Panten U, Burgfeld J, Goerke F, Rennicke M, Schwanstecher M, Wallasch A, Zünkler B J, Lenzen S
Institute of Pharmacology and Toxicology, University of Göttingen, Federal Republic of Germany.
Biochem Pharmacol. 1989 Apr 15;38(8):1217-29. doi: 10.1016/0006-2952(89)90327-4.
Sulfonylureas inhibit an ATP-dependent K+ channel in the B-cell plasma membrane and thereby initiate insulin release. Diazoxide opens this channel and inhibits insulin release. In mouse pancreatic islets, we have explored whether other targets for these drugs must be postulated to explain their hypo- or hyperglycaemic properties. At non-saturating drug concentrations the rates of increase in insulin secretion declined in the order tolbutamide = meglitinide greater than glipizide greater than glibenclamide. The same rank order was observed when comparing the rates of disappearance of insulin-releasing and K+ channel-blocking effects. The different kinetics of response depend on the lipid solubility of the drugs, which controls their penetration into the intracellular space. Allowing for the different kinetics, the same maximum secretory rates were caused by saturating concentrations of tolbutamide, meglitinide, glipizide and glibenclamide. A close correlation between insulin-releasing and K+ channel-blocking potencies of these drugs was observed. The relative potencies of tolbutamide, meglitinide, glipizide and glibenclamide corresponded well to their relative affinities for binding to islet-cell membranes, suggesting that the binding site represents the sulfonylurea receptor. The biphasic time-course of dissociation of glibenclamide binding indicates a complex receptor-drug interaction. For diazoxide there was no correlation between affinity of binding to the sulfonylurea receptor and potency of inhibition of insulin secretion. Thus, opening or closing of the ATP-dependent K+ channel by diazoxide or sulfonylureas, respectively, appears to be due to interaction with different binding sites in the B-cell plasma membrane. The free concentrations of tolbutamide, glipizide, glibenclamide and diazoxide which are effective on B-cells are in the range of therapeutic plasma concentrations of the free drugs. It is concluded that the hypo- and hyperglycaemic effects of these drugs result from changing the permeability of the ATP-dependent K+ channel in the B-cell plasma membrane.
磺脲类药物抑制B细胞膜中一种ATP依赖性钾通道，从而引发胰岛素释放。二氮嗪可打开此通道并抑制胰岛素释放。在小鼠胰岛中，我们探讨了是否必须假定这些药物存在其他靶点才能解释其降血糖或升血糖特性。在非饱和药物浓度下，胰岛素分泌增加速率的下降顺序为甲苯磺丁脲 = 米格列奈＞格列吡嗪＞格列本脲。比较胰岛素释放和钾通道阻断作用的消失速率时，也观察到了相同的顺序。不同的反应动力学取决于药物的脂溶性，脂溶性控制着药物向细胞内空间的渗透。考虑到不同的动力学因素，甲苯磺丁脲、米格列奈、格列吡嗪和格列本脲的饱和浓度可引起相同的最大分泌速率。观察到这些药物的胰岛素释放和钾通道阻断效能之间存在密切相关性。甲苯磺丁脲、米格列奈、格列吡嗪和格列本脲的相对效能与其与胰岛细胞膜结合的相对亲和力非常吻合，这表明结合位点代表磺脲类受体。格列本脲结合解离的双相时间进程表明存在复杂的受体 - 药物相互作用。对于二氮嗪，其与磺脲类受体的结合亲和力与抑制胰岛素分泌的效能之间没有相关性。因此，二氮嗪或磺脲类药物分别打开或关闭ATP依赖性钾通道，似乎是由于与B细胞膜中的不同结合位点相互作用所致。对B细胞有效的甲苯磺丁脲、格列吡嗪、格列本脲和二氮嗪的游离浓度处于游离药物治疗性血浆浓度范围内。结论是这些药物的降血糖和升血糖作用是通过改变B细胞膜中ATP依赖性钾通道的通透性而产生的。
