Electromyographic assessment of the neuromuscular blockade produced in vivo by anatoxin-a in the rat

William M. Valentine, David J. Schaeffer, Val R. Beasley

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Abstract

The indirectly evoked compound action potentials (ECAP) of the plantar muscles of the rat were used to investigate the pharmacodynamics in vivo of the neuromuscular blockade produced by anatoxin-a. Onset time to maximum depression and the magnitude of maximum depression in amplitude of the ECAP were dose-dependent. The mean maximum percent depression (±S.D.) of the ECAP induced by single, supramaximal stimulations of the posterior tibial nerve after i.v. doses of (+)anatoxin-a hydrochloride at 0, 50, 100, 200 and 800 μg/kg were 3 (4), 53 (15), 82 (7), 95 (2), and 100 (1), respectively. The ED50 (95% confidence limits) for depression of the ECAP was 47 mg/kg (39-57 μg/kg). Rats administered 200 μg/kg or less of (+)anatoxin-a hydrochloride had 75% return of the pretoxin amplitude of the ECAP within 93 min. Animals dosed at 800 μg/kg did not have return of neuromuscular function and died despite mechanical ventilation, suggesting a lethal mechanism(s) of action in addition to respiratory paralysis. Percent decrements (±S.D.) in the amplitude of the fourth ECAP following repetitive stimulation at 10 Hz were 6 (5), 13 (22), 46 (18) and 59 (8) from (+)anatoxin-a hydrochloride given i.v. at 0, 50, 100 and 200 μg/kg, respectively. The decrement observed following repetitive stimulation was attributed to a presynaptic site of action. No change in maximal motor nerve conduction velocity or latency of the ECAP was observed after i.v. administration of (+)anatoxin-a hydrochloride at 100 μg/kg. LD50 values (95% confidence limits) for anatoxin-a administered i.v. to mice were 386 μg/kg (365-408 μg/kg, for (+)anatoxin-a hydrochloride and 913 μg/kg (846-985 μg/kg) for racemic anatoxin-a hydrochloride. No deaths were observed in mice after i.p. administration of(-)anatoxin-a hydrochloride at doses up to 73 mg/kg.

Original languageEnglish (US)
Pages (from-to)347-357
Number of pages11
JournalToxicon
Volume29
Issue number3
DOIs
Publication statusPublished - 1991

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All Science Journal Classification (ASJC) codes

  • Toxicology

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