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 organophosphate pesticide poisoning is common in India. Organophosphates inhibit acetylcholinesterase resulting in cholinergic hyper-stimulation of the muscle and significant muscle weakness. Prolonged muscle weakness that is poorly defined with respect to its pathogenesis is a major cause of morbidity and mortality of the poisoning. Although acetylcholinesterase inhibition is the primary event that leads to prolonged muscle weakness of organophosphate poisoning, the absence of accompanying acetylcholine induced muscarinic signs suggests the involvement of additional non-cholinergic pathological reactions. This study explores non-cholinergic pathomechanisms that may contribute to organophosphate induced muscle weakness. The muscle is a high energy requiring organ and low ATP levels slow contraction and weaken the muscle. Organophosphate poisoning is characterized by intense muscle activity that follows severe inhibition of acetylcholinesterase. This may lead to ATP depletion in the muscle if utilization is faster than generation. Organophosphate poisoning leads to nitric oxide elevation which is associated with organophosphate induced myopathy. This is by nitric oxide induced mitochondrial dysfunction and decreased ATP production. We suggest that organophosphate induced nitric oxide inhibits mitochondrial ATP synthase and prevents sufficient ATP synthesis for muscle activity that occurs on poisoning. Inadequate muscle ATP levels, in addition to acetylcholinesterase inhibition, contribute to muscle weakness following organophosphate pesticide poisoning. The aim of this study was to examine ATP generation and nitric oxide modulation of mitochondrial function in contributing to muscle paralysis induced by acute severe organophosphate pesticide poisoning. Acute monocrotophos poisoning rapidly induced muscle weakness that progressed to paralysis followed by complete regaining of muscle power in rats. Strong inhibition of muscle acetylcholinesterase was the primary toxicity responsible for induction of muscle weakness, and recovery of enzyme activity was important for regaining muscle power, which was enabled by a rapid metabolic clearance of monocrotophos from the muscle. Muscle weakness was also due to nitric oxide induced inhibition of ATP synthesis and inadequate energy. Reversal of this inhibition increased energy generation which may be important in preventing prolonged muscle weakness associated with severe organophosphate poisoning in humans.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Nitric Oxide, Mitochondria, Muscle Paralysis, Acute Organophosphate Poisoning.
Subjects: Respiratory Medicine > Gastroenterology
> Respiratory Medicine > Gastroenterology
Depositing User: Subramani R
Date Deposited: 18 Jun 2017 07:00
Last Modified: 24 Oct 2022 15:24

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