Neutral endopeptidase modulates endothelin-1-induced airway smooth muscle contraction in guinea-pig trachea.
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 less than 0.05) and by 138 +/- 49% (P less than 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 microgram 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.
Di Maria
G U
GU
Cardiovascular Research Institute, University of California, San Francisco 94143.
Katayama
M
M
Borson
D B
DB
Nadel
J A
JA
D000818:Animals; D004347:Drug Interactions; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015244:Thiorphan / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D016232:Endothelins; D011994:Recombinant Proteins; C054498:leucine thiorphan; D015244:Thiorphan; D015260:Neprilysin