Abstract
Inhaled bradykinin causes bronchoconstriction in asthmatic subjects but not nonasthmatics. To date, animal studies with inhaled bradykinin have been performed only in anesthetized guinea pigs and rats, where it causes bronchoconstriction through sensory nerve pathways. In the present study, airway function was recorded in conscious guinea pigs by whole-body plethysmography. Inhaled bradykinin (1 mM, 20 s) caused bronchoconstriction and influx of inflammatory cells to the lungs, but only when the enzymatic breakdown of bradykinin by angiotensin-converting enzyme and neutral endopeptidase was inhibited by captopril (1 mg/kg i.p.) and phosphoramidon (10 mM, 20-min inhalation), respectively. The bronchoconstriction and cell influx were antagonized by the B2 kinin receptor antagonist 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) when given by inhalation (1 and 10 μM, 20 min) and are therefore mediated via B2 kinin receptors. However, neither intraperitioneal MEN16132 nor the peptide B2 antagonist icatibant, by inhalation, antagonized these bradykinin responses. Sensitization of guinea pigs with ovalbumin was not sufficient to induce airway hyperreactivity (AHR) to the bronchoconstriction by inhaled bradykinin. However, ovalbumin challenge of sensitized guinea pigs caused AHR to bradykinin and histamine. Infection of guinea pigs by nasal instillation of parainfluenza-3 virus produced AHR to inhaled histamine and lung influx of inflammatory cells. These responses were attenuated by the bradykinin B2 receptor antagonist MEN16132 and H-(4-chloro)DPhe-2′(1-naphthylalanine)-(3-aminopropyl)guanidine (VA999024), an inhibitor of tissue kallikrein, the enzyme responsible for lung synthesis of bradykinin. These results suggest that bradykinin is involved in virus-induced inflammatory cell influx and AHR.
Footnotes
This work was supported by Vantia Ltd (Southampton, UK).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.171876.
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ABBREVIATIONS:
- AHR
- airway hyperreactivity
- ACE
- angiotensin-converting enzyme
- ANOVA
- analysis of variance
- BALF
- bronchoalveolar lavage fluid
- DMEM
- Dulbecco's modified essential medium
- NEP
- neutral endopeptidase
- PIV-3
- parainfluenze-3 virus
- sGaw
- specific airway conductance
- VERO cells
- African green monkey kidney epithelial cells
- MGTA
- dl-2-mercaptomethyl-3-guanidinoethylthiopropionic acid
- MEN16132
- 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride
- TCID
- tissue culture infective dose
- VA999024
- H-(4-chloro)DPhe-2′(1-naphthylalanine)-(3-aminopropyl)guanidine.
- Received June 23, 2010.
- Accepted September 15, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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