title: Peptidase modulation of noncholinergic vagal bronchoconstriction and airway microvascular leakage.
abstract: We investigated whether inhibition of neutral endopeptidase 24.11 (NEP) and/or angiotensin-converting enzyme (ACE) modifies vagally induced nonadrenergic noncholinergic (NANC) airflow obstruction and airway microvascular leakage as measured by extravasation of Evans blue dye (intravenous) in anesthetized guinea pigs. We gave phosphoramidon to inhibit NEP and enalapril maleate or captopril to inhibit ACE. Animals pretreated with inhaled phosphoramidon (7.5 or 75 nmol), enalapril maleate (87 or 870 nmol), or captopril (350 nmol) reached higher peak lung resistance (RL) values (14.3 +/- 2.7, 15.7 +/- 3.8, 16.7 +/- 3.8, 11.4 +/- 1.6, and 24.6 +/- 3.5 cmH2O.ml-1.s, respectively) than saline-treated animals (5.9 +/- 1.1; P less than 0.05) after bilateral vagus nerve stimulation (5 Hz, 10 V, 10 ms, 150 s). Intravenous phosphoramidon (1 mg/kg), but not intravenous captopril (6 mg/kg), potentiated peak RL (22.9 +/- 6.9 and 7.1 +/- 1.5 cmH2O.ml-1.s, respectively). Vagal nerve stimulation (1 and 5 Hz) increased the extravasation of Evans blue dye in tracheobronchial tissues compared with sham-stimulated animals, but this was not potentiated by inhaled enzyme inhibitors or intravenous captopril. However, intravenous phosphoramidon significantly augmented the extravasation of Evans blue dye in main bronchi and intrapulmonary airways. We conclude that degradative enzymes regulate both NANC-induced airflow obstruction and airway microvascular leakage.
authors.affiliation: Department of Thoracic Medicine, Brompton Hospital, London, United Kingdom.
authors.forename: J O
authors.initials: JO
authors.lastname: Lötvall
authors.forename: K
authors.initials: K
authors.lastname: Tokuyama
authors.forename: C G
authors.initials: CG
authors.lastname: Löfdahl
authors.forename: A
authors.initials: A
authors.lastname: Ullman
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: K F
authors.initials: KF
authors.lastname: Chung
mesh_terms: D000110:Acetylcholinesterase / Q000502:physiology; D000403:Airway Resistance / Q000187:drug effects / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000502:physiology*; D012137:Respiratory System / Q000098:blood supply / Q000187:drug effects; D014630:Vagus Nerve / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D006020:Glycopeptides; D000110:Acetylcholinesterase; D015260:Neprilysin; C008890:phosphoramidon