ELECTROMYOGRAPHIC ASSESSMENT OF THE NEUROMUSCULAR BLOCKADE PRODUCED INVIVO BY ANATOXIN-A IN THE RAT

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-mu-g/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-mu-g/kg). Rats administered 200-mu-g/kg or less of (+)anatoxin-a hydrochloride had 75% return of the pretoxin amplitude of the ECAP within 93 min. Animals dosed at 800-mu-g/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-mu-g/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-mu-g/kg. LD50 values (95% confidence limits) for anatoxin-a administered i.v. to mice were 386-mu-g/kg (365-408-mu-g/kg, for (+)anatoxin-a hydrochloride and 913-mu-g/kg (846-985-mu-g/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.