Role of L-arginine in the deficiency of nitric oxide and airway hyperreactivity after the allergen-induced early asthmatic reaction in guinea-pigs.
1. Using a guinea-pig model of allergic asthma, we investigated the role of L-arginine limitation in the allergen-induced deficiency of nitric oxide (NO) and airway hyperreactivity (AHR) after the early asthmatic reaction, by examining the effects of various concentrations of the NO synthase (NOS) substrate on the responsiveness to methacholine of isolated perfused tracheae from unchallenged (control) animals and from animals 6 h after ovalbumin challenge. 2. Preparations from ovalbumin-challenged guinea-pigs showed a 1.9 fold increase in the maximal response (Emax) to intraluminal (IL) administration of methacholine compared to controls (P<0.001). A similar 2.0 fold (P<0.05) increase in Emax to methacholine was observed in control airways incubated with the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 0.1 mM, IL), while L-NAME had no further effect on the airways from ovalbumin-challenged animals. 3. In control airways, extraluminal (EL) administration of 0.3, 1.0 and 5.0 mM L-arginine all suppressed the Emax for methacholine by approximately 40% (P<0.01 all), whereas 5.0 mM D-arginine (EL) had no effect. 4. L-Arginine dose-dependently reduced the AHR to methacholine in tracheae from ovalbumin-challenged guinea-pigs, the responsiveness being normalized in the presence of 5.0 mM L-arginine. As in controls, 5.0 mM D-arginine was without effect. 5. The results demonstrate that deficiency of endogenous NO contributes to the allergen-induced AHR to methacholine after the early asthmatic reaction, which is reversed by exogenous administration of L-arginine. This indicates that limitation of substrate may underly the reduced cNOS activity and subsequent AHR after the acute asthmatic response.
Boer
J
J
Department of Molecular Pharmacology, University Centre for Pharmacy, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Duyvendak
M
M
Schuurman
F E
FE
Pouw
F M
FM
Zaagsma
J
J
Meurs
H
H
D000485:Allergens / Q000633:toxicity*; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001249:Asthma / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D016210:Methacholine Chloride; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010047:Ovalbumin / Q000276:immunology; D014132:Trachea / Q000503:physiopathology
D000485:Allergens; D016085:Bronchoconstrictor Agents; D004791:Enzyme Inhibitors; D016210:Methacholine Chloride; D009569:Nitric Oxide; D010047:Ovalbumin; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester