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

Abstract

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, O2 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 O2 exchange, ileal mucosalarterial PCO2 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 PCO2 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.