L-arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction.
Peroxynitrite has been shown to be crucially involved in airway hyperresponsiveness (AHR) after the late asthmatic reaction (LAR). Peroxynitrite production may result from simultaneous synthesis of nitric oxide (NO) and superoxide by inducible NO-synthase (iNOS) at low L-arginine concentrations. L-arginine availability to iNOS is regulated by its cellular uptake, which can be inhibited by eosinophil-derived polycations and by arginase, which competes with iNOS for the common substrate. Using a guinea pig model of allergic asthma, we investigated whether aberrant L-arginine homeostasis could underlie peroxynitrite-mediated AHR after the LAR. After the LAR, arginase activity in the airways and eosinophil peroxidase release from bronchoalveolar lavage cells were increased. These changes were associated with a 2.0-fold AHR to methacholine as measured in isolated perfused tracheal preparations. AHR was reduced by exogenous L-arginine administration. Moreover, both the arginase inhibitor N(omega)-hydroxy-nor-L-arginine (nor-NOHA) and the polycation antagonist heparin normalised airway responsiveness. These effects were reversed by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), indicating that both agents reduced AHR by restoring bronchodilating NO production. In conclusion, in allergen-challenged guinea pigs, the AHR after the LAR is caused by arginase- and polycation-induced attenuation of L-arginine availability to iNOS, which may switch the enzyme to simultaneous production of superoxide and NO, and, consequently, peroxynitrite.
Maarsingh
H
H
Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. h.maarsingh@rug.nl
Bossenga
B E
BE
Bos
I S T
IS
Volders
H H
HH
Zaagsma
J
J
Meurs
H
H
D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000172:deficiency*; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010047:Ovalbumin / Q000378:metabolism; D010477:Perfusion; D030421:Peroxynitrous Acid / Q000378:metabolism; D011073:Polyamines; D000071228:Polyelectrolytes; D014132:Trachea / Q000378:metabolism
D001119:Arginase; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D010047:Ovalbumin; D030421:Peroxynitrous Acid; D011073:Polyamines; D000071228:Polyelectrolytes