Pharmacological manipulation of Ins(1,4,5)P3signaling mimics preconditioning in rabbit heart

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Abstract
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)P3signaling {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 ofd- myo-Ins(1,4,5)P3and 2-APB on Ins(1,4,5)P3signaling were evaluated in isolated fura 2-loaded rat cardiomyocytes. Mean infarct size was reduced with PC and in alld- 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)P3signaling mimics the cardioprotection achieved with ischemic PC in rabbit heart.