Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937 Munich, Germany.
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937 Munich, Germany.
Toxicol Lett. 2019 Jun 15;308:1-6. doi: 10.1016/j.toxlet.2019.03.003. Epub 2019 Mar 8.
The global use of organophosphorus compounds (OP) for pest control and nerve agents being used in military conflicts and for assassinations renders intoxications by these agents a public health concern. OP-poisoned patients often suffer from dysrhythmias which may ultimately result in death. In this study, human-induced pluripotent stem cells derived cardiomyocytes were exposed to OP compounds in a microelectrode array system (MEA). The MEA system is widely accepted to assess the proarrhythmic properties of (candidate) drugs. The directly acting cholinergic compounds acetylcholine and carbachol and the irreversible acetylcholinesterase inhibitor cyclosarin - a highly toxic nerve agent - were assessed. All three compounds induced a dose-dependent (up to 600 nmol/L) corrected field potential duration (FPDc) prolongation of 9.7 ± 0.6% for carbachol, for 9.7 ± 1.2% acetylcholine and 9.4 ± 0.5% for cyclosarin. Additionally, the electrophysiological alterations of the clinically approved oxime reactivators obidoxime, pralidoxime and the oximes in development HI-6 and MMB-4 were investigated in the absence of OP. Neither of these oximes (up to a concentration of 300 μmol/L) caused dysrhythmia nor beat arrest. The competitive muscarinic receptor antagonist atropine as a cornerstone in the treatment of OP poisoning was also analyzed. Interestingly, atropine caused a drop in the beat rate which might result from a non-receptor action of this substance in the absence of OP. Atropine in combination with the OP nerve agent cyclosarin and the direct cholinergics acetylcholine or carabachol completely reversed the induced FPDc prolongation. However, the oxime HI-6 as potent reactivator of cyclosarin-inhibited AChE was not able to prevent the FPDc prolongation in this model. In conclusion, the current model allows the assessment of FPDc prolongation by the nerve agent cyclosarin, the cholinergic compounds carbachol, acetylcholine and the block of this effect by atropine.
全球范围内使用有机磷化合物（OP）来控制害虫，并且在军事冲突和暗杀中使用神经毒剂，这使得这些药剂中毒成为公共卫生关注的问题。OP 中毒的患者经常出现心律失常，最终可能导致死亡。在这项研究中，人类诱导多能干细胞衍生的心肌细胞在微电极阵列系统（MEA）中暴露于 OP 化合物。MEA 系统被广泛接受用于评估（候选）药物的致心律失常特性。直接作用的胆碱能化合物乙酰胆碱和卡巴胆碱以及不可逆的乙酰胆碱酯酶抑制剂梭曼-一种高度有毒的神经毒剂-被评估。这三种化合物都诱导了剂量依赖性（高达 600 nmol/L）的校正场电位持续时间（FPDc）延长，其中卡巴胆碱延长 9.7±0.6%，乙酰胆碱延长 9.7±1.2%，梭曼延长 9.4±0.5%。此外，还在没有 OP 的情况下研究了临床上批准的肟重激活剂氧肟酸、氯解磷定以及在开发中的肟 HI-6 和 MMB-4 的电生理变化。这些肟类化合物（高达 300 μmol/L）都没有引起心律失常或心跳停止。作为 OP 中毒治疗基石的竞争性毒蕈碱受体拮抗剂阿托品也进行了分析。有趣的是，阿托品引起心跳率下降，这可能是由于这种物质在没有 OP 的情况下的非受体作用。阿托品与 OP 神经毒剂梭曼以及直接的胆碱能化合物乙酰胆碱或卡巴胆碱联合使用，完全逆转了诱导的 FPDc 延长。然而，作为梭曼抑制的 AChE 有效重激活剂的肟 HI-6 不能在该模型中防止 FPDc 延长。总之，该模型允许评估神经毒剂梭曼、胆碱能化合物卡巴胆碱、乙酰胆碱引起的 FPDc 延长以及阿托品对这种效应的阻断作用。
