Acute organophosphorus
anticholinesterase poisoning induces a necrotizing end-plate
myopathy in rats and patients.
Acetylcholine (ACh) excess leads to prolonged synaptic currents and increased influx of
cations including
calcium through the postsynaptic
ACh receptor channels with prolonged muscle membrane depolarization, excess
calcium influx into the sarcoplasm, and ultimately muscle fiber
necrosis.
Quinoline derivatives such as
quinidine induce or worsen pre- and postsynaptic disorders of neuromuscular transmission in humans, and are beneficial in patients suffering from a rare
congenital myasthenic syndrome called the
slow channel congenital myasthenic syndrome. These drugs correct the prolonged opening times of the mutated
acetylcholine receptor channels in this myasthenic syndrome. We treated
paraoxon-poisoned rats with 4 x 10 or 4
x 50 mg/kg of
quinidine and assessed the severity of the necrotizing
myopathy in gastrocnemius and diaphragm muscle biopsies.
Fasciculations were decreased and the necrotizing
myopathy was prevented in most treated rats, with absence of necrotic muscle fibers in most animals in the high-dose group. Survival was not different from untreated poisoned animals. A number of physiological mechanisms, including blocking of presynaptic voltage-gated
sodium or
calcium channels or inhibition of the postsynaptic
ACh receptors channels may have contributed to the attenuation of the myonecrosis. The optimal dose and the
drug of choice amongst the clinically available
quinoline derivatives remains to be determined.