REVERSING THE EFFECTS OF ORGANOPHOSPHORUS PESTICIDES

扭转有机磷农药的影响

• 批准号: 3252349
• 负责人: RON J BRADLEY
• 金额: $ 14.07万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1991-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3252349
• 关键词: acetylcholine; action potentials; chlorohydrocarbon insecticide; drug adverse effect; electrophysiology; insecticide biological effect; laboratory rat; muscle contraction; neuromuscular junction; neuromuscular transmission; neurophysiology; neurotoxins; nontherapeutic iontophoresis; organophosphorus insecticide; pesticide interaction; phosphorylation; synapses

Acetylcholinesterase inhibitors used as insecticides, nematocides, acaricides, fungicides, etc., present a considerable environmental hazard to the health of agricultural workers and others. It is therefore necessary to fully understand the mode of action of these substances in blocking synaptic transmission so that effective treatments can be devised for those who are accidently poisoned. In our proposed studies the mode of action of representative anti-AChE pesticides from the organophosphate and carbamate families will be studied at the mammalian neuromuscular junction. Preliminary studies have shown that block of neuromuscular transmission by AChE inhibitors can be due to a depolarization of the postsynaptic membrane which occurs only while the nerve is being stimulated. The muscle responds normally to the first nerve stimulation in a train but subsequent stimulation has little or no effect. After the stimulation train is ended, the muscle rapidly returns to normal. Our hypothesis is that after block of AChE, the endplate potential is so large and so long that there is a build up of depolarization and a frequency dependent block of transmission. After the nerve activity ceases, the membrane quickly returns to normal due to normal due to the rapid diffusion of excess ACh from the endplate. In preliminary studies we have found that transmission may be restored after this transmission block, by using pharmacological procedures which reduce the amplitude and time constant of the endplate potential. These procedures include the reduction of calcium levels which in turn reduces the presynaptic release of ACh. Alternatively, the postsynaptic blockade of receptors by certain drug molecules also reverses the neuromuscular block induced by AChE inhibitors. We propose a detailed analysis of these therapeutic procedures and investigations which will provide useful information on their exact modes of action. The studies will measure both presynaptic and postsynaptic events and will also use a special apparatus where muscle contraction and compound action potential can be measured simultaneously.

乙酰胆碱酯酶抑制剂用作杀虫剂，杀线虫剂， 杀螨剂、杀真菌剂等，呈现出相当大的环境 危害农业工人和其他人的健康。 是 因此，有必要充分了解的行动模式， 这些物质阻止突触传递， 可以为那些意外死亡的人设计有效的治疗方法， 下毒了 在我们提出的研究中， 代表性的抗乙酰胆碱酯酶农药， 和氨基甲酸酯家族将在哺乳动物研究所进行研究。 神经肌肉接头 初步研究表明， 乙酰胆碱酯酶抑制剂阻断神经肌肉传递， 由于突触后膜的去极化， 只有当神经受到刺激时才会发生。 肌肉 对火车上的第一个神经刺激反应正常， 随后的刺激作用很小或没有作用。 后 刺激训练结束后，肌肉迅速恢复正常。 我们的假设是，阻断AChE后，终板电位 是如此之大和如此之长， 和频率相关的传输块。 神经后 活动停止，膜迅速恢复正常，由于 正常的，由于过量的乙酰胆碱从 终板 在初步研究中，我们发现， 可以在此传输块之后通过使用 降低振幅和时间的药理学方法 终板电位常数。 这些程序包括 降低钙水平，这反过来又降低了突触前 释放ACh。 或者，突触后阻滞 某些药物分子的受体也逆转了 AChE抑制剂诱导的神经肌肉阻滞。 我们提出了一个 这些治疗程序的详细分析， 调查将提供有用的信息， 行动方式。 这些研究将测量突触前和 突触后事件，也将使用一种特殊的装置， 肌肉收缩和复合动作电位可以 同时测量。