title: Airway neutral endopeptidase-like enzyme modulates tachykinin-induced bronchoconstriction in vivo.
abstract: To determine whether neutral endopeptidase (NEP), also called enkephalinase (EC 3.4.24.11), modulates the effects of exogenous and endogenous tachykinins in vivo, we studied the effects of aerosolized phosphoramidon, a specific NEP inhibitor, on the responses to aerosolized substance P (SP) and on the atropine-resistant response to vagus nerve stimulation (10 V, 5 ms for 20 s) in guinea pigs. SP alone (10(-7) to 10(-4) M; each concentration, 7 breaths) caused no change in total pulmonary resistance (RL, P greater than 0.5). Phosphoramidon (10(-4) M, 90 breaths) caused no change either in base-line RL (P greater than 0.5) or in the response to aerosolized acetylcholine (P greater than 0.5). However, in the presence of phosphoramidon, SP (7 breaths) produced a concentration-dependent increase in RL at concentrations greater than or equal to 10(-5) M (P less than 0.001). Phosphoramidon (10(-7) to 10(-4) M; each concentration, 90 breaths) induced a concentration-dependent potentiation of SP-induced bronchoconstriction (10(-4) M, 7 breaths; P less than 0.01). Vagus nerve stimulation (0.5-3 Hz), in the presence of atropine, induced a frequency-dependent increase in RL (P less than 0.001). Phosphoramidon potentiated the atropine-resistant responses to vagus nerve stimulation (P less than 0.001) at frequencies greater than 0.5 Hz. The tachykinin antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-substance P abolished the effects of phosphoramidon on the atropine-resistant response to vagus nerve stimulation (2 Hz, P less than 0.005). NEP-like activity in tracheal homogenates of guinea pig was inhibited by phosphoramidon with a concentration producing 50% inhibition of 5.3 +/- 0.8 nM.(ABSTRACT TRUNCATED AT 250 WORDS)
authors: Cardiovascular Research Institute, University of California, San Francisco 94143.
authors: D J
authors: DJ
authors: Dusser
authors: E
authors: E
authors: Umeno
authors: P D
authors: PD
authors: Graf
authors: T
authors: T
authors: Djokic
authors: D B
authors: DB
authors: Borson
authors: J A
authors: JA
authors: Nadel
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000494:pharmacology; D014630:Vagus Nerve / Q000502:physiology
chemical_list: D006020:Glycopeptides; D015320:Tachykinins; D013373:Substance P; D001285:Atropine; D015260:Neprilysin; C008890:phosphoramidon