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 OVA induced concentration-dependent contractions of the GPLP that were enhanced by the NO synthase (NOS) inhibitors Nω-nitro-l-arginine (l-NOARG; 100 μM), Nω-monomethyl-l-arginine (100 μM), Nω-nitro-l-arginine methyl ester (100 μM), and N-(3-(aminomethyl)benzyl)acetamidine (1400W; 1 μM). 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 μM), whereas coadministration 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 the belief that endogenous NO has a protective anti-inflammatory effect in the airways.
Footnotes
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This work was supported by the Swedish Heart Lung Foundation, the Swedish Medical Research Council, Biolipox AB, and Karolinska Institutet.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.086694.
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ABBREVIATIONS: NO, nitric oxide; NOS, nitric-oxide synthase(s); eNOS, endothelial nitric-oxide synthase; iNOS, inducible nitric-oxide synthase; CysLT, cysteinyl-leukotriene(s); COX, cyclooxygenase; GPLP, guinea pig lung parenchyma; 5-LO, 5-lipoxygenase; LT, leukotriene; EIA, enzyme immunoassay(s); OVA, ovalbumin; BAY x1005, (R)-2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid; GPPA, guinea pig pulmonary artery; l-NMMA, Nω-monomethyl-l-arginine; l-NAME, Nω-nitro-l-arginine methyl ester; l-NOARG, Nω-nitro-l-arginine; 1400W, N-(3-(aminomethyl)benzyl)acetamidine; SC560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; PG, prostaglandin; TX, thromboxane.
- Received April 6, 2005.
- Accepted July 13, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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