title: Bradykinin-induced airway microvascular leakage is potentiated by captopril and phosphoramidon.
abstract: Bradykinin can be inactivated by the peptidases angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), both of which are present in the airways. We evaluated the role of these enzymes in bradykinin-induced airway microvascular leakage and lung resistance in anesthetized and mechanically ventilated guinea pigs. We studied the effects of captopril (inhaled; 350 nmol), a specific ACE inhibitor, and phosphoramidon (inhaled; 7.5 nmol), a specific NEP inhibitor. Airway microvascular leakage was measured with the albumin marker Evans Blue dye (20 mg/kg i.v.), and airflow obstruction was measured as lung resistance (RL). Bradykinin was given by inhalation (0.1, 0.3 and 1 mM; 45 breaths), and caused a dose-dependent increase in both RL and airway microvascular leakage. Inhibition of NEP or ACE potentiated the bradykinin-induced microvascular leakage in main bronchi and proximal and distal intrapulmonary airways. However, only NEP inhibition significantly potentiated the extravasation of Evans Blue dye into the tracheal wall and lumen. The combined inhibition of NEP and ACE significantly potentiated plasma leakage at all airway levels, as well as the increase in RL induced by inhaled bradykinin. Recovery RL after one lung inflation significantly correlated with the extravasation of Evans Blue dye in the tissue at all airway levels, indicating that airway edema may have contributed to airway narrowing. We conclude that in the guinea pig, both NEP and ACE modulate bradykinin-induced airway microvascular leakage.
authors.affiliation: Department of Thoracic Medicine, National Heart and Lung Institute, Royal Brompton and National Heart Hospital, London, U.K.
authors.forename: J O
authors.initials: JO
authors.lastname: Lötvall
authors.forename: K
authors.initials: K
authors.lastname: Tokuyama
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: K F
authors.initials: KF
authors.lastname: Chung
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006020:Glycopeptides / Q000494:pharmacology*; D006168:Guinea Pigs; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D006020:Glycopeptides; D002216:Captopril; D015260:Neprilysin; D000109:Acetylcholine; D001920:Bradykinin; C008890:phosphoramidon