Doebler J A
Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA.
Neurochem Res. 2000 Jul;25(7):941-8. doi: 10.1023/a:1007548307554.
The NG 108-15 (neuroblastoma X glioma hybrid) cell line was used as an in vitro neuronal model to evaluate potential antagonists of the Na+-selective carboxylic ionophore monensin. Changes in membrane electrical characteristics induced by monensin with and without the simultaneous administration of antagonists were measured using intracellular microelectrode techniques. Bath application of monensin (3 microM) produced a hyperpolarization of approximately = 35 mV. Monensin also altered the generation of action potentials in response to electrical stimulation in 14 of 24 (58%) exposed cells, as evident in a partial or complete loss of action potentials or in an alteration of action potential waveform. The antagonists used were Na+-K+ pump inhibitor ouabain (1-3 microM), the Ca2+dependent K+ channel blocker quinine (3-30 microM) or drugs known to influence Ca2+ signaling in cells, i.e., trifluoperazine (3-10 microM), verapamil (1-10 microM) or chlorpromazine (3-30 microM). On a molar basis, ouabain was the most and trifluoperazine the least effective of the antagonists. Quinine, verapamil and chlorpromazine all prevented the development of the hyperpolarization in an approximate concentration-dependent manner. However, none of these drugs was able to block the effects of monensin on action potentials. Indeed, high concentrations of the antagonists that were most effective in preventing the hyperpolarization accentuated impairments in action potential generation and also reduced input resistance in many cells. Thus, none of these antagonists appears suitable for transition to in vivo antidotal protection studies.
NG 108-15（神经母细胞瘤X胶质瘤杂交瘤）细胞系被用作体外神经元模型，以评估钠选择性羧酸离子载体莫能菌素的潜在拮抗剂。使用细胞内微电极技术测量在有或没有同时给予拮抗剂的情况下莫能菌素诱导的膜电特性变化。在浴槽中施加莫能菌素（3 microM）产生了约35 mV的超极化。莫能菌素还改变了24个暴露细胞中14个（58%）对电刺激产生的动作电位，表现为动作电位部分或完全丧失或动作电位波形改变。所使用的拮抗剂为钠钾泵抑制剂哇巴因（1-3 microM）、钙依赖性钾通道阻滞剂奎宁（3-30 microM）或已知影响细胞内钙信号传导的药物，即三氟拉嗪（3-10 microM）、维拉帕米（1-10 microM）或氯丙嗪（3-30 microM）。按摩尔计算，哇巴因是最有效的拮抗剂，而三氟拉嗪是最无效的。奎宁、维拉帕米和氯丙嗪都以近似浓度依赖性的方式阻止了超极化的发展。然而，这些药物都不能阻断莫能菌素对动作电位的影响。实际上，在预防超极化方面最有效的高浓度拮抗剂加剧了动作电位产生的损伤，并且还降低了许多细胞的输入电阻。因此，这些拮抗剂似乎都不适合过渡到体内解毒保护研究。
