Quinidine prevents paraoxon-induced necrotizing myopathy in rats.
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.
De Bleecker
J L
JL
Neurology Department, University Hospital, Gent, Belgium.
Meire
V I
VI
Pappens
S
S
D000818:Animals; D001706:Biopsy; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D007306:Insecticides / Q000037:antagonists & inhibitors / Q000506:poisoning*; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009336:Necrosis; D010261:Paraoxon / Q000037:antagonists & inhibitors / Q000506:poisoning*; D011802:Quinidine / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D011802:Quinidine; D010261:Paraoxon