The effect of iNOS deletion on hepatic gluconeogenesis in hyperdynamic murine septic shock.
OBJECTIVE
To investigate the role of the inducible nitric oxide synthase activation-induced excess nitric oxide formation on the rate of hepatic glucose production during fully resuscitated murine septic shock.


METHODS
Prospective, controlled, randomized animal study.


METHODS
University animal research laboratory.


METHODS
Male C57Bl/6 and B6.129P2-Nos2(tm1Lau)/J (iNOS-/-) mice.


METHODS
Fifteen hours after cecal ligation and puncture, anesthetized, mechanically ventilated and instrumented mice (wild-type controls, n = 13; iNOS-/-, n = 12; wild-type mice receiving 5 mg.kg(-1) i.p. of the selective iNOS inhibitor GW274150 immediately after cecal ligation and puncture, n =8) received continuous i.v. hydroxyethylstarch and norepinephrine to achieve normotensive and hyperdynamic hemodynamics.


RESULTS
Measurements were recorded 18, 21 and 24 h after cecal ligation and puncture. Liver microcirculatory perfusion and capillary hemoglobin O2 saturation (laser Doppler flowmetry and remission spectrophotometry) were well maintained in all groups. Despite significantly lower norepinephrine doses required to achieve the hemodynamic targets, the rate of hepatic glucose production (gas chromatography--mass spectrometry measurements of tissue isotope enrichment during continuous i.v. 1,2,3,4,5,6-13C6-glucose infusion) at 24 h after cecal ligation and puncture was significantly higher in both iNOS-/- and GW274150-treated mice, which was concomitant with a significantly higher hepatic phosphoenolpyruvate carboxykinase activity (spectrophotometry) in these animals.


CONCLUSIONS
In normotensive, hyperdynamic septic shock, both pharmacologic and genetic deletion of the inducible nitric oxide synthase allowed maintenance of hepatic glucose production, most likely due to maintained activity of the key regulatory enzyme of gluconeogenesis, phosphoenolpyruvate carboxykinase.
Albuszies
Gerd
G
Universitätsklinikum, Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Parkstrasse 11, 89073 Ulm, Germany.
Vogt
Josef
J
Wachter
Ulrich
U
Thiemermann
Christoph
C
Leverve
Xavier M
XM
Weber
Sandra
S
Georgieff
Michael
M
Radermacher
Peter
P
Barth
Eberhard
E
D000818:Animals; D004195:Disease Models, Animal; D005943:Gluconeogenesis / Q000187:drug effects*; D005952:Glucose-6-Phosphatase; D017078:Laser-Doppler Flowmetry; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011446:Prospective Studies; D011897:Random Allocation; D012772:Shock, Septic / Q000378:metabolism*
D019001:Nitric Oxide Synthase; D005952:Glucose-6-Phosphatase