Sulphonylurea drugs no longer inhibit ATP-sensitive K+ channels during metabolic stress in cardiac muscle.
The effects of the sulphonlyurea drugs glibenclamide and tolbutamide were tested upon ATP-sensitive K+ channels activated by dinitrophenol or carbonyl cyanide p-(trifluoromethoxy)-phenylhydrazone (FCCP) in ventricular myocytes isolated from rat hearts. In whole-cell current recording, 1 microM glibenclamide or 1 mM tolbutamide totally but only transiently inhibited the K+ current activated by dinitrophenol or FCCP. In cell-attached membrane patches, 1 to 100 microM glibenclamide initially inhibited the activation of ATP-sensitive K+ channels induced by dinitrophenol or FCCP, but failed to prevent the activation of these channels during contracture. Myocyte contracture induced by caffeine or Ca++ entry during K+ depolarization did not activate ATP-sensitive K+ channels. In excised membrane patches, 1 to 10 microM glibenclamide did not block completely opening of ATP-sensitive K+ channels. Neither intracellular ADP nor phosphorylable substrate were able to reliably influence the effect of glibenclamide. It is concluded that sulphonylurea drugs, otherwise highly effective blockers of this type of ion channel, were no longer able to inhibit the opening of ATP-sensitive K+ channels during the final stages of metabolic stress. These channels could therefore be responsible for both the glibenclamide-sensitive and glibenclamide-insensitive phases of K+ loss during cardiac ischemia.
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Laboratoire de Physiologie Comparée (URA CNRS 1121), Bâtiment 443, Université de Paris XI, Orsay, France.
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D004140:Dinitrophenols / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012680:Sensitivity and Specificity; D013312:Stress, Physiological / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology
D001578:Benzopyrans; D004095:Dihydropyridines; D004140:Dinitrophenols; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C061050:bimakalim; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005905:Glyburide