Received for publication April 6, 2005.
Revised June 17, 2005.
Accepted for publication July 13, 2005.

Inhibition of NOS enhances antigen-induced contractions and increases release of cysteinyl-leukotrienes in guinea pig lung parenchyma: NO 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 µg/L) of ovalbumin (OVA) induced concentration-dependent contractions of the GPLP that were enhanced by the nitric oxide synthase (NOS) inhibitors N-nitro-L-arginine (L-NOARG, 100 µM) N-monomethyl-L-arginine (L-NMMA, 100 µM), N-Nitro-L-arginine Methyl Ester (L-NAME, 100 µM) and 1400W (1 µM). The enhancement induced by L-NOARG was reversed by co-administration with the 5-lipoxygenase inhibitor BAYx1005 (3 µM), whereas co-administration of L-NOARG with the cyclooxygenase inhibitor indomethacin (10 µM) did not change the effect of L-NOARG alone. L-NOARG (100 µM) did not affect the cumulative concentration response relations for either leukotriene (LT) D₄ (0.1-100 nM) or histamine (1-30 µM). The NO donor NONOate (0.001-100 µM) 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 that NO is a protective anti-inflammatory factor.

Key words: airway smooth muscle, antigen-induced, guinea pig lung parenchyma, leukotrienes, nitric oxide, prostaglandins

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