INO-1001 a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation.

Gábor Szabó, Pál Soós, Susanne Mandera, Ulrike Heger, Christa Flechtenmacher, Susanne Bährle, Leila Seres, Attila Cziráki, Andre Gries, Zsuszanna Zsengellér, Christian F. Vahl, Siegfried Hagl, Csaba Szabó

    Research output: Contribution to journalArticle

    39 Scopus citations

    Abstract

    Poly(ADP-ribose) polymerase (PARP) activation plays a key role in free radical-induced injury in the context of systemic inflammation and ischemia/reperfusion. In the present preclinical study, we investigated the effects of INO-1001, a novel PARP inhibitor, on cardiac and pulmonary function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or INO-1001 (1 mg/kg), a potent PARP inhibitor (n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow and vasodilative responses to acetylcholine and sodium nitroprusside as well as pulmonary gas exchange were also determined. The administration of INO-1001 led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the INO-1001 group (P < 0.05). Although the vasodilative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary and pulmonary blood flow in the INO-1001 group (P < 0.05). Pulmonary function in terms of alveolar arterial oxygen difference was better preserved in the INO-1001-treated group (P < 0.05). Thus, PARP inhibition improves the recovery of myocardial and endothelial function after hypothermic cardiac arrest and reduces pulmonary injury associated with extracorporal circulation.

    Original languageEnglish (US)
    Pages (from-to)426-432
    Number of pages7
    JournalShock (Augusta, Ga.)
    Volume21
    Issue number5
    StatePublished - May 2004

    ASJC Scopus subject areas

    • Emergency Medicine
    • Critical Care and Intensive Care Medicine

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    Szabó, G., Soós, P., Mandera, S., Heger, U., Flechtenmacher, C., Bährle, S., Seres, L., Cziráki, A., Gries, A., Zsengellér, Z., Vahl, C. F., Hagl, S., & Szabó, C. (2004). INO-1001 a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation. Shock (Augusta, Ga.), 21(5), 426-432.