Ohta M, Nelson J, Nelson D, Meglasson M D, Erecińska M
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia.
J Pharmacol Exp Ther. 1993 Jan;264(1):35-40.
To investigate the effect of calcium channel blockade on intracellular energy levels and stimulated insulin secretion in isolated rat pancreatic islets, five different blockers of calcium channels were used. Insulin secretion stimulated with 16 mM glucose, 40 mM KCl or 20 mM alpha-ketoisocaproic acid was inhibited dose dependently by nifedipine, diltiazem, flunarizine and verapamil, albeit with different potencies. Nifedipine and flunarizine were more potent than diltiazem and verapamil. omega-Conotoxin GVIA (100 nM) had no significant effect on insulin release with all stimuli tested, although it caused approximately 20% inhibition of the late phase of secretion stimulated with high glucose. The doses of L-type channel antagonists and of flunarizine chosen for the measurements of cellular energy levels gave 60 to 80% inhibition of total stimulated insulin release. The [ATP]/[ADP] ratio, with 5 mM glucose in the perifusion medium, was greater when these channel blockers were present than in controls, whereas it was smaller with omega-conotoxin. The rises in the nucleotide ratio elicited by 16 mM glucose were not affected by any of the antagonists tested. Thus, influx of Ca++ and a consequent rise in its intracellular level are unlikely to be the primary causal event in stimulation of energy synthesis which occurs upon addition of high concentrations of metabolic secretagogues.
为研究钙通道阻滞对分离的大鼠胰岛细胞内能量水平及刺激胰岛素分泌的影响，使用了五种不同的钙通道阻滞剂。硝苯地平、地尔硫䓬、氟桂利嗪和维拉帕米可剂量依赖性地抑制由16 mM葡萄糖、40 mM氯化钾或20 mMα-酮异己酸刺激引起的胰岛素分泌，尽管其效力不同。硝苯地平和氟桂利嗪比地尔硫䓬和维拉帕米更有效。ω-芋螺毒素GVIA（100 nM）对所有测试刺激的胰岛素释放均无显著影响，尽管它对高糖刺激引起的分泌后期有大约20%的抑制作用。用于测量细胞能量水平的L型通道拮抗剂和氟桂利嗪剂量可使总刺激胰岛素释放受到60%至80%的抑制。当存在这些通道阻滞剂时，灌流培养基中含5 mM葡萄糖时的[ATP]/[ADP]比值高于对照组，而ω-芋螺毒素存在时则较低。16 mM葡萄糖引起的核苷酸比值升高不受任何测试拮抗剂的影响。因此，Ca++内流及其细胞内水平的随之升高不太可能是添加高浓度代谢性促分泌剂时发生的能量合成刺激的主要因果事件。
