Effects of selective iNOS inhibition on gut and liver O2-exchange and energy metabolism during hyperdynamic porcine endotoxemia.
We have previously demonstrated that non-selective nitric oxide synthase (NOS) inhibition did not reverse the LPS-induced deterioration of hepato-splanchnic energy status in porcine endotoxic shock. Therefore, this study investigated the effect of selective inducible NOS (iNOS) inhibition using 1400 W on intestinal and liver perfusion, O2 kinetics, and energy metabolism during hyperdynamic porcine endotoxemia. Intravenous E. Coli LPS was continuously infused over 24 h concomitant with fluid resuscitation. After 12 h of endotoxemia, continuous intravenous infusion of 1400 W was started until the end of the experiment and was titrated to maintain mean blood pressure (MAP) at baseline levels. Twelve, 18, and 24 h after starting LPS, we measured hepatic arterial and portal venous blood flow, ileal mucosal-arterial PCO2 gap, portal as well as hepatic venous lactate/pyruvate ratios, and endogenous glucose production rate. Expired NO and plasma nitrate levels were assessed as a measure of NO production. 1400 W decreased LPS-induced increase in expired NO and allowed for the maintenance of MAP without modification of cardiac output. Despite unchanged regional macrocirculation, 1400 W prevented the progressive rise of ileal mucosal-arterial PCO2 gap, significantly improved the LPS-induced impairment of hepato-splanchnic redox state, and blunted the decline in liver lactate clearance. Increased glucose production rate was not influenced. Thus, the selective iNOS inhibition with 1400 W prevented circulatory failure and largely attenuated otherwise progressive LPS-induced deterioration of intestinal and hepatocellular energy metabolism.
Matejovic
M
M
Sektion Anästhesiologische Pathophysiologie und Vefahrensentwicklung, Universitätsklinik für Anästhesiologie, Universität Ulm, Germany.
Radermacher
P
P
Tugtekin
I
I
Stehr
A
A
Theisen
M
M
Vogt
J
J
Wachter
U
U
Ploner
F
F
Georgieff
M
M
Träger
K
K
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism*; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010100:Oxygen / Q000378:metabolism*; D010477:Perfusion; D013552:Swine
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D010100:Oxygen