Enhanced expression of inducible nitric oxide synthase without vasodilatoreffect in chronically infected lungs

We hypothesized that abnormal ventilation-perfusion matching in chronically infected lungs was in part due to excess nitric oxide (NO) production afte r upregulation of inducible NO synthase (iNOS) expression. Rats were anesth etized and inoculated intratracheally with Pseudomonas aeruginosa incorpora ted into agar beads (chronically infected) or with sterile agar beads (plac ebo inoculated) and killed 10-15 days later. Immunohistochemistry demonstra ted increased expression of iNOS and reduced expression of endothelial NOS (eNOS) in chronically infected compared with placebo-inoculated or noninocu lated lungs. In isolated lungs fi om chronically infected rats, NOS inhibit ion with N-omega-nitro-L-arginine methyl ester increased the mean perfusion pressure (14.4 +/- 2.7 mmHg) significantly more than in the placebo-inocul ated (4.8 +/- 1.0 mmHg) or noninoculated (5.3 +/- 0.8 mmHg) lungs (P < 0.01 ). Although the chronically infected lungs were more sensitive to NOS inhib ition, further evidence suggested that the increased iNOS expression was no t associated with enhanced iNOS activity. Selective inhibitors of iNOS did not produce an increase in vascular resistance similar to that produced by nonselective inhibitors. Accumulation of nitrate/nitrite in the perfusate o f isolated lungs was unchanged by chronic infection. Thus although iNOS exp ression was increased in chronic pulmonary infection, iNOS activity in the intact lung was not. Nonetheless, endogenous NO production was essential to maintain normal Vascular resistance in these lungs.