Background Accumulating evidence suggests that mitochondrial rather than sa
rcolemmal adenosine triphosphate-sensitive K+ (K-ATP) channels may have an
important role in the protection of myocardium during ischemia. Because bot
h lidocaine and mexiletine are frequently used antiarrhythmic drugs during
myocardial ischemia, it is important to investigate whether they affect mit
ochondrial K-ATP, channel activities.
Methods: Male Wistar rats were anesthetized with ether. Single, quiescent v
entricular myocytes were dispersed enzymatically. The authors measured flav
oprotein fluorescence to evaluate mitochondrial redox state. Lidocaine or m
exiletine was applied after administration of diazoxide (25 muM), a selecti
ve mitochondrial K-ATP channel opener. The redox signal was normalized to t
he baseline flavoprotein fluorescence obtained during exposure to 2,4-dinit
rophenol, a protonophore that uncouples respiration from ATP synthesis and
collapses the mitochondrial potential.
Results: Diazoxide-induced oxidation of flavoproteins and the redox changes
were inhibited by 5-hydroxydecanoic acid, a selective mitochondrial KATP c
hannel blocker, suggesting that flavoprotein fluorescence can be used as an
index of mitochondrial oxidation mediated by mitochondrial K-ATP channels.
Lidocaine (10(-3) to 10 mM) and mexiletine (10(-3) to 10 mM) reduced oxida
tion of the mitochondrial matrix in a dose-dependent manner with an EC50 of
98 +/- 63 mum for lidocaine and 107 +/- 89 mum for mexiletine.
Conclusions: Both lidocaine and mexiletine reduced flavoprotein fluorescenc
e induced by diazoxide in rat ventricular myocytes, indicating that these a
ntiarrhythmic drugs may produce Impairment of mitochondrial oxidation media
ted by mitochondrial K-ATP channels.