Thiermann Horst, Eyer Peter, Worek Franz, Szinicz Ladislaus
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937 München, Gemany.
Toxicology. 2005 Oct 30;214(3):190-7. doi: 10.1016/j.tox.2005.06.013. Epub 2005 Jul 22.
Toxicity of organophosphates (OP) is caused by inhibition of acetylcholinesterase (AChE), resulting in accumulation of acetylcholine. While cholinolytics such as atropine are able to counteract muscarinic symptoms, they are unable to restore the impaired neuromuscular transmission (NMT). Here, oximes as potential reactivators of inhibited AChE may be effective. Until now, no unequivocal relation between oxime-induced increase in muscle force and reactivation has been demonstrated. To address this issue the isolated circumfused mouse hemidiaphragm was used as an experimental model. The muscle force generation upon tetanic stimuli was recorded during AChE inhibition by 1 microM paraoxon and after a wash-out period in the presence of obidoxime, pralidoxime and the experimental oximes HI 6, and HLö 7, 10 microM each. At the end of the experiments AChE activity was determined in the diaphragm homogenates by a radiometric assay. At 50-Hz stimulation, recovery was complete with obidoxime, nearly complete with HLö 7 but incomplete with HI 6 and pralidoxime. Only with obidoxime a significant increase in AChE activity was found. An increase of AChE to 10% of normal was sufficient to allow normal muscle force generation. When paraoxon was still present, obidoxime and HLö 7 were effective at 0.1 microM paraoxon, but failed so at paraoxon >1 microM. The data show different effectiveness of the oximes investigated in reactivation of muscle AChE and recovery of NMT after inhibition by paraoxon. Although an increase in muscle force by the oximes was accompanied by a measurable increase in AChE activity only in the case of obidoxime, the plot of muscle force against AChE activity as well as lacking evidence for a direct effect and adaptive processes indicate that reactivation of the enzyme is the main mechanism of NMT recovery. In agreement, in presence of AChE inhibitory concentrations of paraoxon during reactivation a reduced effectiveness of oximes was found.
有机磷酸酯（OP）的毒性是由乙酰胆碱酯酶（AChE）受抑制引起的，导致乙酰胆碱蓄积。虽然诸如阿托品等胆碱能拮抗剂能够对抗毒蕈碱样症状，但它们无法恢复受损的神经肌肉传递（NMT）。在此，肟类作为被抑制的AChE的潜在重活化剂可能有效。到目前为止，尚未证实肟类诱导的肌肉力量增加与重活化之间存在明确关系。为解决这一问题，将离体灌注的小鼠半膈肌用作实验模型。在1微摩尔对氧磷抑制AChE期间以及在存在双复磷、解磷定和实验性肟类HI 6及HLö 7（各10微摩尔）的洗脱期后，记录强直刺激时的肌肉力量产生情况。实验结束时，通过放射性测定法测定膈肌匀浆中的AChE活性。在50赫兹刺激下，双复磷使恢复完全，HLö 7使恢复接近完全，但HI 6和解磷定使恢复不完全。仅双复磷使AChE活性有显著增加。AChE活性增加至正常的10%足以使肌肉力量正常产生。当对氧磷仍存在时，双复磷和HLö 7在0.1微摩尔对氧磷时有效，但在对氧磷浓度>1微摩尔时无效。数据显示，所研究的肟类在对氧磷抑制后对肌肉AChE的重活化及NMT恢复具有不同的有效性。尽管仅在双复磷的情况下肟类使肌肉力量增加伴随着AChE活性的可测量增加，但肌肉力量相对于AChE活性的曲线以及缺乏直接作用和适应性过程的证据表明，酶的重活化是NMT恢复的主要机制。同样，在重活化过程中存在AChE抑制浓度的对氧磷时，发现肟类的有效性降低。
