From the Section of Molecular and Cellular Cardiology, Department of
Medicine, Johns Hopkins University, Baltimore, Md. Yongge Liu is now at
Maryland Research Laboratories, Otsuka America Pharmaceutical Inc, Rockville,
Md.
Correspondence to Eduardo Marban, MD, PhD, Section of Molecular and Cellular Cardiology, Department of Medicine, Johns Hopkins University, Ross 844, 720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}welchlink.welch.jhu.edu
Background—Brief interruptions
of coronary blood flow paradoxically protect the heart from
subsequent prolonged ischemia. The basis of such
endogenous cardioprotection, known as "ischemic
preconditioning," remains uncertain. Pharmacological evidence has
implicated ATP-dependent potassium (KATP) channels in the
mechanism of preconditioning; however, the effects of sarcolemmal
KATP channels on excitability cannot account for the
protection.
Methods and Results—We simultaneously measured
flavoprotein fluorescence, an index of mitochondrial redox
state, and sarcolemmal KATP currents in intact rabbit
ventricular myocytes. Our results show that diazoxide, a
KATP channel opener, selectively activates
mitochondrial KATP channels. Diazoxide induced reversible
oxidation of flavoproteins with an EC50 of 27 µmol/L
but did not activate sarcolemmal KATP channels. The
subcellular site of diazoxide action is further localized to
mitochondria by confocal imaging of fluorescence arising from
flavoproteins and tetramethylrhodamine ethyl ester. In a cellular model
of simulated ischemia, inclusion of diazoxide decreased the
rate of cell death to about half of that in controls. Both the redox
changes and protection are inhibited by the KATP channel
blocker 5-hydroxydecanoic acid.
Conclusions—Our results demonstrate that diazoxide targets
mitochondrial but not sarcolemmal KATP channels and imply
that mitochondrial KATP channels may mediate the protection
from KATP channel openers.
© 1998 American Heart Association, Inc.
Basic Science Reports
Mitochondrial ATP-Dependent Potassium Channels
Novel Effectors of Cardioprotection?
Key Words: ischemia • potassium channels • mitochondria
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