Increase in transmitter release from motor nerve terminals induced by some pyridine derivatives.
The effects of 4-nitropyridine (4-NP), 4-aminopyridine-N-oxide (4-AP-N-O), 4-hydroxypyridine (4-HP), 2,6-diaminopyridine (2,6-DAP), 2,4-dihydroxypyridine (2,4-DHP) and pyridine on isolated sciatic nerve-sartorius muscle preparations were studied by means of intracellular and extracellular recording techniques. In junctions treated with (+) tubocurarine, 4-NP, 4-AP-N-O, 4-HP and 2,6-DAP reversibly increased the amplitude and the latency of end-plate potentials (EPPs) and induced repetitive EPPs in response to single nerve impulses. As shown by extracellular focal recordings, the increase in latency of EPPs was due to a prolongation of the minimum synaptic delay, while the appearance of repetitive EPPs was the result of repetitive firing of motor nerve terminals. 4-NP, 4-AP-N-O, 4-HP and 2,6-DAP increased dose-dependently the quantal content of EPPs, while 2,4-DHP and pyridine were found to be inactive. Comparison of the apparent rank order of potency in increasing quantal transmitter release indicates that the relative activity of the different pyridine derivatives studied is unrelated to their pK values. Spontaneous quantal transmitter release in resting junctions was unaffected by 4-NP, 4-AP-N-O, 4-HP and 2,6-DAP when applied at concentrations that enhanced evoked transmitter release. 4-NP differed from the other pyridine derivatives by producing in high concentrations a time-dependent increase in miniature end-plate potential frequency and a depolarization of the muscle fibres. In addition, 4-AP-N-O, 4-HP and 2,6-DAP were found to have no effect on MEPP frequency accelerated by increasing the external K+ concentration. In conclusion the data presented strongly suggest that 4-NP, 4-HP, 4-AP-N-O and 2,6-DAP facilitate evoked transmitter release from motor nerve terminals by a presynaptic action that seems related to an increased calcium influx secondary to the blockade of potassium channels in the nerve terminal.
D000109:Acetylcholine / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D009045:Motor Endplate / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011893:Rana esculenta; D013268:Stimulation, Chemical; D014403:Tubocurarine / Q000494:pharmacology
D003470:Culture Media; D011725:Pyridines; D000109:Acetylcholine; D014403:Tubocurarine