THE ROLE OF iNOS FOR HEPATIC GLUCOSE PRODUCTION IN MURINE SEPTIC SHOCK

Abstract

Introduction: Sepsis leads to depressed endogenous glucose production rate, and in this context the role of inducible NO synthase (iNOS) has been controversially discussed. Therefore, we investigated the effects of genetic and pharmacologic iNOS deletion on hepatic glucose production during murine septic shock. Methods: 15 h after cecal ligation and puncture (CLP) iNOS-/- mice, wildtype mice (WT) treated with the selective iNOS-inhibitor GW274150 and WT controls were anesthetized, mechanically ventilated and instrumented. Intravenous colloids and noradrenaline (NA) were titrated to achieve normotensive, hyperdynamic hemodynamics. 24 h after CLP, hepatic glucose production was derived from liver tissue isotope concentrations measured after steady-state infusion of stable isotope-labelled 1,2,3,4,5,6-13C6-glucose. Date are median (range) tested with a rank sum analysis. Results: Both genetic and pharmacologic iNOS blockade resulted in significantly lower NA requirements to achieve target hemodynamics (P < 0.001 vs. WT controls). Hepatic glucose production was also significantly higher in these animals (4.3 (3.2-8.4) and 5.0 (3.7-6.3) vs. 1.9 (0.4-2.9) mg/g·h in WT mice, P < 0.001) despite reduced NA infusion rates. Conclusions: Our data suggest a crucial role for iNOS activation-affiliated excess NO release during murine septic shock-induced depression of de novo hepatic glucose production rate, most likely as a result of an NO-mediated defect in cellular energy metabolism.