(23) THE ROLE OF MITOCHONDRIAL KATP CHANNELS IN CARDIAC ISCHEMIA AND IN NORMAL HEART FUNCTION

Keith D. Garlid and Petr Paucek
Department of Biochemistry and Molecular Biology, Oregon Graduate Institute of Science and Technology, P.O. Box 91000, Portland, Oregon 97291-1000

The mitochondrial KATP channel (mitoKATP) is a heteromultimeric, inner membrane complex that catalyzes K+ influx into the matrix. MitoKATP is regulated by nucleotides and long-chain acyl CoA esters, and the regulatory sites are on the outer surface of the channel complex. It is also sensitive to K+ channel openers and blockers, such as diazoxide and glyburide, respectively.

Ischemia-reperfusion damage to the heart is delayed by pretreatment with K+ channel openers that are specific for KATP channels. KATP is also considered to be the end-effectors of cardioprotection by ischemic preconditioning (IPC), in which a brief period of ischemia protects the heart against longer periods of ischemia, and by Ca2+ preconditioning (CPC), in which a transient rise in cytosolic Ca2+ is protective. We have recently presented evidence that the site of these cardioprotective actions is the mitochondrial KATP channel, and not the sarcolemmal KATP channel (Garlid et al., Circ. Res. 81:1072-1082, 1997).

These findings raise several questions. What are the pathways by which IPC and CPC open mitoKATP? How does opening mitoKATP protect the heart? What is the role of mitoKATP in the normal heart? We will suggest answers to these questions based on known phenomenology of the ischemic and normal heart. The underlying hypothesis is that mitoKATP regulates the volume of the intermembrane space and that its role is to protect the architecture of this space in order to preserve metabolic channeling between the cytosol and the inner membrane.