In:
Diabetes/Metabolism Research and Reviews, Wiley, Vol. 22, No. 5 ( 2006-09), p. 341-347
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1520-7552
,
1520-7560
Language:
English
Publisher:
Wiley
Publication Date:
2006
detail.hit.zdb_id:
2001565-3
Permalink