TY - JOUR T1 - <span class="sc">l</span>-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction JF - European Respiratory Journal JO - Eur Respir J SP - 191 LP - 199 DO - 10.1183/09031936.00105408 VL - 34 IS - 1 AU - H. Maarsingh AU - B. E. Bossenga AU - I. S. T. Bos AU - H. H. Volders AU - J. Zaagsma AU - H. Meurs Y1 - 2009/07/01 UR - http://erj.ersjournals.com/content/34/1/191.abstract N2 - 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 Nω-hydroxy-nor-l-arginine (nor-NOHA) and the polycation antagonist heparin normalised airway responsiveness. These effects were reversed by the nitric oxide synthase inhibitor Nω-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. ER -