Abstract

The activation of PARP is attributed a crucial role in the development of multiple organ failure induced by endotoxemia, sepsis and septic shock, in particular as a result of compromised vascular contractility [1] and endothelial vasorelaxation [2], impaired mitochondrial respiration [3], and pulmonary as well as intestinal hyperpermeability [4]. Therefore, the therapeutic potential of PARP-inhibition has been investigated in endotoxic shock using nicotinamide, 3-aminobenzamide and phenantridinones. Nicotinamide, which was originally tested as a substrate supplement already 30 years ago [5], not only to is a (weak) PARP-inhibitor but also reduced NO [6, 7] and cytokine formation [8]. Results are controversial in vivo: while it stabilized hemodynamics, attenuated acute lung injury and ultimately improved survival in some studies [9,10], it failed to prevent lactic acidosis and renal or hepatic injury in others [11]. In our long term model of hyperdynamic porcine endotoxemia which is characterized by a sustained increase in cardiac output and thus mimicks the clinical scenario of human septic shock, nicotinamide did not have any beneficial effect on the endotoxin-induced metabolic disturbances [12]. 3-aminobenzamide, the ‘classical’ PARP-inhibitor used in endotoxic shock models, not only attenuated the LPS-induced vascular failure in vitro, but also reduced the pulmonary and intestinal microvascular injury and thus improved the mucosal barrier function [4, 13]. Nevertheless, in other models 3-aminobenzamide also failed to prevent visceral organ dysfunction [11], and in short term porcine endotoxemia it did not influence the LPS-induced effects on the systemic and pulmonary hemodynamics [14]. Most recently, the novel and highly PARP-1-selective phenanthridinones [15] were reported to prevent vascular failure and acute lung injury in rat endotoxic shock [16]. Moreover, used as a pretreatment, they preserved myocardial contractility both in endotoxin-injected rats [17] and porcine polymicrobial peritonitis [18]. Finally, in our endotoxmic swine model they improved stroke volume and blunted the otherwise progressive intestinal mucosal acidosis [19]. Taken together, nicotinamide showed controversial efficacy in the treatment of endotoxic shock, probably due to its relatively poor activity as a PARP-inhibitor and due to the potential hepatotoxicity when administered in high doses. By contrast, the currently available data study support the hypothesis that potent and selective PARP inhibitors may be of beneficial and therapeutic value in septic shock.

Keywords: endotoxin, Sepsis, nicotinamide, 3-aminobenzamide, phenanthridinone PARS inhibitors, rodent, Swine