Diazoxide Opens the Mitochondrial Permeability Transition Pore and Alters Ca 2+ Transients in Rat Ventricular Myocytes

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Abstract
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 Ca 2+ transients (CaTs) and mitochondrial inner membrane potential (Δψ 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 Δψ 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 P 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 Δψ m . The action of diazoxide on the mitochondrial permeability transition pore also affects the mitochondrial redox state.