Inhibitors of neutral endopeptidase potentiate electrically and capsaicin-induced noncholinergic contraction in guinea pig bronchi.
To evaluate the role of airway neutral endopeptidase (NEP) in the regulation of contraction of airway smooth muscle in response to endogenous tachykinins, we studied the effects of the NEP inhibitor phosphoramidon on contractions of guinea pig bronchial smooth muscle strips induced by either electrical field stimulation (EFS) or by capsaicin. In the presence of atropine (10(-6) M), propranolol (10(-6) M), phentolamine (10(-5) M), indomethacin (10(-6) M) and pyrilamine (5 x 10(-6) M) EFS (biphasic; pulse width, 1.0 msec; frequency 0.5-5 Hz for 30 sec; intensity, 20 V) produced noncholinergic, nonadrenergic muscle contraction in a frequency-dependent fashion (P less than .001). Phosphoramidon potentiated the contractile responses to EFS (P less than .01). Leucine-thiorphan (10(-5) M), another NEP inhibitor, potentiated EFS-induced contraction in a similar fashion as phosphoramidon (186 and 182% of control, respectively; each comparison, P less than .025). Captopril, bestatin, leupeptin and physostigmine (each drug, 10(-5) M) were without effect (P greater than .5, N = 5). Capsaicin (1.5 x 10(-8) M) produced long-lasting atropine-resistant smooth muscle contraction, an effect potentiated by phosphoramidon (10(-5) M (P less than .001). Removal of the epithelium slightly but significantly (P less than .05) increased the contractile responses to capsaicin and to EFS at impulse frequencies of 2 and 5 Hz, and phosphoramidon substantially increased contractions in tissues without epithelium. The trachea, bronchi and lungs each contained significant NEP activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Djokic
T D
TD
Cardiovascular Research Institute, University of California, San Francisco.
Nadel
J A
JA
Dusser
D J
DJ
Sekizawa
K
K
Graf
P D
PD
Borson
D B
DB
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D002211:Capsaicin / Q000494:pharmacology*; D004558:Electric Stimulation; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D015260:Neprilysin / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D013373:Substance P / Q000502:physiology; D015244:Thiorphan / Q000031:analogs & derivatives / Q000494:pharmacology
D006020:Glycopeptides; D013373:Substance P; C054498:leucine thiorphan; D015244:Thiorphan; D015260:Neprilysin; D002211:Capsaicin; C008890:phosphoramidon