Potential neuromuscular toxicity of N′-(2,4-xylyl)- N-methyl formamidine HCl in rodents

Abstract

The mammalian neuromuscular toxicity of N′-(2,4-xylyl)- N-methyl formamidine hydrochloride (U-40481A) was evaluated by programmed screening. The LD 50 for mice, determined 48 h after singe, 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 × 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-40481-A-induced mortality in mice.