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 Szabo, Peter Radermacher, Gebhard Fröba

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 2003
Externally publishedYes

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Adenosine Diphosphate Ribose
Endotoxemia
Lipopolysaccharides
Swine
Hemodynamics
Cardiac Output
Lactic Acid
Pyruvic Acid
Resuscitation
Vascular Resistance
Starch
Stroke Volume
Shock
Arterial Pressure
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Control Groups
Liver
DNA
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Physiology

Cite this

Systemic and hepatosplanchnic hemodynamic and metabolic effects of the PARP inhibitor PJ34 during hyperdynamic porcine endotoxemia. / Iványi, Zsolt; Hauser, Balázs; Pittner, Antje; Asfar, Pierre; Vassilev, Damian; Nalos, Marek; Altherr, Jürgen; Brückner, Uwe Bernd; Szabo, Csaba; Radermacher, Peter; Fröba, Gebhard.

In: Shock, Vol. 19, No. 5, 05.2003, p. 415-421.

Research output: Contribution to journalArticle

Iványi, Z, Hauser, B, Pittner, A, Asfar, P, Vassilev, D, Nalos, M, Altherr, J, Brückner, UB, Szabo, C, Radermacher, P & Fröba, G 2003, 'Systemic and hepatosplanchnic hemodynamic and metabolic effects of the PARP inhibitor PJ34 during hyperdynamic porcine endotoxemia', Shock, vol. 19, no. 5, pp. 415-421. https://doi.org/10.1097/01.shk.0000048904.46342.22
Iványi, Zsolt ; Hauser, Balázs ; Pittner, Antje ; Asfar, Pierre ; Vassilev, Damian ; Nalos, Marek ; Altherr, Jürgen ; Brückner, Uwe Bernd ; Szabo, Csaba ; Radermacher, Peter ; Fröba, Gebhard. / Systemic and hepatosplanchnic hemodynamic and metabolic effects of the PARP inhibitor PJ34 during hyperdynamic porcine endotoxemia. In: Shock. 2003 ; Vol. 19, No. 5. pp. 415-421.
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