Extra-corporal circulation is also known to induce a systemic inflammatory reaction with free radical release leading to secondary organ injury. During ischemia, cellular ATP is degraded into AMP, adenosine, inosine and hypoxanthine. Adenosine and its primary metabolite inosine are ubiquitous nucleosides that can be released from ischemic or reperfused tissue [2]. Adenosine and adenosine analogues have been shown to act as an endogenous cardio-protective agent against ischemia-reperfusion injury [3,4]. Until recently, inosine was generally considered an inactive metabolite. Nevertheless, some past and recent works suggested that inosine may exert inotropic, vasodilatory and anti-inflammatory effects [5-7]. It has recently been discovered, that inosine inhibit poly (ADP-ribose) polymerase (PARP) activation [8]. It is also demonstrated, that PARP activation occurs during the reperfusion but not during the ischaemia [9].

Until recently, inosine was considered an inactive purine metabolite in most biological systems, but several recent studies have shown that it has immuno-modulatory [10], neuroprotective [11], cardioprotective [12] and overall cytoprotective effects. Furthermore, some other studies reported that extracellular inosine has powerful cellular protective effects. For example, inosine decreases the release of intracellular enzymes from hypoxic lymphocytes [13], improves renal function during ischemia [14] and inhibits inflammatory cytokine production [7]. Administration of inosine has also been shown to improve myocardial function during acute left ventricular failure [15,16] and improve myocardial and endothelial function after heart transplantation [12]. Despite the growing evidence of protective effects of inosine, the use of inosine for prevention of reperfusion injury in the context of cardiopulmonary bypass has not yet been investigated.

The most cardiac surgical procedures require cardiopulmonary bypass and cardioplegia, which causes ischemia-reperfusion injury. Ischemia-reperfusion injury initiates pathophysiological cascades including an inflammatory response with liberation of cytokines and free radicals. Triggered by peroxynitrite-induced DNA single-brand breaks, PARP catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis, and the reduction of intracellular high-energy phosphates in the reperfused heart. In various types of ischemia-reperfusion, the prevention of PARP activation results in better preservation of the high-energy phosphates, resulting in an improved energy status [17-19]. It is also demonstrated, that PARP activation occurs during the reperfusion but not during the ischaemia [20]. Our group demonstrated previously, that inosine inhibits PARP activation in vivo and therefore modulates oxidant-induced cell death [12]. To the best of our knowledge, this was the first study that showed the effectiveness of inosine during the reperfusion in a clinically relevant large animal model of cardiopulmonary bypass. Administration of inosine during the reperfusion improved both systolic and diastolic indices of left ventricular contractility. In the current study, the load-independent indices such as preload recruitable stroke work (PRSW) and the slope of end-systolic pressure-volume relationship (ESPVR) of the left ventricle in the inosine group remained practically unchanged when compared with the baseline to 60-minutes reperfusion values. It is also well known, that the active phase of ventricle relaxation is an energy consuming phase of the cardiac circle, much like that of contraction. In the present study, we demonstrated that reperfusion injury is associated with impaired cardiac relaxation and diastolic dysfunction, as reflected by prolonged time constant of pressure decay (Tau) and increased LVDP. The decreased value of Tau in the inosine group clearly showed that inosine may significantly improve left ventricular diastolic function after CPB.