Effects of sulfonylureas on mitochondrial ATP-sensitive K+ channels in cardiac myocytes: implications for sulfonylurea controversy.
BACKGROUND
Mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel plays a key role in cardioprotection. Hence, a sulfonylurea that does not block mitoK(ATP) channels would be desirable to avoid damage to the heart. Accordingly, we examined the effects of sulfonylureas on the mitoK(ATP) channel and mitochondrial Ca(2+) overload.


METHODS
Flavoprotein fluorescence in rabbit ventricular myocytes was measured to assay mitoK(ATP) channel activity. The mitochondrial Ca(2+) concentration was measured by loading cells with rhod-2.


RESULTS
The mitoK(ATP) channel opener diazoxide (100 microM) reversibly increased flavoprotein oxidation to 31.8 +/- 4.3% (n = 5) of the maximum value induced by 2,4-dinitrophenol. Glimepiride (10 microM) alone did not oxidize the flavoprotein, and the oxidative effect of diazoxide was unaffected by glimepiride (35.4 +/- 3.2%, n = 5). Similarly, the diazoxide-induced flavoprotein oxidation was unaffected both by gliclazide (10 microM) and by tolbutamide (100 microM). Exposure to ouabain (1 mM) for 30 min produced mitochondrial Ca(2+) overload, and the intensity of rhod-2 fluorescence increased to 197.4 +/- 7.2% of baseline (n = 11). Treatment with diazoxide significantly reduced the ouabain-induced mitochondrial Ca(2+) overload (149.6 +/- 5.1%, n = 11, p < 0.05 versus ouabain alone), and the effect was antagonized by the mitoK(ATP) channel blocker 5-hydroxydecanoate (189.8 +/- 27.8%, n = 5) and glibenclamide (193.1 +/- 7.7%, n = 8). On the contrary, cardioprotective effect of diazoxide was not abolished by glimepiride (141.8 +/- 7.8%, n = 6), gliclazide (139.0 +/- 9.4%, n = 5), and tolbutamide (141.1 +/- 4.5%, n = 7).


CONCLUSIONS
Our results indicate that glimepiride, gliclazide, and tolbutamide have no effect on mitoK(ATP) channel, and do not abolish the cardioprotective effects of diazoxide. Therefore, these sulfonylureas, unlike glibenclamide, do not interfere with the cellular pathways that confer cardioprotection.
Sato
Toshiaki
T
Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan. tsato@faculty.chiba-u.jp
Nishida
Hirofumi
H
Miyazaki
Masaru
M
Nakaya
Haruaki
H
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005420:Flavoproteins / Q000187:drug effects / Q000378:metabolism*; D005453:Fluorescence; D006352:Heart Ventricles; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008564:Membrane Potentials; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology*; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D002316:Cardiotonic Agents; D005420:Flavoproteins; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; C117780:mitochondrial K(ATP) channel