Dual action of iNOS-derived nitric oxide in allergen-induced airway hyperreactivity in conscious, unrestrained guinea pigs.
Using a guinea pig model of acute allergic asthma, we recently established that a deficiency of nitric oxide (NO) contributes to airway hyperreactivity (AHR) after the early asthmatic reaction (EAR) and that restoration of NO activity may contribute to the (partial) reversal of AHR after the late asthmatic reaction (LAR). In the present study, we investigated the role of iNOS-derived NO in the regulation of AHR to histamine after the LAR. Inhalation of a selective dose of the specific iNOS inhibitor aminoguanidine (0.1 mM, 3 min) had no effect on basal airway reactivity to histamine in unchallenged, ovalbumin-sensitized animals and did not affect the allergen-induced AHR after the EAR. By contrast, this dose of aminoguanidine significantly potentiated the partially reduced AHR after the LAR to the level of AHR observed after the EAR, indicating that induction of iNOS during the LAR contributes to the reversal of AHR. Inhalation of a higher aminoguanidine concentration (2.5 mM) shortly before the onset of the LAR diminished the AHR after the LAR and reduced the number of neutrophils, lymphocytes, and ciliated epithelial cells in the bronchoalveolar lavage at this time point. The results indicate that iNOS-derived NO may have both beneficial and detrimental effects on allergen-induced AHR to histamine after the LAR by functional antagonism of histamine-induced bronchoconstriction, and by promoting airway inflammation and epithelial damage on the other hand, respectively.
Schuiling
M
M
Department of Molecular Pharmacology, University Centre for Pharmacy, Groningen, The Netherlands.
Meurs
H
H
Zuidhof
A B
AB
Venema
N
N
Zaagsma
J
J
D000208:Acute Disease; D000276:Adjuvants, Immunologic; D000485:Allergens / Q000009:adverse effects*; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000503:physiopathology*; D001991:Bronchitis / Q000209:etiology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects; D002452:Cell Count; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010047:Ovalbumin / Q000276:immunology
D000276:Adjuvants, Immunologic; D000485:Allergens; D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D006632:Histamine; D010047:Ovalbumin; D019001:Nitric Oxide Synthase; C004479:pimagedine