of big ET-1 (100nM) and ET-1 (1–31). This study demonstrates that ET-1 (1–31) is less potent than ET-1 in stimulating the release of eicosanoids through ET_B receptor activation in the guinea pig perfused lung. Moreover, the inhibitory properties of thiorphan indicate the possible existence of a bioactive metabolite of ET-1 (1–31). We therefore suggest that NEP 24.11 in the pulmonary vasculature, is implicated in the cleavage of ET-1 (1–31) to produce ET-1 which will further act on both ET receptors.