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• W2023650478 abstract "We have investigated the effects of the sulphonylurea, glimepiride, currently used to treat type 2 diabetes, on ATP-sensitive K+ (KATP) currents of rat cardiac myocytes and on their cloned constituents Kir6.2 and SUR2A expressed in HEK 293 cells. Glimepiride blocked pinacidil-activated whole-cell KATP currents of cardiac myocytes with an IC50 of 6.8 nM, comparable to the potency of glibenclamide in these cells. Glimepiride blocked KATP channels formed by co-expression of Kir6.2/SUR2A subunits in HEK 293 cells in outside-out excised patches with a similar IC50 of 6.2 nM. Glimepiride was much less effective at blocking KATP currents activated by either metabolic inhibition (MI) with CN− and iodoacetate or by the KATP channel opener diazoxide in the presence of inhibitors of F0/F1-ATPase (oligomycin) and creatine kinase (DNFB). Thus 10 μM glimepiride blocked pinacidil-activated currents by >99%, MI-activated currents by 70% and diazoxide-activated currents by 82%. In inside-out patches from HEK 293 cells expressing the cloned KATP channel subunits Kir6.2/SUR2A, increasing the concentration of ADP (1 – 100 μM), in the presence of 100 nM glimepiride, lead to significant increases in Kir6.2/SUR2A channel activity. However, over the range tested, ADP did not affect cloned KATP channel activity in the presence of 100 nM glibenclamide. These results are consistent with the suggestion that ADP reduces glimepiride block of KATP channels. Our results show that glimepiride is a potent blocker of native cardiac KATP channels activated by pinacidil and blocks cloned Kir6.2/SUR2A channels activated by ATP depletion with similar potency. However, glimepiride is much less effective when KATP channels are activated by MI and this may reflect a reduction in glimepiride block by increased intracellular ADP. British Journal of Pharmacology (2002) 136, 746–752; doi:10.1038/sj.bjp.0704770" @default.
• W2023650478 created "2016-06-24" @default.
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• W2023650478 date "2002-07-01" @default.
• W2023650478 modified "2023-10-11" @default.
• W2023650478 title "Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K_ATPchannels" @default.
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• W2023650478 doi "https://doi.org/10.1038/sj.bjp.0704770" @default.
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