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

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

Author information

1
Klinik und Poliklinik für Chirurgie, Universitätsklinikum, 93053, Regensburg, Germany. alexander.stehr@klinik.uni-regensburg.de.
2
Abteilung für Anästhesie, Landeskrankenhaus, 39049, Sterzing/Südtirol, Italy.
3
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinik für Anästhesiologie, 89073, Ulm, Germany.
4
Interni Kliniky, Karlova Univerzita, 30460, Plzen, Czech Republic.
5
Klinik und Poliklinik für Chirurgie, Universitätsklinikum, 93053, Regensburg, Germany.

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.

PMID:
12739012
DOI:
10.1007/s00134-003-1739-6
[Indexed for MEDLINE]

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