Effect of Combining Nicotinamide as a PARS-inhibitor With Selective iNOS Blockade During Porcine Endotoxemia

Intensive Care Med. 2003 Jun;29(6):995-1002. doi: 10.1007/s00134-003-1739-6. Epub 2003 May 9.

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, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidines / pharmacology
  • Amidines / therapeutic use*
  • Animals
  • Benzylamines / pharmacology
  • Benzylamines / therapeutic use*
  • Disease Models, Animal*
  • Drug Evaluation, Preclinical
  • Drug Therapy, Combination
  • Endotoxemia / drug therapy*
  • Endotoxemia / immunology
  • Endotoxemia / metabolism
  • Endotoxemia / physiopathology
  • Energy Metabolism / drug effects
  • Female
  • Hemodynamics / drug effects
  • Intestinal Mucosa / drug effects
  • Lipopolysaccharides / adverse effects
  • Liver Circulation / drug effects
  • Male
  • Niacinamide / pharmacology
  • Niacinamide / therapeutic use*
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Prospective Studies
  • Pulmonary Circulation / drug effects
  • Random Allocation
  • Splanchnic Circulation / drug effects
  • Swine
  • Time Factors

Substances

  • Amidines
  • Benzylamines
  • Lipopolysaccharides
  • N-(3-(aminomethyl)benzyl)acetamidine
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Niacinamide
  • Nitric Oxide Synthase