Previous diaphragm studies found that during intermittent stimulation, intratrain end-plate potential (EPP) amplitude rundown is accelerated by increasing stimulation frequency, whereas intertrain EPP rundown is independent of frequency. We hypothesized that increasing stimulation frequency accelerates rundown recovery, and with a biphasic time course. Intracellular recordings were made in vitro from rat phrenic nerve-hemidiaphragm preparations. EPP amplitude recovery after a 100-ms stimulation train and 100 ms of quiescence was significantly greater following stimulation at 200 HZ than at 20-100 HZ, despite larger antecedent EPP decline. EPP amplitudes recovered with a biphasic pattern: an early component with a fast time-constant (0.03-0.06 s) and a late component with a slow time-constant (0.5-5 s). Increased antecedent stimulation frequency accelerated the early component, but stimulation duration or pulse number modulated the late component. When interpreted in the context of vesicle recycling and replenishment models involving multiple pools and pathways, these data suggest that antecedent stimulation frequency regulates predominantly the fast pathways. This may have important implications for the development of respiratory failure in diseases of the neuromuscular junction, such as myasthenia gravis, when the firing duration and frequency are altered in association with changes in breathing pattern.
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