Published Online
on May 6, 2002

A more recent version of this article appeared on June 4, 2002

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Submitted on January 21, 2002
Revised on March 13, 2002
Accepted on March 14, 2002

Diazoxide Opens the Mitochondrial Permeability Transition Pore and Alters Ca²⁺ Transients in Rat Ventricular Myocytes

Hideki Katoh MD, PhD^*, Nobuhiro Nishigaki PhD, and Hideharu Hayashi MD, PhD

From the Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan.

^* To whom correspondence should be addressed. E-mail: hkatoh{at}hama-med.ac.jp.

Background—The mitochondrial K_ATP channel (mitoK_ATP) has been implicated as an end effector or trigger of ischemic preconditioning (IP). Although a mitoK_ATP opener, diazoxide, mimics IP, mechanisms for the cardioprotective action remain unclear.

Methods and Results—We measured Ca²⁺ transients (CaTs) and mitochondrial inner membrane potential (_m) with confocal microscopy and the fluorescent probes fluo-4 and tetramethylrhodamine ethyl ester perchlorate in rat ventricular myocytes. Diazoxide increased the amplitudes and diastolic levels of CaTs dose dependently. The effects of diazoxide on CaTs were inhibited by the mitoK_ATP antagonist sodium 5-hydroxydecanoic acid (100 µmol/L), whereas application of diazoxide caused little change in _m. After sarcoplasmic reticulum function was disabled with ryanodine and thapsigargin, the effects of diazoxide on CaTs were still observed. The opening of the mitochondrial permeability transition pore was monitored with fluorescent calcein. Diazoxide accelerated the leakage of calcein from mitochondrial matrix (16% of control; P<0.05), and this effect was inhibited by cyclosporin A (2 µmol/L). Cyclosporin A also abolished the effects of diazoxide on CaTs. Diazoxide oxidized flavoprotein fluorescence reversibly, and this effect was partially blunted by cyclosporin A (by 24%; P<0.05).

Conclusions—We conclude that in rat ventricular myocytes, diazoxide modulates the opening of the mitochondrial permeability transition pore, resulting in an increase in CaTs independent of the changes in _m. The action of diazoxide on the mitochondrial permeability transition pore also affects the mitochondrial redox state.

Key words: myocytes • ischemia • calcium

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