Abstract 1614: Chronic Preconditioning: A Novel Approach in Cardiac Protection
Background: Ischemic preconditioning is very powerful phenomenon in cardiac protection and no therapeutic agent has matched its effect. However, its effect is temporary. The more viable strategy is to put the heart in constant preconditioned state so that heart can resist any sudden lethal ischemic episode.
Methods: In this study, we used an effective opener of mitochondrial KATP channel (mitoKATP) to test whether the heart can be preconditioned for a longer period. A selective mitoKATP opener, BMS (1 mg/kg, i.p.), or BMS plus wortmannin (WTN, 15 μg/kg, i.p.), an inhibitor of PI-3 kinase, or BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg, i.p.), an inhibitor of mitoKATP channels, or BMS plus L-NAME (30 μg/kg, i.p.), inhibitor of nitric oxide synthase were administered to male Fisher 344 rats (n =6 for each group). BMS was given after every 24 hrs. The effect of BMS on the cardiac function, infarct size, pathological changes and apoptosis was assessed 24, 48, 72 and 96 hours after administration of BMS in rats subjected to 30 min LAD occlusion followed by 120 minutes of reperfusion.
Results: Saline treated hearts displayed marked contractile dysfunction, greater infarct size and increased TUNEL positive nuclei. BMS treated male rats showed significant improvement in cardiac function (LV +dp/dt, −dp/dt and EF, p<0.05 vs. saline group) and marked reduction in the infarct size, apoptotic myocytes and well preserved cell structure. Rats which received intermittently BMS for 96 hrs displayed increased improvement in post-ischemic contractile function (p<0.05 vs. 24 hrs group). However, protection by BMS was abolished by 5-HD, or WTN, or L-NAME.
Conclusion: These data demonstrate that hearts can be chronically preconditioned and retain their ability to remain tolerant against lethal ischemia and this protection is mediated by mitoKATP channels, PI-3K/Akt and NO signaling pathways.