Facilitatory effects of 4-aminopyridine on normal neuromuscular transmission

The effects of 4-aminopyridine (4-AP) on neuromuscular transmission were studied in vitro in the rat flexor digitorum longus muscles. 4-AP produced dose-dependent increases in endplate potential (EPP) amplitude, in rise time to peak, and in the average number of acetylcholine quanta released by presynaptic nerve impulses. The neuromuscular blocking effects of d-tubocurarine or low Ca2+/high Mg2+ concentrations could be completely reversed by 4-AP, and EPPs developed into muscle action potentials (APs). The drug had minimal effects on the amplitude or frequency of spontaneous miniature endplate potentials, but increased the duration of indirectly elicited muscle APs. The action of 4-AP required the presence of extracellular Ca2+; thus, its effect may be to promote Ca2+ entry into the motor nerve terminal, and thereby increase the neurally evoked transmitter release. 4-AP is effective in overcoming both presynaptic and postsynaptic blockade of neuromuscular transmission, suggesting a potential role for this drug in the treatment of neuromuscular diseases.