Abstract

BackgroundUsing guinea pig tracheal preparations, we have recently shown that endogenous arginase activity attenuates inhibitory nonadrenergic noncholinergic (iNANC) nerve-mediated airway smooth muscle relaxation by reducing nitric oxide (NO) production – due to competition with neuronal NO-synthase (nNOS) for the common substrate, L-arginine. Furthermore, in a guinea pig model of allergic asthma, airway arginase activity is markedly increased after the early asthmatic reaction (EAR), leading to deficiency of agonist-induced, epithelium-derived NO and subsequent airway hyperreactivity.In this study, we investigated whether increased arginase activity after the EAR affects iNANC nerve-derived NO production and airway smooth muscle relaxation.MethodsElectrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5 – 16 Hz)-induced relaxation was measured in tracheal open-ring preparations precontracted to 30% with histamine in the presence of 1 μM atropine and 3 μM indomethacin. The contribution of NO to EFS-induced relaxation was assessed by the nonselective NOS inhibitor Nω-nitro-L-arginine (L-NNA, 100 μM), while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor Nω-hydroxy-nor-L-arginine (nor-NOHA, 10 μM). Furthermore, the role of substrate availability to nNOS was measured in the presence of exogenous L-arginine (5.0 mM).ResultsAt 6 h after ovalbumin-challenge (after the EAR), EFS-induced relaxation (ranging from 3.2 ± 1.1% at 0.5 Hz to 58.5 ± 2.2% at 16 Hz) was significantly decreased compared to unchallenged controls (7.1 ± 0.8% to 75.8 ± 0.7%; P < 0.05 all). In contrast to unchallenged controls, the NOS inhibitor L-NNA did not affect EFS-induced relaxation after allergen challenge, indicating that NO deficiency underlies the impaired relaxation. Remarkably, the specific arginase inhibitor nor-NOHA normalized the impaired relaxation to unchallenged control (P < 0.05 all), which effect was inhibited by L-NNA (P < 0.01 all). Moreover, the effect of nor-NOHA was mimicked by exogenous L-arginine.ConclusionThe results clearly demonstrate that increased arginase activity after the allergen-induced EAR contributes to a deficiency of iNANC nerve-derived NO and decreased airway smooth muscle relaxation, presumably via increased substrate competition with nNOS.

Highlights

  • Using guinea pig tracheal preparations, we have recently shown that endogenous arginase activity attenuates inhibitory nonadrenergic noncholinergic nerve-mediated airway smooth muscle relaxation by reducing nitric oxide (NO) production – due to competition with neuronal NOsynthase for the common substrate, L-arginine

  • The results clearly demonstrate that increased arginase activity after the allergen-induced early asthmatic reaction (EAR) contributes to a deficiency of inhibitory nonadrenergic noncholinergic (iNANC) nerve-derived NO and decreased airway smooth muscle relaxation, presumably via increased substrate competition with neuronal NOsynthase (nNOS)

  • At 6 h after ovalbumin-challenge, EFSinduced relaxations were significantly decreased at all frequencies as compared to unchallenged controls, to a similar extent as observed in L-NNAtreated preparations from unchallenged animals (Fig. 1)

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Summary

Introduction

Using guinea pig tracheal preparations, we have recently shown that endogenous arginase activity attenuates inhibitory nonadrenergic noncholinergic (iNANC) nerve-mediated airway smooth muscle relaxation by reducing nitric oxide (NO) production – due to competition with neuronal NOsynthase (nNOS) for the common substrate, L-arginine. Constitutive NOS (cNOS) isoforms – neuronal (nNOS) and endothelial NOS (eNOS) – are mainly expressed in inhibitory nonadrenergic noncholinergic (iNANC) neurons (nNOS), endothelium (eNOS) and epithelium (nNOS and eNOS), whereas inducible NOS (iNOS), which is induced by proinflammatory cytokines during airway inflammation, is mainly expressed in macrophages and epithelial cells [2] Both in animal models and in patients it has been demonstrated that a deficiency of cNOS-derived NO is importantly involved in the development of airway hyperreactivity in allergic asthma [3,4,5,6,7,8,9]. In line with these observations, increased arginase expression and/or activity have been found in murine models of allergic asthma [15] and in asthmatic patients [15,16]

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