Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K ATP channels

We have investigated the effects of the sulphonylurea, glimepiride, currently used to treat type 2 diabetes, on ATP‐sensitive K + (K ATP ) 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 K ATP currents of cardiac myocytes with an IC 50 of 6.8 n M , comparable to the potency of glibenclamide in these cells. Glimepiride blocked K ATP channels formed by co‐expression of Kir6.2/SUR2A subunits in HEK 293 cells in outside‐out excised patches with a similar IC 50 of 6.2 n M . Glimepiride was much less effective at blocking K ATP currents activated by either metabolic inhibition (MI) with CN − and iodoacetate or by the K ATP channel opener diazoxide in the presence of inhibitors of F 0 /F 1 ‐ATPase (oligomycin) and creatine kinase (DNFB). Thus 10 μ M 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 K ATP channel subunits Kir6.2/SUR2A, increasing the concentration of ADP (1 – 100 μ M ), in the presence of 100 n M glimepiride, lead to significant increases in Kir6.2/SUR2A channel activity. However, over the range tested, ADP did not affect cloned K ATP channel activity in the presence of 100 n M glibenclamide. These results are consistent with the suggestion that ADP reduces glimepiride block of K ATP channels. Our results show that glimepiride is a potent blocker of native cardiac K ATP 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 K ATP 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