Ranolazine triggers pharmacological preconditioning and postconditioning in anesthetized rabbits through activation of RISK pathway

We tested the hypothesis that ranolazine (Ran) is cardioprotective in a model of ischemia /reperfusion and we elucidated the intracellular mechanism. Anesthetized rabbits were subjected to is chemia and reperfusion and were divided into 5 groups: 1) Control, 2) Preconditioning (PreC), 3) Postconditioning (PostC), 4) RanA and 5) RanB, respectively treated with intravenous ranolazine, either 10min before or during index ischemia. Ranolazine was initially given over 60s and then from the beginning and throughout the whole reperfusion period. The infarcted to the risk ratio was calculated (%I/R). In a second series consisting of respective to the first series groups, the animals were subjected to the same interventions up to the 10th min of reperfusion where tissue samples were taken for immunoblotting of Akt, eNOS, ERK½ and GSK3β (RISK pathway). In a third series, RanA+Wort, RanB+Wort and Wort groups were treated with ranolazine as RanA and RanB groups but with the addition of the PI3 inhibitor Wortmaninn (Wort) and %I/R calculated. Ranolazine reduced the % I/R in RanA and RanB compared to the Control (23.1±1.7%, 17.6±2.0% vs 47.6±1.0%, P