Effects of 4-aminopyridine and 3,4-diaminopyridine on transmitter release at the neuromuscular junction.
The presynaptic effects of 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) were investigated at the rat diaphragm neuromuscular junction using intracellular recording techniques. 4-AP caused only minor increases in miniature end-plate potential frequency at junctions depolarized with elevated potassium levels. Calcium ions antagonize this excitatory effect. 4-AP (20-200 microM) enhanced evoked transmitter release and the amplitude of the end-plate potentials (EPPs), but this effect was considerably less than predicted from earlier reports. 4-AP (100 microM) enhanced quantal content of the first EPP by only 97% and 3,4-DAP by 95%. 4-AP and 3,4-DAP also enhanced transmitter release during maintained stimulation at 50 Hz. The APs did not exhaust the output capabilities of the nerve terminal. 4-AP and 3,4-DAP blocked facilitation. This is attributed to the observation that 4-AP and 3,4-DAP increases the statistical probability of release to its maximum level (1.0). Increased transmitter release by 4-AP and 3,4-DAP is attributed primarily to their ability to increase the releasable store of transmitter and mobilization activity. It was observed that 4-AP and 3,4-DAP enhances the duration of the EPP. This observation supports the suggestion that 4-AP prolongs the time course of the presynaptic spike. The effects of 4-AP and 3,4-DAP on quantal release are compatible with the hypothesis that these drugs enhance calcium entry indirectly by blocking voltage sensitive potassium channels.
D015761:4-Aminopyridine; D000077770:Amifampridine; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005071:Evoked Potentials; D005260:Female; D007473:Ion Channels / Q000187:drug effects; D008839:Microelectrodes; D009045:Motor Endplate / Q000187:drug effects; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013268:Stimulation, Chemical; D009435:Synaptic Transmission / Q000187:drug effects
D000631:Aminopyridines; D007473:Ion Channels; D009467:Neuromuscular Depolarizing Agents; D018377:Neurotransmitter Agents; D015761:4-Aminopyridine; D000077770:Amifampridine; D011188:Potassium; D002118:Calcium