title: Effects of sulfonylureas on mitochondrial ATP-sensitive K+ channels in cardiac myocytes: implications for sulfonylurea controversy.
abstract: 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.
authors.affiliation: Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan. tsato@faculty.chiba-u.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sato
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nishida
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
mesh_terms: 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*
chemical_list: D002316:Cardiotonic Agents; D005420:Flavoproteins; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; C117780:mitochondrial K(ATP) channel