Effect of combining nicotinamide as a PARS-inhibitor with selective iNOS blockade during porcine endotoxemia.

OBJECTIVE: To investigate the effects of combined selective inducible nitric oxide synthase (iNOS) inhibition using 1400 W with nicotinamide (NAD) as a PARS-inhibitor on hepato-splanchnic hemodynamics, O(2) kinetics, and energy metabolism during hyperdynamic porcine endotoxemia.
DESIGN: Prospective, randomized, controlled, interventional experiment.
SETTING: Animal research laboratory.
SUBJECTS: Seventeen domestic pigs.
INTERVENTIONS: After 12 h of continuous i.v. endotoxin (LPS) infusion 17 pigs received either no drug (CON, n=9) or 1400 W, titrated to maintain mean arterial pressure (MAP) at pre-endotoxin level, plus 10 mg.kg.h NAD ( n=8;). Measurements were obtained before, 12 h, 18 h, and 24 h after starting LPS infusion. MEASUREMENTS AND
RESULTS: In addition to systemic and pulmonary hemodynamics and gas exchange, we measured hepatic arterial and portal venous blood flow, liver and portal venous drained viscera O(2) exchange, ileal mucosal-arterial PCO(2) gap, and portal as well as hepatic venous lactate/pyruvate ratios. Expired NO and plasma nitrate levels were assessed as a parameter of NO production. Without affecting cardiac output, therapy maintained MAP and blunted the LPS-induced rise in expired NO levels, attenuated the progressive fall in liver lactate clearance, and blunted the impairment of hepato-splanchnic redox state. The rise of ileal mucosal-arterial PCO(2) gap was not influenced.
CONCLUSIONS: Combining selective iNOS inhibition with NAD as a PARS blocker may prevent circulatory failure and attenuate the detrimental consequences of LPS in intestinal and hepatocellular energy metabolism. Given the potential hepatotoxicity of high-dose NAD treatment, more potent PARS blockers with higher selectivity might further enhance the benefit of this therapeutic approach.