Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig. Possible role of free radicals.
We examined the effects of acute exposure to cigarette smoke on the airway responses to substance P in anesthetized guinea pigs and on the activity of airway neutral endopeptidase (NEP). After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon. In the absence of phosphramidon the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea pigs than in air-exposed animals. Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals. In the presence of phosphoramidon, bronchoconstrictor responses to substance P in animals exposed to air or to cigarette smoke were not different. Aerosols of SOD delivered before cigarette smoke exposures dramatically reduced smoke-induced hyperresponsiveness to substance P, whereas heat-inactivated SOD had no effect on smoke-induced hyper-responsiveness to substance P. Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine. The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity. We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP. We suggest that cigarette smoke-induced inhibition of airway NEP is due to effects of free radicals.
Dusser
D J
DJ
Cardiovascular Research Institute, University of California, San Francisco 94143-0130.
Djokic
T D
TD
Borson
D B
DB
Nadel
J A
JA
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001980:Bronchi / Q000201:enzymology*; D001985:Bronchial Provocation Tests; D002211:Capsaicin / Q000008:administration & dosage; D004789:Enzyme Activation; D005609:Free Radicals; D006020:Glycopeptides / Q000008:administration & dosage; D006168:Guinea Pigs; D008297:Male; D015260:Neprilysin / Q000378:metabolism*; D009538:Nicotine / Q000008:administration & dosage; D012907:Smoking / Q000009:adverse effects*; D012996:Solutions; D013373:Substance P / Q000008:administration & dosage*; D013388:Succinimides / Q000008:administration & dosage; D013482:Superoxide Dismutase / Q000008:administration & dosage
D005609:Free Radicals; D006020:Glycopeptides; D012996:Solutions; D013388:Succinimides; C015752:N-chlorosuccinimide; D013373:Substance P; D009538:Nicotine; D013482:Superoxide Dismutase; D015260:Neprilysin; D002211:Capsaicin; C008890:phosphoramidon