ObjectiveTo test the hypothesis that intravascular acid infusion promotes intrapulmonary nitric oxide formation by promoting inducible nitric oxide synthase (iNOS) and inhibiting endothelial nitric oxide synthase (eNOS) expression in rats.DesignProspective, placebo controlled, randomized laboratory study.SettingUniversity laboratory.SubjectsTwelve male Sprague-Dawley rats weighing 317 ± 30 g served as study subjects. All animals were anesthetized, paralyzed, and mechanically ventilated throughout the experiment.InterventionsThe animals were randomized to receive either 0.1 N hydrochloric acid or 0.9% saline intravenously. The infusions were initially given at a rate of 11 mL/kg/hr for 15 mins and then at a rate of 0.95 mL/kg/hr for the remainder of the experiment. Exhaled nitric oxide concentrations and hemodynamic measurements were monitored throughout the experiment. Lung tissues were harvested for Western blot analysis and immunostaining 4 hrs after starting the intravascular infusion.Measurement and Main ResultsAt the end of the experiment, we found more than a four-fold higher concentration of exhaled nitric oxide in the acid-treated animals than in the saline-treated animals (p< .001). Western blot analysis revealed that the acid infusion increased intrapulmonary iNOS concentrations (p< .001), yet it decreased intrapulmonary eNOS concentrations (p= .009). Acid-related lung injury manifested as a decrease in blood oxygen tensions (p= .045) and as an increase in lung homogenate interleukin-6 concentrations (p= .003).ConclusionsOur results reveal that hydrochloric acid infusion stimulates intrapulmonary nitric oxide formation at least in part by promoting the expression of iNOS. Our findings suggest that correcting acidosis should attenuate iNOS formation. Our data also support the idea that metabolic acidosis itself can lead to impaired intrapulmonary gas exchange and increased expression of pro-inflammatory cytokines such as interleukin-6. Whether the induction of intrapulmonary nitric oxide formation mediates or simply indicates lung injury warrants further investigation.