[Presynaptic effects of aminopyridines on the neuromuscular junction of vertebrates].

In this review the effects of aminopyridines and chemically related compounds are documented in an attempt to analyse the mechanism underlying their presynaptic actions at the vertebrate neuromuscular junction. Aminopyridines and related compounds are of particular interest because they greatly increase the amount of acetylcholine released in response to both conducted nerve impulses and electrotonic depolarizations of tetrodotoxin blocked motor nerve terminals. The apparent rank order of potency for increasing quantal transmitter release evoked by nerve impulse at physiological pH was as follows: 3,4-diaminopyridine greater than 4-aminopyridine greater than 4-aminoquinoline greater than 3-aminopyridine greater than 2,6-diaminopyridine greater than 2-aminopyridine greater than 4-nitropyridine greater than 4-aminopyridine N-oxyde greater than 4-hydroxypyridine greater than 2,4-dihydroxypyridine. The fact that both pyridine and aniline were found to be inactive indicate that both a pyridine ring and an amino-substituent are necessary for activity. A common site of action for the drugs here reported should be rationalized on the basis that their protonated molecular forms generate a common electrostatic potential field pattern. This results together with those concerning the dependence of pyridine activity on extracellular pH leads to the conclusion that this family of compounds exert its activity at the internal face of the motor nerve terminal membrane. Aminopyridines in concentrations that increase transmitter release evoked by nerve impulses block potassium conductance in motor nerve terminals and lengthen the presynaptic action potential, this effect leads to an enhanced calcium influx and consequently to an increase in acetylcholine release. The fact that aminopyridines had no consistent effect on transmitter release at junctions depolarized by elevated potassium ions strongly supports the view that these drugs have no direct effect on voltage-dependent calcium channels and that their primary site of action is on voltage-sensitive potassium channels of motor nerve terminals.