The motor nerve terminal as the primary focus for drug-in-duced facilitation of neuromuscular transmission.

Abstract

The experiments were designed to distinguish mechanisms of pharmacologic potentiation and blockade at the neuromuscular junction. Particularly, interest was focussed on potentiation. For this purpose, phenyltrimethylammonium ion (PTMA), 3-hydroxy phenyltrimethylammonium ion (3-OH PTMA), phenyl triethylammonium ion (PTEA), 3-hydroxy phenyltriethylammonium ion (3-OH PTEA) and 3-methyl phenyltrimethylammonium ion (3-CH3 PTMA) were employed. Potentiation of neuromuscular transmission was ascertained from the action of a substance to enhance the tension developed by the cat gastrocnemius muscle stimulated in situ by single maximal nerve shocks. PTMA was found to blockade neuromuscular transmission readily but not to potentiate response. In contrast 3-OH PTMA exhibited a bimodal action, potentiation predominated in small doses and blockade in large. Like PTMA, 3-CH3 PTMA caused only blockade. On the other hand, 3-OH PTEA produced only potentiation over a wide range of doses without evidence of neuromuscular block. The unsubstituted PTEA ion was inactive. Electrically, potentiation was detected in muscle as a repetitive discharge. Prominent repetitive activity was produced by 3-OH PTMA and 3-OH PTEA. Repetitive effects following PTMA and 3-CH3 PTMA were minimal and fleeting. After PTEA, no alteration of muscle action potential occurred. Depolarizing potency was estimated from the capacity of an ion to increase fibrillary discharge frequency in a single fiber of denervated muscle. PTMA proved approximately five times more potent than 3-OH PTMA. This coincides remarkably with the ratio of their blocking potencies on innervated muscle. In comparison the depolarizing potencies of PTEA and 3-OH PTEA appeared negligible. While stimulating muscle nerve and recording from a ifiament of the severed distal segment of ventral root L7, repetitive discharge of motor nerve occurred after intraarterial injection of either PTMA, 3-OH PTMA or 3-OH PTEA. This discharge most probably originated from the intramuscular terminations since the nature of the preparation restricted the initial distribution of the drug to the muscle. This conclusion was further supported by the fact that the evoked antidromic spike remained unaltered. Like the repetitive discharge in muscle, that in the nerve was most prominent, synchronous and enduring after 3-OH PTEA. Also like muscle, the repetitive response of the nerve to PTMA was fleeting. The effect produced by 3-OH PTMA was intermediate. The anti-curare action of 3-OH PTEA was significant. The dose range for this action of 3-OH PTEA was identical to that which caused potentiation in the uncurarized preparation. Contrariwise the doses of 3-OH PTMA required were greater than those needed to potentiate, yet the anti-curare effectiveness of 3-OH PTMA was greater than that of 3-OH PTEA. Thus, 3-OH PTMA may overcome completely a profound curare paralysis, while a less severe block may be incompletely dissipated by 3-OH PTEA. These findings emphasize the importance of the methonium center as an adjunct in anti-curare action. The potentiation and anti-curare effects are viewed as consequences of a primary action of phenolic quaternary ammonium ions on motor nerve terminals. As a result the motor nerve is caused to fire repetitively and thereby increase transmitter action. PTMA and 3-OH PTEA appear as two contrasting reagents of unusually simple structure. With the one, 3-OH PTEA, specific activation of the motor nerve terminal appears possible; with the other, end plate depolarization predominates.