Increased arginase activity underlies allergen‐induced deficiency of cNOS‐derived nitric oxide and airway hyperresponsiveness

Abstract

1 A de®ciency of constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO), due to reduced availability of L-arginine, importantly contributes to allergen-induced airway hyperresponsiveness (AHR) after the early asthmatic reaction (EAR). Since cNOS and arginase use L-arginine as a common substrate, we hypothesized that increased arginase activity is involved in the allergeninduced NO de®ciency and AHR. 2 Using a guinea-pig model of allergic asthma, we addressed this hypothesis by examining the e ects of the speci®c arginase inhibitor N o -hydroxy-nor-L-arginine (nor-NOHA) on the responsiveness to methacholine of isolated perfused tracheae from unchallenged control animals and from animals 6 h after ovalbumin challenge. Arginase activity in these preparations was investigated by measuring the conversion of L-[ 14 C]arginine to [ 14 C]urea. 3 Airways from allergen-challenged animals showed a 2 fold (P50.001) increase in responsiveness to intraluminal (IL) administration of methacholine compared to controls. A similar hyperresponsiveness (1.8 fold, P50.01) was observed in control airways incubated with the NOS inhibitor N onitro-L-arginine methyl ester (L-NAME, 0.1 mM, IL), while L-NAME had no further e ect on the airways from challenged animals. 4 Remarkably, 5 mM nor-NOHA (IL) normalized the hyperresponsiveness of challenged airways to basal control (P50.001), and this e ect was fully reversed again by 0.1 mM L-NAME (P50.05). Moreover, arginase activity in homogenates of the hyperresponsive airways was 3.5 fold (P50.001) enhanced compared to controls. 5 The results indicate that enhanced arginase activity contributes to allergen-induced de®ciency of cNOS-derived NO and AHR after the EAR, presumably by competition with cNOS for the common substrate, L-arginine. This is the ®rst demonstration that arginase is involved in the pathophysiology of asthma. British Journal of Pharmacology (2002) 136, 391 ± 398 Keywords: Arginase; constitutive nitric oxide synthase; nitric oxide; methacholine; N o -hydroxy-nor-L-arginine; allergic asthma; early asthmatic reaction; airway hyperresponsiveness; tracheal perfusion; guinea-pig Abbreviations: AHR, airway hyperreactivity; cNOS, constitutive nitric oxide synthase; EAR, early asthmatic reaction; EL, extraluminal; E max , maximal e ect; eNOS, endothelial nitric oxide synthase; IL, intraluminal; iNANC, inhibitory nonadrenergic noncholinergic; iNOS, inducible nitric oxide synthase; KH, Krebs-Henseleit; LAR, late asthmatic reaction; L-NAME, N o -nitro-L-arginine methyl ester; L-NMMA, N G -monomethyl-L-arginine; nNOS, neuronal nitric oxide synthase; nor-NOHA, N o -hydroxy-nor-L-arginine; DP, di erential (hydrostatic) pressure; P inlet , (hydrostatic) pressure at the inlet; P outlet , (hydrostatic) pressure at the outlet; pEC 50 , 7log 10 of the concentration causing 50% of the e ect

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

“…proline, valine, homoserine and alanine), but reversed the drop in glucose, mannose, galactose, arabinose and galacturonic acid in asthma. The arginine-proline pathway is implicated in asthma (Meurs et al 2002;Lara et al 2008), whereby increase in arginase activity can lead to augmented conversion of L-arginine to urea and ornithine. Ornithine is converted to proline and then to valine (Weeda et al 1980).…”

Th2 Cytokine-Induced Alterations in Intestinal Smooth Muscle Function Depend on Alternatively Activated Macrophages

“…Both of these pathways are implicated in cell proliferation and collagen production. Indeed, increased arginase activity is linked to airway hyper responsiveness or decreased airway smooth muscle relaxation in asthma 26,27 . Moreover, elevated arginase I expression increases airway smooth muscle proliferation by mechanisms involving the production of polyamines 28 .…”

Is arginase a potential drug target in tobacco-induced pulmonary endothelial dysfunction?

“…To the best of our knowledge, our study is the first to have demonstrated the role of increased arginase activity in tobacco associatedpulmonary endothelial dysfunction. Increased arginase activity has also been associated with airway hyperresponsiveness [33,34]; we previously demonstrated that increased arginase activity is involved in airway sensitivity in smokers [35]. Overall, elevated arginase activity may be one of the mechanisms underlying both pulmonary arterial dysfunction and bronchial dysfunction [36].…”