Neutral endopeptidase inhibitor potentiates endothelin-1-induced airway smooth muscle contraction.
To study the role of neutral endopeptidase (NEP) on endothelin-1-induced contraction of the airway smooth muscle, we examined the contractile effect of endothelin-1 in the isolated guinea pig trachea and human bronchus in the presence or absence of NEP inhibitor phosphoramidon. After incubation with phosphoramidon (10(-8) to 10(-5) M), we added endothelin-1 cumulatively from 10(-11) to 10(-7) M to the airway tissues in organ baths. Phosphoramidon significantly potentiated the endothelin-1-induced contraction in a concentration-dependent fashion in both guinea pig trachea and human bronchus, and it shifted the concentration-response curves to the left. Because NEP is known to cleave tachykinins, we next studied whether endothelin-1 contracts airway tissues by releasing endogenous tachykinins from bronchial C-fibers. After incubation with phosphoramidon (10(-5) M), we added endothelin-1 cumulatively from 10(-11) to 10(-7) M to the tissues that were treated with capsaicin to deplete the tachykinins. Phosphoramidon significantly potentiated the endothelin-1-induced contraction in the capsaicin-treated tissues, suggesting that endothelin-1 causes the contraction, at least in part, without releasing tachykinins. In contrast to the effect of phosphoramidon, captopril (an angiotensin-converting enzyme inhibitor), leupeptin (a serine protease inhibitor), and bestatin (an aminopeptidase inhibitor) did not modulate the effect of endothelin-1-induced contraction in both guinea pig trachea and human bronchus. From these results, we conclude that NEP plays an important role in regulating endothelin-1-induced contraction in the guinea pig trachea and human bronchus.
Yamaguchi
T
T
First Department of Internal Medicine, Kumamoto University Medical School, Japan.
Kohrogi
H
H
Kawano
O
O
Ando
M
M
Araki
S
S
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004357:Drug Synergism; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology*; D006020:Glycopeptides / Q000008:administration & dosage; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D012132:Respiratory Muscles / Q000187:drug effects* / Q000502:physiology
D016232:Endothelins; D006020:Glycopeptides; D015260:Neprilysin; D002211:Capsaicin; C008890:phosphoramidon