The Role of Pre- And Post-Junctional Cholinoceptors in the Action of Neostigmine at the Neuromuscular Junction

Abstract

S U M M A R Y 1. The actions have been compared of the acetylcholine antagonists, hexamethonium, tuborcurarine, pancuronium and gallamine on the effects of neostigmine at the neuromuscular junction of the soleus muscle in cats under chloralose anaesthesia.2. Neostigmine produced augmentation of twitch tension, muscle fasciculat ions, repetitive firing in the muscle and antidromic repetitive firing in the ventral roots: all these effects were blocked by the acetylcholine antagonists. The effective doses of hexamethonium were similar to its ganglion blocking doses, being much smaller than those necessary to block the normal soleus twitch, and it is concluded i.hat the effects of neostigmine arise mainly from the action of preserved transmitter (acetylcholine) on the motor nerve endings.3. In the smallest effective doses, hexamethonium preferentially blocked muscle fasciculations and the associated electrical activity in nerve. Tubocurarine, which has considerable ganglion blocking activity (reflecting its affinity for neuronal cholinoceptors) resembled hexamethonium. In contrast, pancuronium and gallamine, which are considered to have a higher affinity for post-junctional muscle cholinoceptors, depressed muscle fasciculations only in doses that also depressed twitch augmentation and repetitive firing in muscle.4. In slightly larger doses, pancuronium and gallamine also blocked antidromic repetitive firing in nerve indicating that these drugs also combine with prejunctional neuronal cholinoceptors, and suggesting that these cholinoceptors are intermediate in character between ganglionic and muscle cholinoceptors.

The relationship between stimulus‐induced antidromic firing and twitch potentiation produced by paraoxon in rat phrenic nerve‐diaphragm preparations

“…A number of authors (Barstad & Lilleheil, 1968;Webb & Bowman, 1974;Bowman, 1980a,b) have suggested that although ADF and twitch potentiation may both arise as a result of the prolonged action of ACh in the synaptic cleft, the two events are independent and not causally related. ADF would be expected to initiate repetitive endplate potentials and it is difficult to see why these would not trigger additional muscle APs under the appropriate conditions.…”

Effects of pancuronium and hexamethonium on paraoxon‐induced twitch potentiation and antidromic firing in rat phrenic nerve diaphragm preparations

“…Under these conditions the lowest concentrations of pancuronium and hexamethonium used restored twitch potentiation to the level present at the time of removal of paraoxon from the organ bath but reduced ADF. It is thus possible that a fortuitous choice of doses and timing of their administration might also account at least in part for the observations of Webb & Bowman (1974). We have also shown previously (Clark, Hobbiger & Terrar, 1979, 1983 that, under certain conditions, twitch potentiation can be sustained in the absence of ADF.…”

“…The reason why Webb & Bowman (1974) were able to abolish ADF without affecting twitch potentiation in neostigmine-treated cat muscles is not clear. It could arise from species differences between neuromuscular junctions and/or experimental conditions.…”

“…Binding studies in rats (Lentz, Mazurkiewicz & Rosenthal, 1977) and mice (Daniels & Vogel, 1975) have provided direct evidence for the existence of prejunctional nicotinic cholinoceptors at motor endplates. Webb & Bowman (1974) suggested that the prejunctional cholinoceptors were of the ganglionic nicotinic type since in cat hind limb muscles exposed to neostigmine, hexamethonium, a selective antagonist of ACh in autonomic ganglia, could suppress ADF without affecting twitch potentiation or the normal twitch response. They also observed that pancuronium, a selective antagonist of ACh at nicotinic cholinoceptors at motor endplates, showed no such effects.…”

“…It was subsequently proposed (Blaber & Karczmar, 1967;Webb & Bowman, 1974;Bowman, 1980a, b) that this action of ACh was mediated by cholinoceptors located either at the nerve terminal or at the first node of Ranvier. Binding studies in rats (Lentz, Mazurkiewicz & Rosenthal, 1977) and mice (Daniels & Vogel, 1975) have provided direct evidence for the existence of prejunctional nicotinic cholinoceptors at motor endplates.…”