Systemic and hepatosplanchnic hemodynamic and metabolic effects of the PARP inhibitor PJ34 during hyperdynamic porcine endotoxemia.
Activation of the poly(ADP-ribose)polymerase (PARP), a highly energy-consuming DNA-repairing enzyme, plays a crucial role in the pathogenesis of multiorgan failure. Most results, however, were derived from experiments with hypodynamic shock states characterized by a markedly decreased cardiac output (CO) and/or using a pretreatment approach. Therefore, we investigated the effects of the novel potent and selective PARP-1 inhibitor PJ34 in a posttreatment model of long-term, volume-resuscitated porcine endotoxemia. Anesthetized, mechanically ventilated and instrumented pigs received continuous intravenous (i.v.) lipopolysaccharide (LPS) over 24 h. Hydroxyethyl starch was administered to maintain a mean arterial pressure > 65 mmHg. After 12 h of LPS infusion, the animals were randomized to receive either vehicle (Control, n = 9) or i.v. PJ34 (n = 6; 10 mg/kg over 1 h followed by 2 mg/kg/h until the end of the experiment). Measurements were performed before as well as at 12, 18, and 24 h of LPS infusion. In all animals CO increased because of reduced systemic vascular resistance (SVR) and fluid resuscitation. PJ34 further raised CO (P < 0.05 vs. control group) as the result of a higher stroke volume indicating its positive inotropic effect. In addition, it diminished the rise in the ileal mucosal-arterial PCO2 gap, which returned to baseline levels at 24 h of LPS, and improved the gut lactate balance (P = 0.093 PJ34 vs. control) together with significantly lower portal venous lactate/pyruvate ratios. By contrast, it failed to influence the LPS-induced derangements of liver metabolism. Incomplete PARP inhibition because of dilutional effects and/or an only partial efficacy when used in post-treatment approaches may account for this finding.
Sektion Anasthesiologische Pathophysiologie und Verfahrensentwicklung Universitatsklinikum, Ulm, Germany.
Zsolt
Z
Iványi
Balázs
B
Hauser
Antje
A
Pittner
Pierre
P
Asfar
Damian
D
Vassilev
Marek
M
Nalos
Jürgen
J
Altherr
Uwe Bernd
UB
Brückner
Csaba
C
Szabó
Peter
P
Radermacher
Gebhard
G
Fröba
D000136:Acid-Base Equilibrium / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D007773:Lactates / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects; D010616:Phenanthrenes / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012016:Reference Values; D013152:Splanchnic Circulation / Q000187:drug effects*; D013552:Swine
D004791:Enzyme Inhibitors; D007773:Lactates; D008070:Lipopolysaccharides; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D010100:Oxygen