Mitochondrial KATPChannel Opening During Index Ischemia and Following Myocardial Reperfusion in Ischemic Rat Hearts

Abstract

It has been known for some time that opening of Although a trigger role for the mKATP was firmly established by those experiments, the identity of the ATP-sensitive potassium channels in the mitochondrial inner membrane (mKATP) is an essential end-effector was unclear. It is useful to characterize steps in the preconditioning paradigm as either step leading to ischemic preconditioning’s antiinfarct effect. Recently, however, data from Yao triggers or mediators. A trigger would be an event that, by itself, will put the heart into a preet al. indicated that free radicals were associated with mKATP channel opening in chick carconditioned state. Once triggered, preconditioning’s memory then keeps the heart in a preconditioned diomyocytes. Because free radicals are known triggers of ischemic preconditioning, Pain et al. state long after the trigger is removed. The mediators exert their protective effect during the index proposed that receptor activation opens mKATP channels causing the mitochondria to release free ischemia and perhaps even during the subsequent reperfusion period. PKC is an example of a mediator. radicals which in turn trigger kinase activity. In this paradigm the mKATP channels serve as upstream Blocking PKC during the index ischemia aborts protection. However, if the blocker is present only triggers rather than as end-effectors. The evidence was that transient mKATP opening with a pulse of during the preconditioning ischemia and then washed out prior to the index ischemia, protection diazoxide put the heart into a protected state that persisted long after the channels should have again is not blocked. That was a surprising finding since phosphorylation of substrate was thought to be closed. In addition, protection from diazoxide could be blocked with either a tyrosine kinase blocker in the likely mechanism of preconditioning’s memory. Mediators include both the signaling pathways that rabbit or a protein kinase C (PKC) blocker in rat. The kinase studies indicated that the mKATP was must be active during the ischemic process and the end-effector(s) upon which these signals terminate. upstream rather than downstream of the kinases. Finally, to test whether this trigger function ocOne distinct possibility is that mKATP may serve both trigger and mediator roles. In the latter case, curred physiologically, Pain et al. bracketed the ischemic preconditioning period with the reversible reopening of the channels during the index ischemia might act to protect the heart against infarction. mKATP inhibitor 5-hydroxydecanoate (5HD) and allowed the 5HD to wash out prior to the index There is a precedent for such a dual role. Adenosine can be shown to be both a trigger of protection ischemia. That blocked protection indicating that mKATP had to open during the preconditioning and a mediator. A transient exposure to adenosine puts the heart into a preconditioned state that ischemia.