CST exerts anti-hypertensive, vasodilator and cardiac inotropic effects acting via nitric oxide signaling. We tested whether CST cardioprotective effect includes RISK pathway. Isolated rat hearts underwent 30-min ischemia and 120-min reperfusion (I/R) without or with CST (75 nM, CST-Post) for 20-min in early reperfusion. To evaluate the role of PKC and mitochondrial K_ATP (mito_KATP) channels, hearts were co-infused with CST and either the PKC inhibitor (chelerythrine) or the mitoK_ATP channel blocker (5-hydroxy-decanoate). We also tested the phosphorylation (PP) of RISK elements (Akt, PKCe and GSK3b) and the levels of anti-apoptotic marker (Bcl-2). Coronary pressure and left ventricular pressure (LVP) were monitored. Infarct size (IS) was evaluated with NBT-staining. IS was 67±6% of risk area in hearts subjected to I/R only. CST-Post reduced IS to 37±4%, and improved postischemic contracture and recovery of developed LVP. CST-Post induced PP of all RISK elements and preserved the levels of Bcl-2. Inhibition of PKC abolished all CST protective effects and allowed a partial PP of Akt only. Blockade of mitoK_ATP abolished the IS limitation and GSK3b-PP, but allowed contracture limitation and partial PP of Akt and PKCe. Results suggest that CST-Post cardioprotection depends on activation of Akt and PKCe, which in turn, signals in a reverberant loop to mitoKATP leading to the PP/inhibition of GSK3b (from Akt to PKCe and to mitoK_ATP, again to PKCe and to GSK3b) and consequent protection against infarct size and contractile dysfunction.