The investigation of the role of intracellular sodium overlaod in ischemia reperfusion injury

The aim of the present study, was to compare cardioprotective effects of 44Bu (transient Na+ channel blocker), ranolazine (persistent Na+ channel blocker), zoniporide (NHE inhibitor) and KBR-7943 (NCX inhibitor) which prevent intracellular Na+ and Ca+2 overload against ischemia-reperfusion injury(I/R), in the same experimental conditions.For inducing I/R injury, isolated rat hearts were subjected to 60 min global ischemia and 30 min reperfusion. Hearts were perfused at a constant flow rate of 10 ml/dk in a Langendorff apparatus and paced with electrical stimulation (5 Hz, 1.5 ms duration, 30 V) throughout the experiments. All drugs were given for 5 min prior to ischemia and for 10 min after the onset of reperfusion. Recovery of post-ischemic contractile function was assessed by the left ventricular developed pressure (LVDP), left ventricular end diastolic pressure (LVEDP), and the rates of pressure development (+dp/dt) and pressure decay (-dp/dt). All parameters were expressed as percentage of their pre-ischemic values. Additionally, ischemic hypercontracture was evaluated by measuring the time to maximum contracture (TMC) and maximum contracture (MC) during ischemia.In control hearts, LVDP and ±dp/dt markedly decreased and LVEDP increased at the end of the reperfusion. Ranolazine (10 µM) and 44Bu (0.3 µM) elicited a significant recovery in the LVDP, LVEDP and ±dp/dt compared to control hearts, but recovery in any of the parameters was not significant after the treatment with zoniporide (0.1 µM) and KBR (1 µM). Also, ranolazine providing better functional recovery than 44Bu against I/R injury. While TMC delayed only ranolazine administrated group, MC was significantly lower than control in all other groups.Our results demonstrate that Na+ channel blockers and especially inhibition of persistent sodium current have more potent cardioprotective effect than other drugs which prevent intracellular Na+ and Ca+2 overload against I/R injury.