Role of Nitric Oxide and Mitochondria in Muscle Paralysis Induced by Acute Organophosphate Poisoning

Raghupathy, V (2012) Role of Nitric Oxide and Mitochondria in Muscle Paralysis Induced by Acute Organophosphate Poisoning. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.

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Acute severe MCP poisoning rapidly induced muscle weakness that progressed to paralysis in rats. The animals recovered from paralysis and regained complete muscle power within 24 hours of MCP poisoning with no treatment. Strong inhibition of muscle AChE (67%) was the primary toxicity responsible for induction of muscle weakness and recovery of enzyme activity to 45% was important for regaining of muscle power. However, regaining of muscle power in spite of incomplete recovery of AChE activity suggests the existence of other mechanisms which prevent prolonged muscle weakness and enable recovery of muscle strength in rats. The premise of this thesis was that intense muscle activity that occurs rapidly on OPP poisoning depletes muscle ATP to levels inadequate for contraction. The finding that ATP synthase was inhibited soon after the development of muscle weakness and paralysis and the fact that recovery of muscle strength was associated with re-activation of ATP synthase supports this. A similar decline and increase of muscle lactate in concert with muscle weakness and recovery of muscle strength also suggested inadequate energy levels contributed to muscle weakness of OPP poisoning. It appeares that events in the early phase of poisoning and during paralysis led to inhibition of oxidative phosphorylation and substrate level phosphorylation and subsequent reduction of ATP available for muscle function. Reversal of this inhibition allowed sufficient energy production and recovery of muscle strength. This is important in prevention of prolonged muscle weakness (Figure 5.1). The energy charge of the muscle, an index of metabolic energy available to the cell, showed that early muscle activity in poisoning depleted energy. This was in keeping 88 with the hypothesis of this thesis. The ability of the poisoned rat muscle to re-synthesize adenine nucleotides and normalize energy charge restored muscle function. We consider that if the energy charge was not restored muscle weakness would continue in the rat. We suggest that prolonged muscle weakness that characterizes OPP poisoning in humans may be a consequence of bioenergetic failure in the muscle. In addition, rapid metabolic clearance of the active form of an OPP pesticide from the muscle is also important in preventing prolonged muscle weakness following severe poisoning as evident in the rat. A slower clearance rate of OPP in humans could also contribute to prolonged muscle weakness. MCP poisoning led to NO induction in the muscle due to the up-regulation of nNOS, which contributed to inhibition of ATP synthase and decreased ATP levels. Pre-treatment with L-NAME significantly protected against sulphydryl group modification at the 36 kDa subunit of ATP synthase and prevented inhibition of ATP synthase activity induced by MCP poisoning, suggesting a role of NO in the process. We conclude that efficient protection of muscle ATP synthase activity would help maintain the energy charge of the muscle and reduce muscle weakness that occurs in OPP poisoning.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Nitric Oxide, Mitochondria, Muscle Paralysis, Acute Organophosphate Poisoning.
Subjects: MEDICAL > Gastroenterology
Depositing User: Subramani R
Date Deposited: 18 Jan 2022 15:03
Last Modified: 18 Jan 2022 15:03

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