Effects of nicotinamide, an inhibitor of PARS activity, on gut and liver O2 exchange and energy metabolism during hyperdynamic porcine endotoxemia

Abstract

Although NIC maintained hemodynamic stabilization during long-term endotoxemia, it was unable to improve LPS-induced deterioration of the hepato-splanchnic energy metabolism. More potent and selective PARS inhibitors are needed to elucidate the role of a PARS-dependent pathway in a clinically relevant models of sepsis.

Nicotinamide increases systemic vascular resistance in ovine endotoxemia

“…Similar to our findings, PARP inhibition attenuated the endotoxin-induced decrease in mean arterial pressure in rats and pigs [7,9,14], whereas PARP inhibition in the absence of endotoxin had no effect on blood pressure. Recently, Goldfarb and colleagues investigated the effect of PJ-34, a novel potent PARP inhibitor, in bacterial hypodynamic sepsis in pigs [13].…”

“…As no difference in hemodynamic response was found between sheep treated with different dosages of nicotinamide, we chose the medium dosage. Similar dosages were previously used in other in vivo models of endotoxemia and shock to inhibit PARP [9,14,20].…”

“…Most of the work on the role of PARP in sepsis and endotoxemia has been done in rodent models. Only a few studies were carried out in large animal models of sepsis [13,14] that more closely mimic the clinical situation. Therefore, we investigated the effect of the PARP inhibitor nicotinamide on hemodynamics and organ function in an ovine model of chronic endotoxemia.…”

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

“…The experiments described were simultaneously carried out with the investigation of selective iNOS inhibition and PARS blockade, respectively, alone. Therefore, the control-group receiving only LPS was the same as reported elsewhere [16,17] in order to minimize the number of animals needed as required by the German regulations for animal protection. The mean weight of the pigs [Deutsches Landschwein) (CON: 51 (47-53) kg; 1400W+NAD: 52 (49-56 kg)] and sex distribution (CON: 7 m and 1 f; 1400W+NAD: 7 m and 1 f) were comparable in both groups.…”

“…The mean weight of the pigs [Deutsches Landschwein) (CON: 51 (47-53) kg; 1400W+NAD: 52 (49-56 kg)] and sex distribution (CON: 7 m and 1 f; 1400W+NAD: 7 m and 1 f) were comparable in both groups. The preparation of the animals-including anesthesia, central venous, arterial, and balloon-tipped thermodilution pulmonary artery catheter, hepatic vein catheter (placed by ultrasound guidance, correct position confirmed by inspection post-mortem), midline laparotomy, placement of ultrasound transit time flow probes around portal vein and common hepatic artery, performing a double-lumen ileostomy, placement of a fiberoptic gas tension and pH sensor, and insertion of a cystostomy catheter-were performed under sterile condition without any adjunctive antibiotic therapy, as described previously in detail [16,17]. Body temperature was kept within 0.5°C of the baseline value using a heating mattress or external cooling as necessary.…”