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Effects of sulfonylureas on mitochondrial ATP‐sensitive K + channels in cardiac myocytes: implications for sulfonylurea controversy
Author(s) -
Sato Toshiaki,
Nishida Hirofumi,
Miyazaki Masaru,
Nakaya Haruaki
Publication year - 2006
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.621
Subject(s) - diazoxide , medicine , glibenclamide , glimepiride , endocrinology , chemistry , sulfonylurea , membrane potential , mitochondrion , flavoprotein , pharmacology , biochemistry , biology , diabetes mellitus , insulin , type 2 diabetes , enzyme
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 µ M ) reversibly increased flavoprotein oxidation to 31.8 ± 4.3% ( n = 5) of the maximum value induced by 2,4‐dinitrophenol. Glimepiride (10 µ M ) 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 µ M ) and by tolbutamide (100 µ M ). Exposure to ouabain (1 m M ) 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. Copyright © 2006 John Wiley & Sons, Ltd.