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(Circulation Research. 1999;85:1113.)
© 1999 American Heart Association, Inc.

Editorials

Signaling in Late Preconditioning

Involvement of Mitochondrial K_ATP Channels

Toshiaki Sato

From the Department of Physiology, Oita Medical University, Oita, Japan.

Correspondence to Toshiaki Sato, MD, PhD, Department of Physiology, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. E-mail tsato@oita-med.ac.jp

Key Words: preconditioning • mitochondria • protein kinase C • protein tyrosine kinase

	Introduction

 
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⁺ (K_ATP) channels may serve as the end effectors in this process.⁶ Although the cardioprotective effects were initially attributed to plasma membrane K_ATP 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 K_ATP channels in mitochondrial inner membrane (mitoK_ATP channels) are the dominant players. The studies of the mitoK_ATP channel were facilitated by the identification of a selective opener and a selective blocker of mitoK_ATP channels (selective relative to cardiac sarcolemmal K_ATP channels, by at least three orders of magnitude), namely diazoxide and 5-hydroxydecanoate.^{9 10} The mitoK_ATP channel opener diazoxide mimics the infarct size–limiting effects of classic IPC, whereas the mitoK_ATP channel blocker . . . [Full Text of this Article]