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BackgroundS-nitrosoglutathione (GSNO) serves as a reservoir for nitric oxide (NO) and thus is a key homeostatic regulator of airway smooth muscle tone and inflammation. Decreased levels of GSNO in the lungs of asthmatics have been attributed to increased GSNO catabolism via GSNO reductase (GSNOR) leading to loss of GSNO- and NO- mediated bronchodilatory and anti-inflammatory actions. GSNOR inhibition with the novel small molecule, N6022, was explored as a therapeutic approach in an experimental model of asthma.MethodsFemale BALB/c mice were sensitized and subsequently challenged with ovalbumin (OVA). Efficacy was determined by measuring both airway hyper-responsiveness (AHR) upon methacholine (MCh) challenge using whole body plethysmography and pulmonary eosinophilia by quantifying the numbers of these cells in the bronchoalveolar lavage fluid (BALF). Several other potential biomarkers of GSNOR inhibition were measured including levels of nitrite, cyclic guanosine monophosphate (cGMP), and inflammatory cytokines, as well as DNA binding activity of nuclear factor kappa B (NFκB). The dose response, onset of action, and duration of action of a single intravenous dose of N6022 given from 30 min to 48 h prior to MCh challenge were determined and compared to effects in mice not sensitized to OVA. The direct effect of N6022 on airway smooth muscle tone also was assessed in isolated rat tracheal rings.ResultsN6022 attenuated AHR (ED50 of 0.015 ± 0.002 mg/kg; Mean ± SEM) and eosinophilia. Effects were observed from 30 min to 48 h after treatment and were comparable to those achieved with three inhaled doses of ipratropium plus albuterol used as the positive control. N6022 increased BALF nitrite and plasma cGMP, while restoring BALF and plasma inflammatory markers toward baseline values. N6022 treatment also attenuated the OVA-induced increase in NFκB activation. In rat tracheal rings, N6022 decreased contractile responses to MCh.ConclusionsThe significant bronchodilatory and anti-inflammatory actions of N6022 in the airways are consistent with restoration of GSNO levels through GSNOR inhibition. GSNOR inhibition may offer a therapeutic approach for the treatment of asthma and other inflammatory lung diseases. N6022 is currently being evaluated in clinical trials for the treatment of inflammatory lung disease.

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One difference between endurance athletes and nonathletes is decreased ventilatory responsiveness to hypoxia and hypercapnia. It has never been clear whether these decreased responses are a consequence of conditioning or precede participation in endurance athletics. Recent studies demonstrating clusters of decreased ventilatory responses to hypoxia in families of patients with unexplained respiratory failure suggest that decreased responses in endurance athletes might be familial. To investigate this possibility, ventilatory response to hypoxia and hypercapnia were measured in 16 nonathletic, healthy parents and siblings of five successful long-distance runners. Response were compared to 34 nonathletic controls. As measured by the shape parameter A, hypoxic response was decreased to a similar extent in runners 74 +/- 6.4 (mean +/- SE) (P less than 0.05) and their relatives 69 +/- 15.2 (P less than 0.01) compared to control 128 +/- 11.3. Hypercapnic responses were slightly, but not significantly, decreased in runners and their families. We conclude familial influences made a major contribution to the decreased hypoxic ventilatory response seen in long-distance runners.