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

Background— The mitochondrial KATP channel (mitoKATP) has been implicated as an end effector or trigger of ischemic preconditioning (IP). Although a mitoKATP opener, diazoxide, mimics IP, mechanisms for the cardioprotective action remain unclear. Methods and Results— We measured Ca2+ transients (CaTs) and mitochondrial inner membrane potential (Δψm) 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 mitoKATP antagonist sodium 5-hydroxydecanoic acid (100 μmol/L), whereas application of diazoxide caused little change in Δψm. 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 le...