Potency of 3,4-Diaminopyridine and 4-aminopyridine on mammalian neuromuscular transmission and the effect of pH changes

Abstract

3,4-Diaminopyridine (3,4-DAP) like 4-aminopyridine (4-AP) greatly increased stimulus-evoked transmitter release, recorded as end-plate potentials, in single fibers of the isolated mouse nerve-hemidiaphragm preparation. 3,4-DAP was 6–7 times more potent in this respect than 4-AP. 3,4-DAP was able to restore, from complete paralysis, neuromuscular transmission in isolated botulinum toxin (type A)-poisoned rat muscles and in this respect also was 6–7 times more potent than 4-AP. Changing the pH of the external solution from 7.4 to 9.0 had no significant effect on nerve-evoked transmitter release. However, both 4-AP and 3,4-DAP, which have pK a values of about 9, were about 3 times more potent in increasing transmitter release at pH 9.0 than at pH 7.4. This was interpreted to mean that the two molecules are more effective in their unionized form and therefore possibly exert their effect on transmitter release at an intracellular site in the nerve terminal. The slope values for the calcium dependence of nerve-evoked transmitter release were similar at pH 7.4 and 9.0 and were not altered by 3,4-DAP or 4-AP. Like 4-AP, 3,4-DAP converted the end-plate potential produced by electronic depolarization of tetrodotoxin-blocked frog nerve terminals into an all-or-none response, implying that the drugs enhance transmitter release by greatly increasing the voltage-dependent calcium conductance of the nerve terminal membrane.