phosphoramidon and Pneumonia

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 B(2) 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 B(2) kinin receptors. However, neither intraperitioneal MEN16132 nor the peptide B(2) 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 B(2) 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.

Topics: Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Captopril; Cell Count; Glycopeptides; Guinea Pigs; Histamine; Male; Ornithine; Ovalbumin; Parainfluenza Virus 3, Human; Peptides; Plethysmography, Whole Body; Pneumonia; Protease Inhibitors; Respirovirus Infections; Sulfonamides; Tissue Kallikreins

The intratracheal (i.t.) instillation of Sephadex beads into rat induced inflammation and a 30-fold increase in the endothelin-1-like immunoreactivity (ET-1-LI) of broncho-alveolar lavage fluid. The levels were highest 24 h after the instillation and had declined significantly after 48 h. At a dose of 1 mg kg-1 i.t., the glucocorticosteroid budesonide almost abolished this response. Phosphoramidon, which inhibits neutral endopeptidase, an enzyme reported to degrade ET-1 and also to inhibit the endothelin-converting enzyme, potentiated the Sephadex-induced rise in ET-1-LI. Chymostatin and heparin, which are reported to reduce the formation of ET-1, did not affect the increase in ET-1-LI. The present model represents a very reactive system for analyzing the changes in ET-1 levels during inflammation.

Topics: Animals; Bronchoalveolar Lavage Fluid; Budesonide; Chromatography, High Pressure Liquid; Dextrans; Endothelin-1; Enzyme Inhibitors; Glycopeptides; Heparin; Hydrogen Peroxide; Male; Oligopeptides; Pneumonia; Pregnenediones; Rats; Rats, Sprague-Dawley

Exposure of phosphoramidon-treated (0.1 mM solution by aerosol for 15 min) guinea pigs to an aerosol of endothelin-1 (ET-1) (10 micrograms/ml) for 30 min induced after 18-24 h an enhanced bronchopulmonary response (BR) to rechallenge with ET-1 (3 micrograms/ml) administered by aerosol. Compared with saline-exposed animals, aerosol exposure of guinea pigs to ET-1 (10 micrograms/ml) for 30 min did not alter the dose-related BR to acetylcholine (ACh) administered by aerosol 18-24 h following challenge with the peptide. In phosphoramidon-treated guinea pigs, ET-1 (5 micrograms/ml) exposure for 30 min evoked a slight but non-significant enhancement of the ACh-induced BR. Administered by aerosol in phosphoramidon-treated guinea pigs, ET-1 did not induce eosinophil accumulation in the lung, as demonstrated by examination of histological preparations and the assessment of the cell composition of bronchoalveolar lavages. The present data indicate that in spite of treatment of guinea pigs with phosphoramidon, ET-1 administration does not lead to the development of bronchial hyperresponsiveness.

Topics: Acetylcholine; Administration, Inhalation; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Endothelins; Glycopeptides; Guinea Pigs; Lung; Male; Pneumonia