Modulation of cholinergic airway reactivity and nitric oxide production by endogenous arginase activity

Abstract

1 Cholinergic airway constriction is functionally antagonized by agonist-induced constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO). Since cNOS and arginase, which hydrolyzes Larginine to L-ornithine and urea, use L-arginine as a common substrate, competition between both enzymes for the substrate could be involved in the regulation of cholinergic airway reactivity. Using a perfused guinea-pig tracheal tube preparation, we investigated the modulation of methacholineinduced airway constriction by the recently developed, potent and speci®c arginase inhibitor N ohydroxy-nor-L-arginine (nor-NOHA). 2 Intraluminal (IL) administration of nor-NOHA caused a concentration-dependent inhibition of the maximal e ect (E max ) in response to IL methacholine, which was maximal in the presence of 5 mM nor-NOHA (E max =31.2+1.6% of extraluminal (EL) 40 mM KCl-induced constriction versus 51.6+2.1% in controls, P50.001). In addition, the pEC 50 (7log 10 EC 50 ) was slightly but signi®cantly reduced in the presence of 5 mM nor-NOHA. 3 The inhibition of E max by 5 mM nor-NOHA was concentration-dependently reversed by the NOS inhibitor N o -nitro-L-arginine methyl ester (L-NAME), reaching an E max of 89.4+7.7% in the presence of 0.5 mM L-NAME (P50.01). A similar E max in the presence of 0.5 mM L-NAME was obtained in control preparations (85.2+9.7%, n.s.). 4 In the presence of excess of exogenously applied L-arginine (5 mM), 5 mM nor-NOHA was ine ective (E max =33.1+5.8 versus 31.1+7.5% in controls, n.s.). 5 The results indicate that endogenous arginase activity potentiates methacholine-induced airway constriction by inhibition of NO production, presumably by competition with cNOS for the common substrate, L-arginine. This ®nding may represent an important novel regulation mechanism of airway reactivity.

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

“…Endotoxin (lipopolysaccharide) administration in macrophages resulted in the coinduction of the Arg isoforms Arg I and Arg II, and inducible NOS (iNOS), leading to the hypothesis that Arg may limit sustained overproduction of NO by limiting substrate availability to iNOS (12,26,41,42). Recently, Arg I and Arg II expression have been demonstrated in the rat lung, where they modulate cholinergic airway responses and NO activity (43). Arg I and Arg II expression has also been demonstrated in the penis (11,16) and A293 cells overexpressing NOS1 (44), where reciprocal regulation of Arg and constitutive NOS1 exists.…”

Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels

“…10,13 In the airway, arginase inhibition attenuates methacholine-induced airway constriction by increasing NO production. 28 Arginase may also limit NO production in macrophages and other tissue after NOS2 induction. 6,29,30 Furthermore, arginase may limit NOS activity in A293 cells overexpressing NOS1 31 and regulate vascular smooth muscle proliferation in an NO-dependent manner.…”

Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models

“…Arginase I and II are both expressed constitutively in the airways, particularly in epithelial cells, (myo)fibroblasts and alveolar macrophages [113][114][115]. In guinea pigs, it has been discovered that arginase activity is functionally involved in basal airway responsiveness by limiting cNOS-derived NO production [116]. Using airway preparations from the same animal model, it was demonstrated that increased arginase activity may be involved in allergen-induced AHR and reduced iNANC relaxation after the early asthmatic reaction [96,111].…”