In patients with sepsis, high blood lactate concentrations ([L]) have been associated with increased mortality. Previous studies indicate that endotoxin(LPS)-induced lactic acidemia is caused by a decrease in lactate extraction rather than increased production. Since lactate extraction is dependent on perfusion, we theorize that LPS causes a decrease in perfusion. Because perfusion is partially controlled by nitric oxide (NO), modulation of nitric oxide synthase (NOS), which exists in two forms, inducible (iNOS) and endothelial constitutive (ecNOS), may mediate LPS-induced changes in perfusion. Studies indicate that LPS induces iNOS and inhibits ecNOS. We hypothesize that further NOS inhibition will exacerbate LPS-induced lactic acidemia. We measured the effects of N-ω-nitro-L-arginine methyl ester(L-NAME), an inhibitor of both iNOS and ecNOS, and S-methylisothiourea (SMT), an iNOS inhibitor, on the lactic acidemia induced by LPS in non-stressed catheterized rats. LPS (6 μg/kg) and either L-NAME (0.3 mg/kg bolus, 0.3 mg/kg/hr) or SMT (0.1 mg/kg) were infused into the IVC. Aortic blood was sampled every 30 min for 4 hours and [L] were measured enzymatically. [L] did not significantly change with the infusion of L-NAME or SMT without LPS. Inhibition of both iNOS and ecNOS by L-NAME increased LPS-induced [L] while selective inhibition of iNOS by SMT decreased the LPS-induced lactic acidemia(p<0.02, repeated measures ANOVA). The apparent paradoxical effect of inhibiting iNOS alone compared to both ecNOS and iNOS on LPS-induced lactic acidemia suggests that NO produced by ecNOS may increase tissue perfusion. In contrast, NO produced by iNOS decreases tissue perfusion. We speculate that selective inhibition of iNOS may benefit patients with sepsis. Values represent mean (SE) in μmol/ml. Table

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