Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca2+ overload during simulated ischemia and reperfusion - Possible mechanism of cardioprotection
M. Murata et al., Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca2+ overload during simulated ischemia and reperfusion - Possible mechanism of cardioprotection, CIRCUL RES, 89(10), 2001, pp. 891-898
Mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels play a key role
in ischemic preconditioning of the heart. However, the mechanism of cardio
protection remains controversial. We measured rhod-2 fluorescence in adult
rabbit ventricular cardiomyocytes as an index of mitochondrial matrix Ca2concentration ([Ca2+](m)), using time-lapse confocal microscopy. To simulat
e ischemia and reperfusion (I/R), cells were exposed to metabolic inhibitio
n (50 minutes) followed by washout with control solution. Rhod-2 fluorescen
ce gradually increased during simulated ischemia and rose even further with
reperfusion. The mitoK(ATP) channel opener diazoxide attenuated the accumu
lation of [Ca2+](m) during simulated I/R (EC50= 18 mu mol/L). These effects
of diazoxide were blocked by the mitoK(ATP) channel antagonist 5-hydroxyde
canoate (5HD). In contrast, inhibitors of the mitochondrial permeability tr
ansition (MPT), cyclosporin A and bongkrekic acid, did not alter [Ca2+](m)
accumulation during ischemia, but markedly suppressed the surge in rhod-2 f
luorescence during reperfusion. Measurements of mitochondrial membrane pote
ntial, Delta Psi (m), permeabilized myocytes revealed that diazoxide depola
rized Delta Psi (m) (by 12% at 10 mu mol/L, P <0.01) in a 5HD-inhibitable m
anner. Our data support the hypothesis that attenuation of mitochondrial Ca
2+ overload, as a consequence of partial mitochondrial membrane depolarizat
ion by mitoK(ATP) channels, underlies cardioprotection. Furthermore, mitoK(
ATP) channels and the MPT differentially affect mitochondrial calcium homeo
stasis: mitoK(ATP) channels suppress calcium accumulation during, I/R, whil
e the MPT comes into play only upon reperfusion.