Effects of nicotinamide, an inhibitor of PARS activity, on gut and liver O-2 exchange and energy metabolism during hyperdynamic porcine endotoxemia

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 emia. Design: Prospective, randomized, controlled experimental study with repeate d measures. 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 riment. 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.