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

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 L-arginine 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 methacholine-induced airway constriction by the recently developed, potent and specific arginase inhibitor N-omega-hydroxy-nor-L-arginine (nor-NOHA).

2 Intraluminal (IL) administration of nor-NOHA caused a concentration-dependent inhibition of the maximal effect (E-max) in response to IL methacholine, which was maximal in the presence of 5 mu M nor-NOHA (E-max = 31.2+/-1.6% of extraluminal (EL) 40 mM KCl-induced constriction versus 51.6+/-2.1% in controls, P

3 The inhibition of E-max by 5 mu M nor-NOHA was concentration-dependently reversed by the NOS inhibitor N-omega-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 (P

4 In the presence of excess of exogenously applied L-arginine (5 mM), 5 mu M nor-NOHA was ineffective (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 finding may represent an important novel regulation mechanism of airway reactivity.