Potential neuromuscular toxicity of N'-(2,4-xylyl)-N-methyl formamidine HCl in rodents.
The mammalian neuromuscular toxicity of N'-(2,4-xylyl)-N-methyl formamidine hydrochloride (U-40481A) was evaluated by programmed screening. The LD50 for mice, determined 48 h after single, subcutaneous (s.c.) injections, was 107 mg/kg body wt. Acute toxicity signs included abnormal gait, hindlimb hyperextension, transient hyperactivity followed by a protracted phase of hypoactivity, ataxia, progressive respiratory difficulty, cyanosis, loss of righting reflex, and death. Relatively low doses of U-40481A (1, 5, 10, and 20 mg/kg, s.c.) markedly impaired the ability of trained mice to ride a rotating rod (rotarod). U-40481 (the base, 1-8 X 10(-4) M) reduced isometric contractions of the isolated rat hemidiaphragm obtained by supramaximal electrical stimulation of either the phrenic nerve or the diaphragm itself in a dose-dependent manner. The neurological deficit and motor incoordination signs observed during acute toxicity testing and in the rotarod study are, at least partly, due to the ability of U-40481A to (i) interfere with neuromuscular transmission, and (ii) decrease skeletal muscle contractility by a direct action on the muscle itself. These 2 effects may also be involved in U-40481A-induced mortality in mice.
D000578:Amidines / Q000633:toxicity*; D000818:Animals; D005260:Female; D066298:In Vitro Techniques; D007306:Insecticides / Q000633:toxicity*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009048:Motor Skills / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D000578:Amidines; D007306:Insecticides; C025699:U 40481