Pharmacological manipulation of Ins(1,4,5)P₃ signaling mimics preconditioning in rabbit heart

Recent evidence revealed biphasic alterations in myocardial concentrations of the second messenger inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃] with ischemic preconditioning (PC), i.e., increase during brief PC ischemia and decrease early during sustained test occlusion. Our aim was to determine whether an agonist and an antagonist of Ins(1,4,5)P₃ signaling {D-myo-inositol-1,4,5-trisphosphate hexasodium salt [D-myo- Ins(1,4,5)P₃] and 2-aminoethoxydiphenyl borate (2-APB), respectively}, given such that they mimic this biphasic profile, would mimic infarct size reduction with PC. To test this concept, isolated, buffer-perfused rabbit hearts received no intervention (control), ischemic PC, D-myo-Ins(1,4,5)P₃, D-myo-Ins(1,4,5)P₃ + PC, 2-APB, or 2-APB + PC. All hearts then underwent 30- min coronary occlusion and 2 h reflow, and infarct size was delineated by tetrazolium staining. In addition, the effects of D-myo-Ins(1,4,5)P₃ and 2- APB on Ins(1,4,5)P₃ signaling were evaluated in isolated fura 2-loaded rat cardiomyocytes. Mean infarct size was reduced with PC and in all D-myo- Ins(1,4,5)P₃- and 2-APB-treated groups versus control (59 and 42-55%, respectively, vs. 80% of myocardium at risk, P < 0.05). Thus pharmacological manipulation of Ins(1,4,5)P₃ signaling mimics the cardioprotection achieved with ischemic PC in rabbit heart.