Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure
Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure
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DOI：
10.1080/15563650.2021.1916519
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发表时间：
2021-05-13
影响因子：
3.3
通讯作者：
Ribchester, Richard R.
中科院分区：
文献类型：
--
作者：
Dissanayake, Kosala N.;Chou, Robert Chang-Chih;Ribchester, Richard R.
背景：摄入农业有机磷杀虫剂是亚洲农村死亡的一个重要原因。患者通常表现为急性呼吸衰竭和/或延迟的、不明原因的神经肌肉麻痹症状，有时被诊断为“中间综合征”。我们检验了一种假设，即一种农业配方的循环代谢物——乐果和环己醇，会导致肌肉无力和瘫痪。方法采用电鳗电斑或肌肉匀浆纯化酶，测定杀虫剂成分及代谢物乙酰胆碱酯酶活性。麻醉猪盆腔肢体对神经刺激反应的机械肌学记录和小鼠离体神经肌肉制剂的等长力记录。氧乐果和环己醇经静脉注射或加入生理盐水沐浴离体肌肉。我们还评估了MgSO4和冷却对神经肌肉功能的影响。结果乐果能引起猪肌肉强韧褪色，小鼠肌肉运动神经长时间收缩。通过体内静脉注射MgSO4或在培养液中加入5 mM Mg2+，这两种效应都得到了缓解。氧乐果和环己醇的组合最初增强了肌肉收缩，但随后迅速阻断了它们。环己醇单独引起猪和分离制剂中肌肉收缩减退和阻滞。环己酮和二甲苯在体外也有类似的效果。环己醇诱导的神经肌肉阻滞是温度敏感且快速可逆的。结论有机磷和溶剂代谢物在摄入有机磷农药制剂后肌肉无力中起关键作用。代谢产物氧乐果和环己醇共同影响神经肌肉功能，但分别通过提高细胞外Mg2+和降低核心温度来减轻其影响。需要进行MgSO4治疗和靶向温度管理对杀虫剂中毒患者的临床研究，以确定它们是否可能是治疗的有效辅助手段。
Background Ingestion of agricultural organophosphorus insecticides is a significant cause of death in rural Asia. Patients often show acute respiratory failure and/or delayed, unexplained signs of neuromuscular paralysis, sometimes diagnosed as "Intermediate Syndrome". We tested the hypothesis that omethoate and cyclohexanol, circulating metabolites of one agricultural formulation, cause muscle weakness and paralysis. Methods Acetylcholinesterase activity of insecticide components and metabolites was measured using purified enzyme from eel electroplaque or muscle homogenates. Mechanomyographic recording of pelvic limb responses to nerve stimulation was made in anaesthetized pigs and isometric force was recorded from isolated nerve-muscle preparations from mice. Omethoate and cyclohexanol were administered intravenously or added to physiological saline bathing isolated muscle. We also assessed the effect of MgSO4 and cooling on neuromuscular function. Results Omethoate caused tetanic fade in pig muscles and long-lasting contractions of the motor innervation zone in mouse muscle. Both effects were mitigated, either by i.v. administration of MgSO4 in vivo or by adding 5 mM Mg2+ to the medium bathing isolated preparations. Combination of omethoate and cyclohexanol initially potentiated muscle contractions but then rapidly blocked them. Cyclohexanol alone caused fade and block of muscle contractions in pigs and in isolated preparations. Similar effects were observed ex vivo with cyclohexanone and xylene. Cyclohexanol-induced neuromuscular block was temperature-sensitive and rapidly reversible. Conclusions The data indicate a crucial role for organophosphorus and solvent metabolites in muscle weakness following ingestion of agricultural OP insecticide formulations. The metabolites omethoate and cyclohexanol acted conjointly to impair neuromuscular function but their effects were mitigated by elevating extracellular Mg2+ and decreasing core temperature, respectively. Clinical studies of MgSO4 therapy and targeted temperature management in insecticide-poisoned patients are required to determine whether they may be effective adjuncts to treatment.