Aerosolized neutral endopeptidase reverses ozone-induced airway hyperreactivity to substance P.
We investigated the effects of ozone exposure (3.0 ppm, 2 h) on airway neutral endopeptidase (NEP) activity and bronchial reactivity to substance P in guinea pigs. Reactivity after ozone or air exposure was determined by measuring specific airway resistance in intact unanesthetized spontaneously breathing animals in response to increasing doses of intravenous substance P boluses. The effective dose of substance P (in micrograms) that produced a doubling of baseline specific airway resistance (ED200SP) was determined by interpolation of cumulative substance P dose-response curves. NEP activity was measured in tracheal homogenates made from each animal of other groups exposed to either ozone or room air. By reverse-phase high-pressure liquid chromatography, this activity was characterized by the phosphoramidon-inhibitable cleavage of alanine-p-nitroaniline from succinyl-(Ala)3-p-nitroaniline in the presence of 100 microM amastatin. Mean values of the changes in log ED200SP were 0.27 +/- 0.07 (SE) for the ozone-exposed group and 0.08 +/- 0.04 for the air-exposed group. We found that phosphoramidon significantly increased substance P reactivity in the air-exposed animals (P less than 0.01), but it had no effect in the ozone-exposed group. This finding was associated with a significant reduction in tracheal homogenate NEP activity of ozone-exposed animals compared with controls: mean values were 18.1 +/- 1.9 nmol.min-1.mg protein-1 for the ozone-exposed group and 25.1 +/- 2.4 nmol.min-1.mg protein-1 for air-exposed animals (P less than 0.05). Inhalation of an aerosolized NEP preparation, partially purified from guinea pig kidney, reversed the substance P hyperreactivity produced by ozone exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Murlas
C G
CG
Department of Medicine, Rush University, Chicago, Illinois 60612.
Lang
Z
Z
Williams
G J
GJ
Chodimella
V
V
D000336:Aerosols; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D009092:Mucous Membrane / Q000201:enzymology; D015260:Neprilysin / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D010126:Ozone / Q000633:toxicity*; D012137:Respiratory System / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013373:Substance P / Q000494:pharmacology
D000336:Aerosols; D006020:Glycopeptides; D013373:Substance P; D010126:Ozone; D015260:Neprilysin; C008890:phosphoramidon