Anti-curare Action Research Articles

Anti-curare action of stannous ion in the frog neuromuscular junction

For the purpose of elucidating the mechanism of action of stannous ion (Sn 2 +), we investigated effects of stannous chloride (SnCl 2) on the twitch and on the electrical phenomena in the muscle fiber. Sciatic nerve-sartorius muscle preparations from the bullfrog were used as the material. Effect of SnCl 2 was examined on the twitch partially inhibited by pretreatment with d -tubocurarine. SnCl 2 (1–100 μ M) antagonized d -tubocurarine and enhanced the twitch dose-dependently. Tartaric acid, which is the solvent used for SnCl 2 solution, had no augmentative effect on the twitch, even at a concentration as high as 250μ M. SnCl 2 (1–50μ M) increased the amplitude of the endplate potential; that is, it exerted an anti-curare action. The resting potential and the membrane resistance of the muscle fiber were not altered by 30 μ M SnCl 2. These findings lead to the conclusion that Sn 2 + enhances the twitch by increasing the endplate potential of the muscle fibers.

SYNAPTIC FACILITATORY AND DEPRESSANT ACTIONS OF 3,4-DIAMINOPYRIDINE: CORRELATION WITH ANTICURARE PROPERTIES

This study aimed to define the complete concentration-effect relationship for anticurare effects of 3,4-diaminopyridine (3,4-DAP) in the isolated sympathetic ganglion of the bullfrog. Synaptic transmission was monitored by extracellular and intracellular recordings of the postganglionic response to preganglionic stimulation. A previous study showed that in the bullfrog sympathetic ganglion 3,4-DAP caused stimulus-bound repetitive postganglionic responses (SBR) to each single preganglionic stimulus. The concentration-effect relationship for 3,4-DAP-induced SBR was bell-shaped, and the descending limb of the curve reflected progressive suppression of SBR while normal synaptic transmission was maintained. In the present study a detailed concentration-effect analysis of 3,4-DAP’s anticurare action also resulted in a bell-shaped curve nearly congruent with that for SBR. SBR and anticurare effects of 3,4-DAP therefore occupy a common concentration-effect domain, and this suggests that a common mechanism (increased transmitter release) may account for both effects.

Synaptic facilitatory and depressant actions of 3,4-diaminopyridine: correlation with anticurare properties.

This study aimed to define the complete concentration-effect relationship for anticurare effects of 3,4-diaminopyridine (3,4-DAP) in the isolated sympathetic ganglion of the bullfrog. Synaptic transmission was monitored by extracellular and intracellular recordings of the postganglionic response to preganglionic stimulation. A previous study showed that in the bullfrog sympathetic ganglion 3,4-DAP caused stimulus-bound repetitive postganglionic responses (SBR) to each single preganglionic stimulus. The concentration-effect relationship for 3,4-DAP-induced SBR was bell-shaped, and the descending limb of the curve reflected progressive suppression of SBR while normal synaptic transmission was maintained. In the present study a detailed concentration-effect analysis of 3,4-DAP's anticurare action also resulted in a bell-shaped curve nearly congruent with that for SBR. SBR and anticurare effects of 3,4-DAP therefore occupy a common concentration-effect domain, and this suggests that a common mechanism (increased transmitter release) may account for both effects.

Direct action of 4-aminopyridine on the contractility of a fast-contracting muscle in the cat.

1. The effects of 4-aminopyridine on the contractility of the fast-contracting tibialis anterior and the slow-contracting soleus muscles of cats under chloralose anaesthesia have been studied. 2. 4-Aminopyridine, in doses of 0.5 mg/kg and above, produced a slowly developing increase in the twitch tension of directly stimulated chronically denervated and of indirectly stimulated innervated tibialis anterior muscles, but had little or no effect on twitches of soleus muscles. The effect of innervated tibialis anterior muscles was more pronounced than that on chronically denervated muscles, but it was nevertheless concluded that the whole effect on innervated muscles was the result of a direct action on the muscle fibres. The simultaneously occurring facilitatory action on neuromuscular transmission, which is manifested in the anti-curare action of 4-aminopyridine, had a faster time-course and occurred in both the tibialis anterior and the soleus muscles. 3. 4-Aminopyridine antagonized dantrolene sodium on on the tibialis anterior muscle but not on the soleus muscle. The antagonism could be described as physiological antagonism since it simply reflected the opposing actions on contractility of the two drugs. 4. 4-Aminopyridine was without effect on maximal tetanic tension of either the tibialis anterior or the soleus muscle. 5. It seems clear from the literature that a species difference exists with regard to the ability of 4-aminopyridine to increase muscle contractility. The results described in this paper show that muscle differences within the same species also exist.

Facilitatory sites of action of theophylline in isolated cat tenuissimus muscle

Facilitatory effects of theophylline in neuromuscular transmission were studied using cat tenuissimus muscle fibre. Trains of end-plate potentials (EPP'S), in the presence and absence of (+)-tubocurarine were investigated. In (+)-tubocurarine-blocked muscle, theophylline did not change the quantal content ( M), readily releasable stores ( N), probability of release ( P), and mobilization ( d m ), but it increased the quantal size ( q) and the amplitude of the first EPP. In the absence of (+)-tubocurarine, theophylline treatment increased probability of release and increased the quantal content of the first EPP in the train. Analysis of EPP time course in the presence and absence of (+)-tubocurarine suggested a postsynaptic action of theophylline as evidenced by an increased rise-time and 1 2 - fall . Similar effects on time course were observed with miniature end-plate potentials (MEPP's). EPP and MEPP amplitude was increased in the absence of (+)-tubocurarine. Reversal of a (+)-tubocurarine blocked muscle and antagonism of MEPP's depressed by (+)-tubocurarine, further indicate the postsynaptic action of theophylline. Our data suggest not only a presynaptic effect via increased probability of release but also a post-synaptic anti-curare action of theophylline. These facilitatory effects of xanthines may be related to the enhancement of neuromuscular transmission seen in isolated human myasthenie nerve-muscle preparations.

An anti-curare effect of hexamethonium at the mammalian neuromuscular junction.

1. Experiments were performed on the isolated phrenic nerve and diaphragm preparation of the rat.2. In preparations partly blocked with (+)-tubocurarine, the twitch amplitude increased after hexamethonium. This enhancement was not seen in preparations partly blocked with Mg(++) or with gallamine. High concentrations of hexamethonium produced failure of contraction.3. Extracellular endplate potentials were recorded from blocked preparations. The administration of hexamethonium resulted in an increased amplitude of these potentials only in curarized muscle.4. Hexamethonium had no anticholinesterase activity nor did it depolarize muscle cells or increase the quantal release of transmitter.5. It is concluded that hexamethonium exerts a specific anti-curare action. Experiments on the recovery of the twitch after washing out antagonists indicate that this process is limited by diffusion. The difference in rates of diffusion of hexamethonium and (+)-tubocurarine does not account for their interaction. The basis of the anti-curare action of hexamethonium is discussed.

Interactions of serotonin with neuromuscular blocking agents

Serotonin has been shown to reverse blockade induced by the nondepolarizing agents and hemicholinium and to potentiate blockade produced by the depolarizers. It is more effective at low frequencies of stimulation. The drug augments the twitch potentiations produced by small doses of decamethonium and neostigmine. It has no effect on exogenously applied acetylcholine. The agent increases the vascular resistance but this is not a prerequisite to its myoneural actions. Rubidium efflux from vascular strips, which is a measure of potassium permeability, is not affected by the chemical. At a dose of 10 μg/ml there is no anticurare action in vitro. All of the neuromuscular actions of serotonin can be prevented by administration of methysergide. It is postulated that the agent might act presynaptically to release acetylcholine by the interaction with serotonin D-receptors.

The anti-curare action of sodium fluoride at the neuromuscular junction of cat tenuissimus muscle

The anti-curare action of sodium fluoride was investigated in cat tenuissimus muscle by means of intracellular micro-electrode techniques. Eight millimoles of sodium fluoride augmented the amplitude of end-plate potentials in the presence of d-tubocurarine by elevating quantal content. This presynaptic effect was consistent with a concomitant rise in readily releasable stores of transmitter. In the absence of d-tubocurarine, eight millimoles of sodium fluoride depressed end-plate potential amplitude and prolonged half-decay. These latter responses appear to be in part the result of a depressant action of sodium fluoride on transmitter mobilization rate.

A STUDY OF THE ANTICHOLENESTERASE AND ANTICURARE EFFECTS OF SOME CHOLINESTERASE INHIBITORS

SUMMARY The inhibition of serum cholinesterase by neostigmine, tacrine, pyridostigmine and edrophonium has been measured in vivo under clinical conditions. The inhibition by these agents of both serum cholinesterase and red blood cell cholinesterasehas been compared in vitro. The anticurare action of neostigmine and of tacrine has been compared myographically. Previousclinical observations have been confirmed, and further support is given to the theory that neostigmine has a direct actionon the neuromuscular junction or muscle fibre, apart from its anticholinesterase property. However, the degree of inhibition of the enzyme depends upon the concentrations of enzyme, substrate and inhibitor, and since the concentrations existing at the neuromuscular junction are unknown, they cannot be reproduced for experimental purposes.

A comparison between the effects of edrophonium and choline in the skeletal muscles of the cat.

The effects of edrophonium and choline have been compared with those of the depolarizing substances acetylcholine, decamethonium, and suxamethonium, in both innervated and chronically denervated tibialis anterior muscles of cats under chloralose anaesthesia. Both edrophonium and choline were more potent antagonists to paralysis by tubocurarine than could be accounted for by their ability to stimulate the motor end-plates directly. It appeared likely that direct depolarization of the end-plate played no part in the anti-curare action of edrophonium and only some part in the anti-curare action of choline. A paralysis produced by the neuromuscular blocking agent, benzoquinonium, was more readily antagonized by a tetanus or by acetylcholine, suxamethonium, and decamethonium than a similar paralysis produced by tubocurarine. The tetraethyl ammonium ion was also slightly more effective against a paralysis by benzoquinonium. On the other hand, edrophonium was about 300 times and choline about five times less potent as an antagonist to benzoquinonium than to tubocurarine. Furthermore, the previous administration of benzoquinonium abolished the antagonistic action to tubocurarine of normally effective doses of edrophonium and reduced that of choline. These results were similar to those previously obtained with neostigmine, physostigmine and ethyl pyrophosphate and suggested that there was some similarity in the mechanism of action of all of these substances. Benzoquinonium, therefore, showed promise as a useful pharmacological tool for distinguishing compounds with this particular type of action. These anti-curare compounds did not appear to act by cholinesterase inhibition, not by an increase in the sensitivity of the motor end-plates. In common with other workers, we suggest that there is a pre-synaptic mechanism of action.

The neuromuscular blocking action of benzoquinonium chloride in the cat and in the hen.

Benzoquinonium (Mytolon) has been shown to produce a curare-like rather than a decamethonium-like paralysis of neuromuscular transmission in the tibialis anterior and soleus muscle of cats and the gastrocnemius muscle of hens. In the cat, but not in the hen, benzoquinonium had an additional action in preventing both the twitch potentiating action and the anti-curare action of edrophonium, neostigmine, eserine, and tetraethyl pyrophosphate. Paralysis produced by benzoquinonium was antagonized by injected acetylcholine and by acetylcholine liberated by tetanic stimulation of the motor nerve but, in the cat, anticholinesterases were without effect even when they were first administered in circumstances in which acetylcholine accumulation might be expected to occur. These findings suggested that inhibition of cholinesterase played little part in the skeletal muscle effects of the anticholinesterases studied. Although anticholinesterases did not antagonize benzoquinonium paralysis in the cat, they nevertheless potentiated the antagonistic action of injected acetylcholine.

Berberineの抗Curare作用

Berberineの抗Curare作用

Effects of sodium fluoride on nerve-muscle transmission.

Anticurare action of NaF at the neuromuscular junction is demonstrated and analyzed for various stages of impulse transmission from nerve to muscle. The e.p.p. of preparations blocked by d-tubocurarine is augmented by 0.5–10 mm NaF. The e.p.p. amplitude is increased about 2.5 times by 0.5–1 mm, nearly three times by 3 mm or higher concentrations, and some prolongation occurs. The e.p.p. of a preparation blocked by tetanization is also augmented promtly by NaF, and transmission is restored. In this case, the threshold voltage for propagated muscle responses is lowered. NaF has no effect on the normal muscle membrane potential, even in the end-plate region —nor has it any effect on the electrical threshold. The end-plate depolarization produced by acetylcholine is considerably increased by NaF; and the curve of NaF concentration against the increase of depolarization is identical with that of the increase of e.p.p. The time course of acetylcholine depolarization, when augmented by small concentrations of NaF produce some prolongation of the falling limb, but the curve is still quite different from one augmented by eserin. NaF has no effect on the frequency of spontaneous e.p.p.s, but it considerably augments the height of each individual miniature e.p.p. The augmentation of the e.p.p. produced by NaF is not explained by an anticholinesterase action; it is mainly due to an increased sensitivity of the end-plate to acetylcholine induced by the fluoride ion.

Inability of Acetylcholine Antagonists to protect Mice against the Toxicity of ‘Tensilon’

THE anticurare action of ‘Tensilon’ (3-hydroxy-N-dimethylethylanilinium bromide) was considered by Randall1,2 not to depend upon cholinesterase inhibition. Hobbiger3 and Hall and Parkes4 showed, however, that ‘Tensilon’ does not reverse neuromuscular block after treatment of the preparation with tetraethyl pyrophosphate, implying the necessity of active cholinesterase for the effect.

Studies in myasthenia gravis; preliminary report on therapy with mestinon bromide.

Since 1934, with the discovery of the value of cholinergic drugs for myasthenia gravis,1the treatment for this disease has been the use of analogues of physostigmine. The first of these, neostigmine, has long been the undisputed drug of choice.2It has both an anticholinesterase (antiChE) and an anticurare action at the neuromuscular junction. Because of this dual action, neostigmine has been effective for the treatment of the greater majority of patients with this disease, especially for the patients with the milder types of myasthenia gravis for whom relatively small doses of neostigmine are necessary. It is in the more severe types that neostigmine has a distinct disadvantage because of its short duration of action. Because of the increased amount and frequency of dosage, cholinergic side-effects become pronounced and difficult to control despite the use of atropine. These side-effects are either muscarinic or nicotinic in action, causing increased

TENSILON: A NEW ANTI-CURARE AGENT

The anti-curare action of Tensilon (3 hydroxy-phenyl dimethyl ethyl ammonium bromide) has been investigated. It was found that the effect of this drug, though apparently complete and permanent in experimental animals was somewhat evanescent in man. If complete decurarization was to be maintained in the human subject it was often necessary to give second or even third doses of Tensilon. Circulatory side-effects were slight when atropine was given with Tensilon. The conclusion is drawn that Tensilon, though free from the more serious muscarinic actions of neostigmine, is not as reliable an antidote to the muscle paralysing action of d-tubocurarine.

Anticurare Action of Phenolic Quaternary Ammonium Salts

Anticurare Action of Phenolic Quaternary Ammonium Salts

Prevention of the Anti-Curare Action of Epinephrine by Dibenamine

SummaryThe effects of Dibenamine on the anti-curare actions of epinephrine and of KC1 have been studied in 7 dogs anesthetized with sodium pentobarbital or with morphine and ether. Dibenamine, in doses of 25-45 mg per kg, prevents the anti-curare action of epinephrine but does not prevent the anti-curare action of potassium chloride.