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

Abstract

1 We have investigated the e ects 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. 2 Glimepiride blocked pinacidil-activated whole-cell K ATP currents of cardiac myocytes with an IC 50 of 6.8 nM, 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 nM. 3 Glimepiride was much less e ective at blocking K ATP currents activated by either metabolic inhibition (MI) with CN 7 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 mM glimepiride blocked pinacidil-activated currents by 499%, MI-activated currents by 70% and diazoxideactivated currents by 82%. 4 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 mM), in the presence of 100 nM glimepiride, lead to signi®cant increases in Kir6.2/SUR2A channel activity. However, over the range tested, ADP did not a ect cloned K ATP channel activity in the presence of 100 nM glibenclamide. These results are consistent with the suggestion that ADP reduces glimepiride block of K ATP channels. 5 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 e ective when K ATP channels are activated by MI and this may re¯ect a reduction in glimepiride block by increased intracellular ADP.

Diazoxide causes early activation of cardiac sarcolemmal KATP channels during metabolic inhibition by an indirect mechanism

“…The blocking effectiveness of sulphonylureas on cardiac sarcoK ATP channels is reduced by MgADP [32]. Block by glimepiride is inhibited as ADP is raised [33], and our unpublished observations suggest that block by HMR 1883 behaves in a similar manner.…”

Early opening of sarcolemmal ATP-sensitive potassium channels is not a key step in PKC-mediated cardioprotection

“…Additionally, the role of sarcoK ATP channels in cardioprotection may be as part of a larger signalasome-type complex [40]. [44] and glimepiride [45], is markedly attenuated by elevated intracellular…”

Cardiovascular safety of oral antidiabetic therapy in type 2 diabetes mellitus- review article

“…24,25 Second-generation agents include glipizide, glibenclamide and gliclazide. Sulfonylurea monotherapy reduces HbA1c by 1-2% but weight gain is almost inevitable.…”

“…Sulfonylurea monotherapy reduces HbA1c by 1-2% but weight gain is almost inevitable. 24,25 Sulfonylureas gain a mean of 5.3 kg over 6 years. [26][27][28] Glimepiride, a third-generation agent, has at least therapeutic equivalence to the secondgeneration agents, but is less associated with both weight gain and hypoglycemia.…”

“…Overall, due to their low cost and short term glycemic efficacy, the sulfonylureas are still strongly endorsed as second-line agents by international guidelines. 23,24,38 …”