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.


METHODS
Prospective, randomized, controlled, interventional experiment.


METHODS
Animal research laboratory.


METHODS
Seventeen domestic pigs.


METHODS
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.


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.
Klinik und Poliklinik für Chirurgie, Universitätsklinikum, 93053, Regensburg, Germany. alexander.stehr@klinik.uni-regensburg.de.
A
A
Stehr
Abteilung für Anästhesie, Landeskrankenhaus, 39049, Sterzing/Südtirol, Italy.
F
F
Ploner
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinik für Anästhesiologie, 89073, Ulm, Germany.
I
I
Tugtekin
Interni Kliniky, Karlova Univerzita, 30460, Plzen, Czech Republic.
M
M
Matejovic
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinik für Anästhesiologie, 89073, Ulm, Germany.
M
M
Theisen
Klinik und Poliklinik für Chirurgie, Universitätsklinikum, 93053, Regensburg, Germany.
C
C
Zülke
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinik für Anästhesiologie, 89073, Ulm, Germany.
M
M
Georgieff
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinik für Anästhesiologie, 89073, Ulm, Germany.
P
P
Radermacher
Klinik und Poliklinik für Chirurgie, Universitätsklinikum, 93053, Regensburg, Germany.
K-W
KW
Jauch
D000578:Amidines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects; D008070:Lipopolysaccharides / Q000009:adverse effects; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D009536:Niacinamide / Q000494:pharmacology / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011446:Prospective Studies; D011652:Pulmonary Circulation / Q000187:drug effects; D011897:Random Allocation; D013152:Splanchnic Circulation / Q000187:drug effects; D013552:Swine; D013997:Time Factors
D000578:Amidines; D001596:Benzylamines; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D019001:Nitric Oxide Synthase