Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma

Rationale: Exhaled breath nitric oxide (FENO) is increased in asthma. NO is produced predominantly by inducible nitric oxide synthase (iNOS). Objectives: We evaluated the selective and potent iNOS inhibitor GW274150 in asthma. Methods: Twenty-eight steroid-naive patients with asthma participated in a double-blind, randomized, double-dummy, placebo-controlled, three-period cross-over study. Subjects received GW274150 (90 mg), montelukast (10 mg), or placebo once daily for 14 days. FENO was assessed predose on Days 1, 7, 10, and 14. Adenosine 5′-monophosphate (AMP) challenge was performed on Day 10, allergen challenge on Day 14 followed by methacholine challenge (MCh) 24 hours later, and then bronchoscopy. Measurements and Main Results: GW274150 reduced predose FENO by 73, 75, and 71% on Days 7, 10, and 14, respectively, compared with placebo. Montelukast did not reduce FNO. GW274150 did not inhibit AMP reactivity whereas for montelukast there was a trend toward inhibition: the mean doubling dose difference versus placebo was 0.64 (95% confidence interval [95% CI], 0 to 1.28). GW274150 did not inhibit early (EAR) and late (LAR) asthmatic responses to allergen, or MCh reactivity, despite reduced FENO levels. Montelukast inhibited EAR and LAR FEV1; the mean difference versus placebo for minimal FEV1 was 0.37 L (95% CI, 0.19 to 0.55) and 0.18 L (95% CI, 0.04 to 0.32), respectively. MCh reactivity was inhibited by montelukast (mean doubling dose difference vs. placebo, 0.51; 95% CI, 0.02 to 1.01). GW271540 also had no effect on inflammatory cell numbers in bronchoalveolar lavage fluid after allergen challenge. Conclusions: Selective iNOS inhibition effectively reduces FE NO but does not affect airway hyperreactivity or airway inflammatory cell numbers after allergen challenge in subjects with asthma.