ObjectiveThe derangement of the nitric oxide pathway is an important contributing factor to the pathogenesis of septic shock. The aim of this study was to investigate potential differences in modulation of such a pathway in two experimental models of endotoxemia.DesignProspective, randomized, placebo-controlled animal investigation.SettingCardiovascular research laboratory.SubjectsMale, anesthetized, and mechanically ventilated New-Zealand rabbits (n = 24) and Sprague-Dawley rats (n = 24).InterventionsAfter pretreatment with 1400W (1 mg kg−1subcutaneously), an inhibitor of inducible nitric oxide synthase, animals received an intravenous bolus ofEscherichia Colilipopolysaccharides (5 mg kg−1). After 4 hrs, lungs, myocardial left ventricles, and aortas were collected.Measurements and Main ResultsBlood mean arterial pressure, pH, and nitrite/nitrate were monitored. Nitric oxide in the exhaled air was measured by chemiluminescence. Tissue activity of both constitutive nitric oxide synthase and inducible nitric oxide synthase was determined by measuring the conversion of [3H]l-arginine to [3H]l-citrulline. In lipopolysaccharide-treated animals, both mean arterial pressure (after 60 to 90 mins) and blood pH (after 4 hrs) decreased with respect to baseline values. 1400W prevented lipopolysaccharide-induced hypotension only in rats (p< .01). Exhaled nitric oxide decreased in lipopolysaccharide-treated rabbits by 120 mins (from 12.6 ± 0.6 to 8.4 ± 0.6 ppb,p< .01) and remained low until the end of the experiment (p< .01 vs. baseline). Conversely, exhaled nitric oxide increased in lipopolysaccharide-treated rats by 120 mins (from 0.4 ± 0.1 to 5.3 ± 1.7 ppb,p< .01) and reached aplateauby 210 mins (19.8 ± 3.1 ppb,p< .01 vs. baseline). 1400W prevented the lipopolysaccharide-induced increase in exhaled nitric oxide and blood nitrite/nitrate in rats (p< .05). Inducible nitric oxide synthase activity increased in endotoxemic rabbit heart (0.19 ± 0.05 vs. 0.07 ± 0.02 pmol l-citrulline/min/mg protein in the control group,p< .05) and in all rat tissues, being more striking in the lungs (25.00 ± 0.01 vs. 0.19 ± 0.04 pmol l-citrulline/min/mg protein in the control group,p< .001).ConclusionsThe nitric oxide pathway is differently modulated between endotoxemic rabbits and rats.