Systemic and Hepatosplanchnic Hemodynamic and Metabolic Effects of the PARP Inhibitor PJ34 During Hyperdynamic Porcine Endotoxemia
| Autor: | Damian Vassilev, Marek Nalos, Peter Radermacher, Uwe B. Brückner, Gebhard Fröba, Csaba Szabó, Zsolt Iványi, Pierre Asfar, Antje Pittner, Jürgen Altherr, Balázs Hauser |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Lipopolysaccharides
Male Resuscitation medicine.medical_specialty Mean arterial pressure Swine Hemodynamics Poly(ADP-ribose) Polymerase Inhibitors Hydroxyethyl starch Critical Care and Intensive Care Medicine Oxygen Consumption Reference Values Intensive care Internal medicine Animals Medicine Splanchnic Circulation Enzyme Inhibitors Acid-Base Equilibrium business.industry Phenanthrenes Endotoxemia Oxygen Disease Models Animal Endocrinology medicine.anatomical_structure Liver Shock (circulatory) PARP inhibitor Lactates Emergency Medicine Vascular resistance Female medicine.symptom business Liver Circulation medicine.drug |
| Zdroj: | Shock. 19:415-421 |
| ISSN: | 1073-2322 |
| Popis: | 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 PCO 2 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. |
| Databáze: | OpenAIRE |
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