Akiyoshi M, Kakei M, Nakazaki M, Tanaka H
First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Japan.
Am J Physiol. 1995 Feb;268(2 Pt 1):E185-93. doi: 10.1152/ajpendo.1995.268.2.E185.
Effects of a new hypoglycemic drug, N-[trans-4-isopropylcyclohexy-carbonyl]-D-phenylalanine (A-4166), on membrane current were investigated using the patch-clamp technique in single pancreatic beta-cells isolated from rats. A-4166, at a concentration of 10 microM, depolarized membrane potential of beta-cells and evoked action potentials in the presence of 2.8 mM glucose. The single ATP-sensitive K+ channel (K-ATP channel) current recorded in cell-attached membrane patches was reversibly inhibited by A-4166 (> 0.1 microM) without a change in the single-channel conductance of the K-ATP channel. Both A-4166 and tolbutamide inhibited the whole cell K-ATP channel current with half-maximum inhibition (IC50) of 0.23 and 12.8 microM, respectively (Hill coefficient = 1). In inside-out membrane patches, the IC50 with A-4166 occurred at 4.5 nM, in contrast to 0.7 microM for tolbutamide. A-4166 did not affect L- and T-type Ca2+ channels or the time-dependent outward current. We conclude that A-4166 specifically blocks the K-ATP channel and that the blockade is more potent than that of tolbutamide. The action of A-4166 underlies the mechanism by which the drug stimulates insulin secretion from beta-cells.
利用膜片钳技术，在从大鼠分离出的单个胰腺β细胞中研究了一种新型降糖药物N-[反式-4-异丙基环己基羰基]-D-苯丙氨酸（A-4166）对膜电流的影响。在存在2.8 mM葡萄糖的情况下，浓度为10 μM的A-4166使β细胞膜电位去极化并诱发动作电位。在细胞贴附膜片上记录的单个ATP敏感性钾通道（K-ATP通道）电流被A-4166（>0.1 μM）可逆性抑制，而K-ATP通道的单通道电导没有变化。A-4166和甲苯磺丁脲均抑制全细胞K-ATP通道电流，半数最大抑制浓度（IC50）分别为0.23和12.8 μM（希尔系数=1）。在膜内面向外的膜片中，A-4166的IC50为4.5 nM，而甲苯磺丁脲为0.7 μM。A-4166不影响L型和T型钙通道或时间依赖性外向电流。我们得出结论，A-4166特异性阻断K-ATP通道，且这种阻断作用比甲苯磺丁脲更强。A-4166的作用是该药物刺激β细胞分泌胰岛素的机制基础。
