Enkephalinase inhibitor potentiates substance P- and capsaicin-induced bronchial smooth muscle contractions in humans.
To determine the roles of endogenously released tachykinins (substance P, neurokinins A and B) in human bronchial tissues, and to determine the roles of enkephalinase (neutral endopeptidase, E.C. 3.4.24.11) in regulating the effects of the tachykinins, we studied the effects of substance P and capsaicin, which releases tachykinins, on human bronchial smooth muscle contraction in the presence or absence of enkephalinase inhibitor phosphoramidon in vitro. Substance P alone caused human bronchial smooth muscle contraction at 10(-6) M or more. Phosphoramidon (10(-7) to 10(-5) M) potentiated the substance P-induced contraction in a dose-dependent fashion, and phosphoramidon shifted the dose-response curve to lower concentrations. Capsaicin (10(-5) or 10(-4) M) alone caused bronchial smooth muscle contraction in four tissues from nine patients. After the contraction by capsaicin reached a plateau, phosphoramidon (10(-5) M) increased and prolonged the contraction significantly. Furthermore, pretreatment of bronchial tissues with phosphoramidon (10(-5) M) potentiated capsaicin-induced contraction in all tissues from five patients. Phosphoramidon (10(-5) M) shifted the dose-response curve to capsaicin to lower concentrations more than 1 log unit. Captopril did not alter the contractile response to substance P, suggesting that angiotensin-converting enzyme does not regulate the contractile response to substance P in human bronchial smooth muscle in vitro. These results suggest that enkephalinase regulates the contractile effects of exogenous substance P and endogenous substances, probably tachykinins, released by capsaicin in the human bronchus.
Honda
I
I
First Department of Internal Medicine, Kumamoto University Medical School, Japan.
Kohrogi
H
H
Yamaguchi
T
T
Ando
M
M
Araki
S
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001980:Bronchi / Q000187:drug effects*; D016084:Bronchoconstriction / Q000187:drug effects*; D002211:Capsaicin / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology; D004357:Drug Synergism; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D013373:Substance P / Q000494:pharmacology*
D006020:Glycopeptides; D013373:Substance P; D002216:Captopril; D015260:Neprilysin; D002211:Capsaicin; C008890:phosphoramidon