Journal Article

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

Hamer, Marco A M, Boucher, Jean‐Luc, Pethe, Stephanie, Zaagsma, Johan, Meurs, Herman, Vadon‐Le Goff, Sandrine

2000

Overview

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 NΩ‐hydroxy‐nor‐L‐arginine (nor‐NOHA). Intraluminal (IL) administration of nor‐NOHA caused a concentration‐dependent inhibition of the maximal effect (Emax) in response to IL methacholine, which was maximal in the presence of 5 μM nor‐NOHA (Emax=31.2±1.6% of extraluminal (EL) 40 mM KCl‐induced constriction versus 51.6±2.1% in controls, P<0.001). In addition, the pEC50 (−log10 EC50) was slightly but significantly reduced in the presence of 5 μM nor‐NOHA. The inhibition of Emax by 5 μM nor‐NOHA was concentration‐dependently reversed by the NOS inhibitor NΩ‐nitro‐L‐arginine methyl ester (L‐NAME), reaching an Emax of 89.4±7.7% in the presence of 0.5 mM L‐NAME (P<0.01). A similar Emax in the presence of 0.5 mM L‐NAME was obtained in control preparations (85.2±9.7%, n.s.). In the presence of excess of exogenously applied L‐arginine (5 mM), 5 μM nor‐NOHA was ineffective (Emax=33.1±5.8 versus 31.1±7.5% in controls, n.s.). 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. British Journal of Pharmacology (2000) 130, 1793–1798; doi:10.1038/sj.bjp.0703488

• Publisher: Blackwell Publishing Ltd,Nature Publishing,Wiley
• Subject: airway hyperreactivity / Animals / Arginase / Arginase - antagonists & inhibitors / Arginase - metabolism / Arginine - analogs & derivatives / Arginine - pharmacology / Biochemistry, Molecular Biology / Biological and medical sciences / Bronchoconstriction - drug effects / Bronchoconstrictor Agents - pharmacology / cholinergic / constitutive nitric oxide synthase / Dose-Response Relationship, Drug / Enzyme Inhibitors - pharmacology / Guinea Pigs / guinea‐pig / In Vitro Techniques / Life Sciences / L‐arginine / Medical sciences / Methacholine Chloride - pharmacology / NG-Nitroarginine Methyl Ester - pharmacology / nitric oxide / Nitric Oxide - metabolism / Nitric Oxide Synthase - antagonists & inhibitors / Nitric Oxide Synthase - metabolism / Nω‐hydroxy‐nor‐L‐arginine / Nω‐nitro‐L‐arginine‐methyl ester / Pharmacology. Drug treatments / Respiratory system / Specific Pathogen-Free Organisms / Trachea - drug effects / Trachea - metabolism / Trachea - physiology / tracheal perfusion