Lidocaine and mexiletine inhibit mitochondrial oxidation in rat ventricular myocytes.
BACKGROUND
Accumulating evidence suggests that mitochondrial rather than sarcolemmal adenosine triphosphate-sensitive K+ (K(ATP)) channels may have an important role in the protection of myocardium during ischemia. Because both lidocaine and mexiletine are frequently used antiarrhythmic drugs during myocardial ischemia, it is important to investigate whether they affect mitochondrial K(ATP) channel activities.


METHODS
Male Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. The authors measured flavoprotein fluorescence to evaluate mitochondrial redox state. Lidocaine or mexiletine was applied after administration of diazoxide (25 microM), a selective mitochondrial K(ATP) channel opener. The redox signal was normalized to the baseline flavoprotein fluorescence obtained during exposure to 2,4-dinitrophenol, 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 K(ATP) channel 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 oxidation of the mitochondrial matrix in a dose-dependent manner with an EC50 of 98+/-63 microM for lidocaine and 107+/-89 microM for mexiletine.


CONCLUSIONS
Both lidocaine and mexiletine reduced flavoprotein fluorescence induced by diazoxide in rat ventricular myocytes, indicating that these antiarrhythmic drugs may produce impairment of mitochondrial oxidation mediated by mitochondrial K(ATP) channels.
Tsutsumi
Y
Y
Department of Anesthesiology, Tokushima University School of Medicine, Japan. tsutsumi@clin.med.tokushima-u.ac.jp
Oshita
S
S
Kawano
T
T
Kitahata
H
H
Tomiyama
Y
Y
Kuroda
Y
Y
Nakaya
Y
Y
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects*; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D008801:Mexiletine / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D008801:Mexiletine; D000255:Adenosine Triphosphate; D008012:Lidocaine; D003981:Diazoxide; D002118:Calcium