Nicotinamide increases systemic vascular resistance in ovine endotoxemia.
OBJECTIVE
The nuclear enzyme Poly(ADP-Ribose)-Polymerase (PARP) has been hypothesized as playing a major role in various forms of inflammation. PARP activation is induced by DNA strand breakage and can result in intracellular energy depletion and, ultimately, cell death. Further, it is thought to influence cardiovascular function and organ failure in endotoxemia. Here, we investigated the effect of the PARP inhibitor nicotinamide on cardiovascular and liver function in healthy and chronically endotoxemic sheep.


METHODS
Prospective controlled trial.


METHODS
University research laboratory.


METHODS
12 female adult sheep.


METHODS
Six healthy sheep, instrumented for chronic study, received nicotinamide intravenously as a bolus of 40 mg/kg followed by a continuous infusion of 10 mg.kg(-1).h(-1); six animals received the vehicle. One hour after bolus application, a continuous infusion of endotoxin ( Salmonella typhosa, 10 ng.kg(-1).min(-1)) was started. Hemodynamic parameters were determined before and during endotoxemia.


RESULTS
Treatment with nicotinamide resulted in a significantly higher systemic vascular resistance index and lower cardiac index in endotoxemic animals, but not in controls. It also attenuated endotoxin-induced increase in gamma-glutamyl transferase.


CONCLUSIONS
The PARP inhibitor nicotinamide attenuates impairment of cardiovascular function during endotoxemia. In addition, PARP activation may be involved in endotoxin-induced liver injury.
Scharte
Marion
M
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Strasse 33, 48149, Münster, Germany.
Nofer
Jerzy-Roch
JR
Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum Münster, Münster, Germany.
Aken
Hugo Van
HV
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Strasse 33, 48149, Münster, Germany.
Waurick
Rene
R
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Strasse 33, 48149, Münster, Germany.
Meyer
Jörg
J
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Strasse 33, 48149, Münster, Germany.
Bone
Hans-Georg
HG
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Strasse 33, 48149, Münster, Germany.
D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects; D001663:Bilirubin / Q000097:blood; D002908:Chronic Disease; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D007249:Inflammation; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D009536:Niacinamide / Q000494:pharmacology / Q000627:therapeutic use*; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000276:immunology; D011446:Prospective Studies; D011897:Random Allocation; D012756:Sheep; D014435:Typhoid Fever / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D014655:Vascular Resistance / Q000187:drug effects*; D005723:gamma-Glutamyltransferase / Q000097:blood / Q000187:drug effects
D009566:Nitrates; D009573:Nitrites; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D005723:gamma-Glutamyltransferase; D011065:Poly(ADP-ribose) Polymerases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin