High dose refractoriness to the neuromuscular toxicity of dithiobiuret in rats

Increasing the daily dose of dithiobiuret (DTB) given to rats from 0.5 to 1 to 5 mg/kg shortened the latency to onset of treadmill failure and associated flaccid muscle tone from 7 to 5 to 3 days, respectively. Death generally did not follow treadmill failure for at least 2-3 days. After 3 consecutive days of treatment with 5 mg/kg, gastrocnemius muscle contractions elicited by high frequency trains of nerve stimulation were lower in peak tension and more susceptible to tetanic fade (rapid tension decline in tetanus) than were contractions from control rats. Conversely, rats given 12 mg/kg of DTB for 3 days did not exhibit treadmill failure, flaccid skeletal muscle tone, or tetanic contractile abnormalities. Additional treatment with this dose for 2-3 days was required to produce treadmill failure which was not accompanied by flaccid muscle tone. Refractoriness to development of toxicity with DTB was limited in its spectrum; decreased feed and water intake, weight loss, diuresis, dehydration, chromodacryorrhea, and production of mucoid feces occurred even in the absence of flaccid muscle tone. Tissue distribution of DTB-derived [14C] determined 3 hr after injection of [14C]-DTB (12 mg/kg) was largely unaffected by prior treatment with unlabeled DTB (12 mg/kg/day x 2 days). Conventional microelectrode recording studies using end-plates of extensor digitorum longus muscles indicated that abnormalities occurred in quantal release of acetylcholine (ACh) after 5mg/kg/day but not 12 mg/kg/day of DTB. Specifically, reduced quantal content, increased amplitude and prolonged decay of miniature end-plate potentials were observed. The mechanism by which large daily doses overcome or prevent the expected development of flaccid muscle tone and depressed release of ACh typically associated with treatment with DTB does not involve compensatory increases in quantal release of ACh, or altered distribution of the compound.