Maturation of big endothelin-1 (big ET-1) commonly produces the 21 amino acid vasoactive ET-1, which binds two ET receptors (ETA and ETB) 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 ETB receptor activation. A new potent metabolite of big ET-1, ET-1 (1–31), has been reported to act as an ETA 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 ETA or ETB 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 ETB 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.

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