Comparison of the effects of trimethadione and its primary metabolite dimethadione on neuromuscular function and the effects of altered pH on the actions of dimethadione.

The effects of the anticonvulsant trimethadione (TMO) and its primary metabolite dimethadione (DMO) were investigated at the frog neuromuscular junction using intracellular recording techniques. TMO (1, 2 and 5 mM) caused dose-dependent decreases in miniature end-plate potential (MEPP) and end-plate potential (EPP) amplitudes, decreased quantal content only at the highest dose and did not affect MEPP frequency. DMO (2 and 5 mM) at the normal pH of 7.2 significantly decreased quantal content and decreased EPP amplitude at the higher concentration used. Neither MEPP amplitude nor frequency was significantly affected by DMO at pH 7.2. When 2 mM DMO was added at the same time that pH was lowered to 6.6, considerably larger decreases in EPP( amplitude and quantal content were observed. Under these conditions, DMO still did not alter MEPP amplitude but did cause about a doubling in MEPP frequency. The effects of pH 6.6 alone were also examined, but lowered pH did not account for all of the exaggerated effect of DMO in pH 6.6. Presumably, more DMO accumulates intracellularly in low pH conditions because it is a weak acid and sensitive to alterations in pH. In conclusion, both TMO and DMO cause depression of neuromuscular transmission; however, their mechanisms for depression are different, especially when therapeutically relevant concentrations are considered. TMO acts primarily by suppressing postjunctional sensitivity to acetylcholine, whereas DMO primarily decreases transmitter release from the nerve terminal.