M. Theisen et al., Effects of nicotinamide, an inhibitor of PARS activity, on gut and liver O-2 exchange and energy metabolism during hyperdynamic porcine endotoxemia, INTEN CAR M, 27(3), 2001, pp. 586-592
Objective: To investigate the effects of nicotinamide (NIC), an inhibitor o
f poly(ADP-ribose) synthetase (PARS), on intestinal and liver perfusion, O-
2 kinetics, and energy metabolism over 24 h of hyperdynamic porcine endotox
Design: Prospective, randomized, controlled experimental study with repeate
Setting: Animal laboratory in a university hospital.
Subjects: Sixteen pigs, divided into two groups: nine endotoxemic animals w
ithout therapy (CON); seven animals treated with NIC.
Interventions: Pigs were anesthetized, mechanically ventilated, and instrum
ented. Intravenous E. Coli LPS was continuously infused over 24 h concomita
nt with fluid resuscitation. After 12 h of endotoxemia continuous i. v. inf
usion of NIC (10 mg/kg per hour) was administered until the end of the expe
Measurements ann results: All animals developed hyperdynamic circulation wi
th sustained increase in cardiac output and progressive fall in mean arteri
al pressure. NIC maintained blood pressure without affecting CO. Hepato-spl
anchnic macrocirculation was not modified by the treatment. Nevertheless, a
lthough 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 i
ncreased hepatic venous L/P ratio nor the simultaneous drop in hepatic lact
ate 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 inhibi
tors are needed to elucidate the role of a PARS-dependent pathway in a clin
ically relevant models of sepsis.