Systemic and hepatosplanchnic hemodynamic and metabolic effects of the PARP inhibitor PJ34 during hyperdynamic porcine endotoxemia

Zsolt Iványi, Balázs Hauser, Antje Pittner, Pierre Asfar, Damian Vassilev, Marek Nalos, Jürgen Altherr, Uwe Bernd Brückner, Csaba Szabó, Peter Radermacher, Gebhard Fröba

    Research output: Contribution to journalArticle

    20 Scopus citations

    Abstract

    Activation of the poy(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.

    Original languageEnglish (US)
    Pages (from-to)415-421
    Number of pages7
    JournalShock
    Volume19
    Issue number5
    DOIs
    StatePublished - May 1 2003

    Keywords

    • Blood flow
    • Gut
    • Ileal mucosal-arterial PCO gap
    • Lactate/pyruvate ratio
    • Liver
    • Metabolism
    • Oxygen

    ASJC Scopus subject areas

    • Emergency Medicine
    • Critical Care and Intensive Care Medicine

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  • Cite this

    Iványi, Z., Hauser, B., Pittner, A., Asfar, P., Vassilev, D., Nalos, M., Altherr, J., Brückner, U. B., Szabó, C., Radermacher, P., & Fröba, G. (2003). Systemic and hepatosplanchnic hemodynamic and metabolic effects of the PARP inhibitor PJ34 during hyperdynamic porcine endotoxemia. Shock, 19(5), 415-421. https://doi.org/10.1097/01.shk.0000048904.46342.22