Lethal injury to the heart can be dramatically blunted by brief periods of prior ischemia. 1 Such an endogenous cardioprotective mechanism, known as ischemic preconditioning (IPC), exists in all species examined to date, including humans. 2 IPC occurs in a biphasic pattern of myocardial protection: an early phase (classic IPC), which develops immediately and lasts approximately 2 hours after the IPC stimulus, and a delayed phase (late IPC or second window of protection), which reappears after 24 hours and lasts at least 72 hours. 3, 4 Despite intensive investigation, the cellular mechanism of IPC still remains obscure, although important clues are beginning to emerge. A number of substances and signaling pathways have been proposed to be involved in mediating the cardioprotective effect of IPC (reviewed in Downey and Cohen5). Nevertheless, considerable evidence has suggested that ATP-sensitive K+(KATP) channels may serve as the end effectors in this process. 6 Although the cardioprotective effects were initially attributed to plasma membrane KATP channels, the degree of action potential shortening can be divorced from the extent of protection. 7, 8 Instead, it now seems much more likely that KATP channels in mitochondrial inner membrane (mitoKATP channels) are the dominant players. The studies of the mitoKATP channel were facilitated by the identification of a selective opener and a selective blocker of mitoKATP channels (selective relative to cardiac sarcolemmal KATP channels, by at least three orders of magnitude), namely diazoxide and 5-hydroxydecanoate. 9, 10 The mitoKATP channel opener diazoxide mimics the infarct size–limiting effects of classic IPC, whereas the mitoKATP channel blocker 5-hydroxydecanoate obliterates the beneficial effects of conditioning ischemia. 9, 11 Thus, mitoKATP channels have emerged as the likely effectors of classic IPC.

The underlying pathophysiology and mechanisms between early and delayed phases of cardioprotection are likely to differ, with posttranslational modifications dominating the early phase; given the timing, changes in gene expression should only come to play in the delayed phase. Interestingly, the mitoKATP channel now appears to feature prominently in