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- Title
Effect of combining nicotinamide as a PARS-inhibitor with selective iNOS blockade during porcine endotoxemia.
- Authors
Stehr, A.; Ploner, F.; Tugtekin, I.; Matejovic, M.; Theisen, M.; Zülke, C.; Georgieff, M.; Radermacher, P.; Jauch, K.-W.; Zülke, C
- Abstract
<bold>Objective: </bold>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.<bold>Design: </bold>Prospective, randomized, controlled, interventional experiment.<bold>Setting: </bold>Animal research laboratory.<bold>Subjects: </bold>Seventeen domestic pigs.<bold>Interventions: </bold>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.<bold>Measurements and Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
HEMODYNAMICS; ABDOMINAL blood vessels; BLOOD circulation; INFUSION therapy; ENERGY metabolism; BIOCHEMISTRY; AMINES; ANIMAL experimentation; BIOLOGICAL models; COMBINATION drug therapy; COMPARATIVE studies; DRUG design; CLINICAL drug trials; INTESTINAL mucosa; LIVER blood-vessels; LONGITUDINAL method; RESEARCH methodology; MEDICAL cooperation; MESENTERIC blood vessels; ORGANIC compounds; OXIDOREDUCTASES; PULMONARY circulation; RESEARCH; STATISTICAL sampling; SWINE; TIME; EVALUATION research; VITAMIN B complex; ENDOTOXEMIA; LIPOPOLYSACCHARIDES; CHEMICAL inhibitors; VITAMIN therapy; THERAPEUTICS
- Publication
Intensive Care Medicine, 2003, Vol 29, Issue 6, p995
- ISSN
0342-4642
- Publication type
journal article
- DOI
10.1007/s00134-003-1739-6