Findlay I
Laboratoire de Physiologie Comparée (URA CNRS 1121), Bâtiment 443, Université de Paris XI, Orsay, France.
J Pharmacol Exp Ther. 1993 Jul;266(1):456-67.
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.
在从大鼠心脏分离的心室肌细胞中，测试了磺酰脲类药物格列本脲和甲苯磺丁脲对由二硝基苯酚或羰基氰对-(三氟甲氧基)苯腙(FCCP)激活的ATP敏感性钾通道的作用。在全细胞电流记录中，1 μM格列本脲或1 mM甲苯磺丁脲完全但只是短暂地抑制了由二硝基苯酚或FCCP激活的钾电流。在细胞贴附膜片上，1至100 μM格列本脲最初抑制了由二硝基苯酚或FCCP诱导的ATP敏感性钾通道的激活，但在挛缩期间未能阻止这些通道的激活。咖啡因或钾去极化期间钙离子内流诱导的心肌细胞挛缩并未激活ATP敏感性钾通道。在切除的膜片中，1至10 μM格列本脲并未完全阻断ATP敏感性钾通道的开放。细胞内二磷酸腺苷和可磷酸化底物均不能可靠地影响格列本脲的作用。得出的结论是，磺酰脲类药物虽然是这类离子通道的高效阻滞剂，但在代谢应激的最后阶段不再能够抑制ATP敏感性钾通道的开放。因此，这些通道可能是心脏缺血期间钾流失的格列本脲敏感和格列本脲不敏感阶段的原因。
