Inhibition of Nitric-Oxide Synthase Enhances Antigen-Induced Contractions and Increases Release of Cysteinyl-Leukotrienes in Guinea Pig Lung Parenchyma: Nitric Oxide as a Protective Factor

Abstract

Nitric oxide (NO) in exhaled air is a biomarker of airway inflammation. However, the role of NO in the peripheral lung is not known. The aim of this study was to determine the role of endogenous NO in antigen-induced contractions of ovalbumin (OVA)-sensitized guinea pig lung parenchyma (GPLP). The contraction in this in vitro model of the peripheral lung closely resembles the corresponding response in human airways. Cumulatively increasing concentrations (10-10,000 microg/l) of OVA induced concentration-dependent contractions of the GPLP that were enhanced by the NO synthase (NOS) inhibitors N(omega)-nitro-L-arginine (L-NOARG; 100 microM), N(omega)-monomethyl-L-arginine (100 microM), N(omega)-nitro-L-arginine methyl ester (100 microM), and N-(3-(aminomethyl)benzyl)acetamidine (1400W; 1 microM). The enhancement induced by L-NOARG was reversed by coadministration with the 5-lipoxygenase inhibitor (R)-2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid (BAY x1005; 3 microM), whereas coadministration of L-NOARG with the cyclooxygenase inhibitor indomethacin (10 microM) did not change the effect of L-NOARG alone. L-NOARG (100 microM) did not affect the cumulative concentration-response relations for either leukotriene (LT) D4 (0.1-100 nM) or histamine (1-30 microM). The NO donor NONOate (0.001-100 microM) was ineffective in GPLP but potently relaxed precontracted guinea pig pulmonary artery. Furthermore, L-NOARG enhanced the release of LTE4 and decreased the release of prostaglandin E2 induced by OVA. In conclusion, endogenous NO exerts an inhibitory effect on antigen-induced contractions in the peripheral lung. The action of NO apparently involves inhibition of the release of mediators rather than direct relaxation of airway smooth muscle. The findings support the belief that endogenous NO has a protective anti-inflammatory effect in the airways.