Neutral endopeptidase modulates endothelin-1-induced airway smooth muscle contraction in guinea-pig trachea

Abstract

This study was designed to evaluate the role of neutral endopeptidase (NEP) in modulating the airway smooth muscle contraction induced by endothelin-1 in isolated segments of guinea-pig trachea. Endothelin-1 (10 −9–10 −6 M) produced a concentration-dependent contraction that reached a maximum by 30 min. The NEP inhibitor leucine-thiorphan (10 −5 M) significantly increased the contractile response to endothelin-1. The addition of leucine-thiorphan to tracheal segments precontracted by 10 −9 and 10 −8 M endothelin-1 increased isometric tension by 181 ± 65% (mean ± 1 S.E.M.; P < 0.05) and by 138 ± 49% ( P < 0.05), respectively. In contrast, the kininase II inhibitor captopril and the peptidase inhibitors leupeptin and bestatin had no effect. Preincubation of endothelin-1 with 1 μg recombinant human NEP decreased the contractile activity of endothelin-1 by 72 ± 9%, whereas no effect was observed using heat-inactivated NEP. We conclude that NEP modulates endothelin-induced contraction of airway smooth muscle in the guinea-pig trachea.