Effects of nicotinamide, an inhibitor of PARS activity, on gut and liver O2 exchange and energy metabolism during hyperdynamic porcine endotoxemia.
OBJECTIVE
To investigate the effects of nicotinamide (NIC), an inhibitor of poly(ADP-ribose) synthetase (PARS), on intestinal and liver perfusion, O2 kinetics, and energy metabolism over 24 h of hyperdynamic porcine endotoxemia.


METHODS
Prospective, randomized, controlled experimental study with repeated measures.


METHODS
Animal laboratory in a university hospital.


METHODS
Sixteen pigs, divided into two groups: nine endotoxemic animals without therapy (CON); seven animals treated with NIC.


METHODS
Pigs were anesthetized, mechanically ventilated, and instrumented. Intravenous E. Coli LPS was continuously infused over 24 h concomitant with fluid resuscitation. After 12 h of endotoxemia continuous i.v. infusion of NIC (10 mg/kg per hour) was administered until the end of the experiment.


RESULTS
All animals developed hyperdynamic circulation with sustained increase in cardiac output and progressive fall in mean arterial pressure. NIC maintained blood pressure without affecting CO. Hepato-splanchnic macrocirculation was not modified by the treatment. Nevertheless, although NIC attenuated the progressive rise of ileal mucosal-arterial PCO2 gap, it failed to improve portal venous L/P ratio, a marker of the overall energy state of the portal venous drained viscera. Similarly, neither the increased hepatic venous L/P ratio nor the simultaneous drop in hepatic lactate uptake were influenced by NIC.


CONCLUSIONS
Although NIC maintained hemodynamic stabilization during long-term endotoxemia, it was unable to improve LPS-induced deterioration of the hepato-splanchnic energy metabolism. More potent and selective PARS inhibitors are needed to elucidate the role of a PARS-dependent pathway in a clinically relevant models of sepsis.
Theisen
M
M
Sektion Anästhesiologische Pathophysiologie und Vefahrensentwicklung, Universitätsklinik für Anästhesiologie, Universität Ulm, Parkstrasse 11, 89073 Ulm, Germany.
Träger
K
K
Tugtekin
I
I
Stehr
A
A
Ploner
F
F
Georgieff
M
M
Radermacher
P
P
Matĕjovic
M
M
D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects*; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009536:Niacinamide / Q000494:pharmacology / Q000627:therapeutic use*; D010101:Oxygen Consumption / Q000187:drug effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011446:Prospective Studies; D011897:Random Allocation; D013152:Splanchnic Circulation / Q000187:drug effects; D013552:Swine; D013997:Time Factors
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D019344:Lactic Acid