Morgan N G, Short C D, Rumford G M, Montague W
Biochem J. 1985 Nov 1;231(3):629-34. doi: 10.1042/bj2310629.
The rate of insulin secretion from isolated rat islets of Langerhans was affected by a number of dihydropyridine derivatives known to interact with voltage-sensitive Ca2+ channels in excitable cells. The channel antagonists nifedipine and nitrendipine were potent inhibitors of glucose-induced insulin secretion in response to both 8 mM- and 20 mM-glucose, although they did not lower the basal secretion rate observed in the presence of 4 mM-glucose. The Ca2+-channel agonist, CGP 28392, also failed to alter the basal rate of insulin secretion. In the presence of 8 mM-glucose, however, 1 microM-CGP 28392 enhanced the insulin-secretion rate to a value approximately double that with 8 mM-glucose alone. This effect was dose-dependent, with half the maximal response elicited by 0.1 microM-CGP 28392, and full enhancement at 10 microM. The response was rapid in onset, with an increase in insulin secretion evident within 2 min of CGP 28392 infusion in perifused islets. Stimulation of insulin secretion by CGP 28392 was correlated with a rapid enhancement of glucose-stimulated 45Ca2+ uptake into islets cells, and with a transiently increased rate of 45Ca2+ efflux from pre-loaded islets. Stimulation of insulin secretion by CGP 28392 was abolished in the presence of noradrenaline, although under these conditions the rapid stimulation of 45Ca2+ influx induced by CGP 28392 was only partially inhibited. In contrast with these results, when islets were incubated in the presence of 20 mM-glucose, CGP 28392 caused a dose-dependent inhibition of insulin secretion. Half-maximal inhibition required approx. 0.2 microM-CGP 28392, with maximal effects observed at 10 microM. Under these conditions, however, the extent of insulin secretion was still only decreased by about 50%, to a value which was similar to that seen in the presence of 8 mM-glucose and CGP 28392. These results suggest that dihydropyridine derivatives can alter the activity of voltage-dependent Ca2+ channels in islet cells, and are consistent with the possibility that gating of these channels plays an important role in regulating the rate of insulin secretion after glucose stimulation.
已知一些二氢吡啶衍生物可与可兴奋细胞中的电压敏感性Ca2+通道相互作用，它们对分离出的大鼠胰岛的胰岛素分泌速率产生了影响。通道拮抗剂硝苯地平和尼群地平是葡萄糖诱导的胰岛素分泌的有效抑制剂，无论葡萄糖浓度是8 mM还是20 mM，尽管它们并未降低在4 mM葡萄糖存在下观察到的基础分泌速率。Ca2+通道激动剂CGP 28392也未能改变胰岛素分泌的基础速率。然而，在8 mM葡萄糖存在的情况下，1 microM - CGP 28392可将胰岛素分泌速率提高到约为仅使用8 mM葡萄糖时的两倍。这种作用呈剂量依赖性，0.1 microM - CGP 28392可引发最大反应的一半，10 microM时可实现完全增强。反应起效迅速，在灌注胰岛中注入CGP 28392后2分钟内胰岛素分泌明显增加。CGP 28392对胰岛素分泌的刺激与葡萄糖刺激的胰岛细胞对45Ca2+摄取的快速增强以及预加载胰岛中45Ca2+外流速率的短暂增加相关。在去甲肾上腺素存在的情况下，CGP 28392对胰岛素分泌的刺激作用被消除，尽管在这些条件下，CGP 28392诱导的45Ca2+内流的快速刺激仅被部分抑制。与这些结果相反，当胰岛在20 mM葡萄糖存在下孵育时，CGP 28392会导致胰岛素分泌呈剂量依赖性抑制。半最大抑制需要约0.2 microM - CGP 28392，在10 microM时观察到最大效应。然而，在这些条件下，胰岛素分泌的程度仍仅降低约50%，降至与在8 mM葡萄糖和CGP 28392存在下观察到的值相似的水平。这些结果表明，二氢吡啶衍生物可改变胰岛细胞中电压依赖性Ca2+通道的活性，并且与这些通道的门控在调节葡萄糖刺激后胰岛素分泌速率中起重要作用的可能性一致。
