Electroneurophysiological studies in rats of acute dimethoate poisoning.

In order to investigate the mechanism of muscular weakness in the intermediate myasthenia syndrome (IMS) following acute organophosphate poisoning, the effect of dimethoate on the neuromuscular transmission was studied in rats by using the electrical stimulation single fiber electromyography (SSFEMG) and repetitive nerve stimulation (RNS). The results showed that there was a prolongation of mean consecutive difference (MCD) of the latencies of single fiber potential shown by SSFEMG in dimethoate intoxicated rats during the presence of muscle weakness when the stimuli were given at 10 or 20 Hz, and there was a remarkable decrement of compound muscle action potential (CMAP) of gastrocnemius muscle evoked by RNS on the sciatic nerve at 20 Hz in some rats with myasthenia. The frequency of neuromuscular transmission abnormalities detected by SSFEMG was significantly higher than those detected by RNS. This study demonstrates that the SSFEMG is a more sensitive electrophysiological method in the detection of neuromuscular transmission block occurred in rats of acute organophosphate poisoning with muscle weakness.     

Functional changes of nicotinic acetylcholine receptor in muscle and lymphocyte of myasthenic rats following acute dimethoate poisoning

The mechanism underlying intermediate myasthenia syndrome (IMS) following acute organophosphate poisoning remains largely unknown. Previous studies indicated that the mechanism of myasthenia in rats and IMS patients is most likely due to a postsynaptic neurotransmission blocking at neuromuscular junctions (NMJ). Nicotinic acetylcholine receptor (nAChR) is a key postsynaptic component at NMJ. Whether functional changes of nAChR are related to the development of myasthenia has not been demonstrated and addressed in vivo so far. In this study, we attempted to investigate temporal and spatial changes of nAChR in the blood lymphocyte, muscle and brain of rats during the course of myasthenia after acute dimethoate poisoning by using radioligand-binding assay. We found that specific nAChR binding activity in the gastrocnemius muscle and blood lymphocytes of myasthenia rats was significantly increased at 48h after dimethoate poisoning. However, no changes of nAChR binding activity were found in the lymphocytes and muscle of non-myasthenia rats which were sacrificed at 1h after intoxication. Interestingly, no changes of nAChR and muscarinic acetylcholine receptor (mAChR) binding activity were found in the cerebrum and cerebellum of all rats after dimethoate intoxication either at 1 or 48h. The change of nAChR specific binding activity in the lymphocytes is parallel with that in the skeletal muscle during the development of myasthenia. This implied that the changes of nAChR receptor binding activity in the skeletal muscle and lymphocytes are highly associated with the development of myasthenia. The functional changes of nAChR at NMJ might play an important role in the paralysis of skeletal muscle following acute organophosphates (OPs) poisoning.     

吡喹酮对神经肌肉接头传递的作用

吡喹酮可使电刺激腓总神经所引起的胫前肌收缩反应明显加强。如给腓总神经施加超强刺激,静脉注射筒箭毒碱可减弱肌肉收缩反应,吡喹酮却能加强筒箭毒碱的抑制作用,使神经肌肉传递迅即完全阻断。采用微电极细胞内记录技术研究吡喹酮对离体大鼠膈神经隔肌的作用,发现吡喹酮不明显影响膈肌细胞的静息膜电位。低浓度吡喹酮(2×10^-4M)可使微终板电位(mepp)频率明显增加。高浓度吡喹酮8×10^-4M则使mepp振幅逐渐变小和消失。吡喹酮在使神经肌肉传递阻滞不断加深的同时,尚能使终板电位的振幅变小,终致完全消失。     

肟硫磷中毒肌无力大鼠骨骼肌烟碱样乙酰胆碱受体通道特性

目的　探讨肟硫磷引起肌无力大鼠骨骼肌烟碱样乙酰胆碱受体 (nAChR)通道特性的改变 ,揭示其发生机制。方法　用ip 1 .1 5g·kg-1肟硫磷制作成年大鼠肌无力模型 ,同时ip 1 6mg·kg-1阿托品以对抗毒蕈碱样症状。染毒后 0 .5～ 2h,8只大鼠出现肌无力 ,7只大鼠肌力正常。将 3只肌无力大鼠于肌力恢复后 (染毒后 1 2～ 1 8h) ,其余大鼠于染毒2～ 3h后 ,断颈处死 ,取后肢趾短屈肌 ,酶解制备骨骼肌纤维 ,用膜片钳对肌纤维nAChR通道做单通道电流记录。结果　肌无力大鼠nAChR单通道开放频率、表观平均开放时间、平均开放时间和电导均显著低于对照组和肌力正常的染毒大鼠 ,且肌力恢复后 ,以上各参数均接近对照组。结论　肟硫磷中毒引起肌无力可能与肟硫磷导致或促进nAChR的脱敏 ,以及阻断nAChR通道的开放有关。     

Signaling and aging at the neuromuscular synapse: lessons learnt from neuromuscular diseases

The neuromuscular junction (NMJ) is a specialized synapse between motor neurons and skeletal muscle with a complex signaling network that assures highly reliable neuromuscular transmission. Diseases of the NMJ cause skeletal muscle fatigue and include inherited and acquired disorders that affect presynaptic, intrasynaptic or postsynaptic components. Moreover, fragmentation of the NMJ contributes to sarcopenia, the loss of muscle mass during aging. Studies from recent years indicate that the formation and stabilization of NMJs differs between various muscles and that this difference affects their response under pathological conditions. This review summarizes the most important mechanisms involved in the development, maintenance and dysfunction of the NMJ and it discusses their significance in myasthenic disorders and aging and as targets for possible future treatment of NMJ dysfunction.     

Effect of pantoprazole and its interactions with vecuronium on the neuromuscular junction

Objective:

To study the effect of pantoprazole on neuromuscular transmission and its interactions with vecuronium at the neuromuscular junction (NMJ).

Materials and Methods:

Effect of pantoprazole on neuromuscular transmission (2 μM – 16 mM) and reversal of neuromuscular blockade by pantoprazole and vecuronium with neostigmine (3.3 μM), 3,4-diaminopyridine (0.25 mM), KCl (6 mM), and CaCl₂ (10 mM) were studied by the indirect and direct stimulated preparation of rat phrenic nerve hemidiaphragm. Cumulative reponse curves (CRC) of vecuronium (1 μM to 32 μM) were studied in the absence and presence of 32 μM, 64 μM, and 128 μM pantoprazole. Time for head drop by vecuronium infusion was recorded in the absence and presence of acute and chronic administration of pantoprazole (1.9 mg/kg) in rabbits.

Results:

Pantoprazole potentiated the basal contractile twitch responses at a lower concentration followed by neuromuscular blockade at a higher concentration. The neuromuscular blockade was not reversed by neostigmine (3.3 μM), 3,4-diaminopyridine (0.25 mM), KCl (6 mM), and CaCl₂ (10 mM). Pantoprazole potentiated the vecuronium-induced neuromuscular blockade. It decreased the total time for complete blockade in rat phrenic nerve hemidiaphragm preparation (P < 0.05) and decreased the time for the head drop in rabbits with vecuronium infusion (P < 0.0001).

Conclusion:

Pantoprazole has a direct neuromuscular blocking action. It has the potential to interact with vecuronium.     

Actions of triethylcholine on neuromuscular transmission

The effects of the triethyl analogue of choline (triethyl 2-hydroxyethyl ammonium) on muscular activity have been studied in conscious rabbits, chicks, dogs and a cat. The contractions of the tibialis anticus and soleus muscles of cats under chloralose anaesthesia, and of the tibialis anticus muscle of rabbits under urethane anaesthesia and the isolated diaphragm preparation of the rat were also used. In conscious animals, triethylcholine caused a slowly developing muscular weakness which was more severe after exercise and which resembled the symptoms of myasthenia gravis. In nerve-muscle preparations triethylcholine had a selective action in reducing the contractions of muscles elicited by a high rate of nerve stimulation while leaving unaffected the contractions caused by slower rates of stimulation. During the paralysis of the tibialis muscle of the cat produced by triethylcholine, action potentials recorded from the motor nerve were unaffected and the muscle responded normally to injected acetylcholine and to direct electrical stimulation. The failure of neuromuscular transmission produced by triethylcholine was reversed by injection of choline, but anticholinesterases were ineffective. Choline reduced the toxicity of triethylcholine in mice. It is concluded that triethylcholine produces transmission failure at the neuromuscular junction by interfering with the ability of the nerve endings to synthesize acetylcholine. The possibility that triethylcholine is itself acetylated by the nerve endings and released as an inactive neurohormone is discussed. It was shown that triethylcholine was devoid of depolarizing action and curare-like blocking action. It possesses a transient ganglion blocking action of the tetraethylammonium-type as shown in experiments in which it caused a fall in blood pressure and blocked the response of the nictitating membrane to pre- but not to post-ganglionic stimulation of the cervical sympathetic nerve.     

Snake Venom Neurotoxins: Pharmacological Classification

Neurotoxic proteins isolated from various snake venoms, because of their high affinity for a particular target site are used extensively as pharmacological tools to gain insights into the function of the nervous system. The potency of these molecules lies in their affinities towards the biomolecules involved in the functioning of neuromuscular transmission. Neuromuscular and pathophysiological effects of neurotoxic proteins result from their interaction with various microcompartments based on their similarities in mass and conformation to the types of amino acids and disulfide bridges in the normal ligands. Snake venom toxins can be broadly classified depending on whether their site of action is at the skeletal neuromuscular junction, or at sites other than the skeletal neuromuscular junction. Skeletal neuromuscular junction‐specific neurotoxins include the following: postsynaptic toxins, presynaptic toxins, presynaptic toxins with musculotropic or myonecrotic actions, presynaptic and postsynaptic, presynaptic and postsynaptic toxins with musculotropic or myonecrotic actions, myotoxic and antiAChE neurotoxins, etc. Snake venom neurotoxins with affinities selective to the sites other than the skeletal NMJ were categorised as non‐skeletal neuromuscular junction snake venom neurotoxins and they include toxins with affinity for muscarinic and neuronal receptors; toxins with affinity for K⁺ and Ca^{2 +} ion channels, toxins with affinity for enzymes and muscle elements, centrally‐acting neurotoxins, peptide neurotoxin and miscellaneous neurotoxins. There is an additional miscellaneous class of snake venom neurotoxins that includes weak neurotoxin, muscarinic toxin‐like proteins and vipoxin. The toxic mechanisms of well‐studied snake venom neurotoxins and their sites of action underlying neurotoxicity are discussed in this review, and they form the basis for classification of snake venom neurotoxins.     

A comprehensive review on experimental and clinical findings in intermediate syndrome caused by organophosphate poisoning

Acute organophosphate (OP) intoxication is important because of its high morbidity and mortality and occurrence of muscular paralysis associated by inhibition of acetylcholinesterase (AChE) activity at the neuromuscular junction. Cholinergic crisis, intermediate syndrome (IMS), and OP-induced delayed neuropathy (OPIDN) are the evidences that can be observed in OP intoxication. The main cause of morbidity due to OP poisoning is IMS that occurs 24-96 h after poisoning. Mechanisms underlying the IMS are not fully known. Although the electrophysiological aspects of delayed neuropathy are best characterized, the IMS remain very little studied. The aim of this study was to revisit current knowledge related to OP and the IMS. For this purpose, a systematic review without date limitation was performed. A total of 599 relevant articles were found and reviewed. Data were categorized according to experimental and clinical studies. Occurrences of persistent AChE inhibition, electromyography changes, muscle cell injury, and oxidative stress are the most important pieces of evidence for involvement of IMS in OP toxicity.Delayed AChE inhibition, muscle necrosis, down regulation or desensitization of postsynaptic ACh receptors, failure of postsynaptic ACh release, and oxidative stress-related myopathy are involved in IMS. Toxicokinetic factors, such as a high lipid-solubility, duration of AChE inhibition and metabolite excretion, evolution of alterations on repetitive nerve stimulation (RNS), type and frequency of muscle lesions can estimate the probability of the IMS. Plasma AChE of less than 200 units is a predictor and the 30 Hz RNS decremental response could be a useful marker for the IMS.     

Effects of the active constituents of Catha edulis on the neuromuscular junction

(-)-Cathinone and d-norpseudoephedrine (DNE) in the dose range 0.2-1.2 mg/ml produced a reduction in contractions of skeletal muscle, evoked by direct and indirect electrical stimulation and antagonised the facilitatory action of physostigmine on the neuromuscular junction; but failed to antagonise a partial blockade induced by d-tubocurarine (dTb) as occurs with norepinephrine or epinephrine. The local anaesthetic actions of (-)-cathinone and DNE were found to be almost equivalent to that of lignocaine. These results indicate that (-)-cathinone and DNE may have a direct blocking action on the neuromuscular junction, which is independent of cholinergic and adrenergic transmission.     

Preparation of semisynthetic (+)-tubocurarine chloride.

Semisynthetic (+)-tubocurarine chloride (II) was prepared by monoquaternization of (+)-tubocurine. The method involved treating (+)-tubocurine with a 0.5 M equivalent of hydrochloric acid prior to quaternization with methyl iodide, followed by neutralization and iodide-chloride ion-exchange. Column chromatography and crystallization procedures were utilized for pure semisynthetic II preparation. The neuromuscular junction blocking activities of the semisynthetic and commercial II were determined by the in vivo cat hypoglossal nerve-tongue muscle preparation. No delectable differences among physical constants, spectral data, and neuromuscular junction blocking activities were noted between the commercial product and the semisynthetic II. This result substantiates the chemical and biological data for the well-accepted new formula for II. The unexplained M + n14 mass spectral peaks shown by the curare-type bases are characteristic of the molecular species rather than a result of contaminants.     

The ganglion blocking and vagolytic actions of three short-acting neuromuscular blocking drugs in the cat

Three recently-introduced short-acting neuromuscular blocking drugs with non-depolarizing mechanisms of action, stercuronium, dacuronium and AH8165 (1,1′-azobis [3-methyl-2-phenyl-1H-imidazo (1, 2a) pyridinium] dibromide) have been tested in the anaesthetized cat on the responses of the nictitating membrane to stimulation of the cervical nerve, and of the heart to vagal stimulation. The effects of the three drugs at the superior cervical ganglion and at the cardiac neuroeffector junction have been compared with their neuromuscular blocking effects. At doses lower than those required to block neuromuscular transmission all three compounds possessed a selective atropine-like action at the cardiac vagus neuroeffector junction in that they inhibited the bradycardia produced by vagal stimulation and by acetyl-β-methylcholine, whilst the depressor action of acetyl-β-methylcholine was unaffected. The ratios of the doses of the drugs to block the responses of the preganglionically-stimulated nictitating membrane and of the tibialis anterior muscle were 16m?7 for stercuronium, 8m?5 for dacuronium and 3m?8 for AH8165. The greater ganglion-blocking activity of AH8165 was reflected in the depressor action of the compound, whereas the weak ganglion-blocking actions of stercuronium and dacuronium were insufficient to mask the tachycardia and pressor effect caused by their blocking action on the cardiac vagus neuroeffector junction.     

The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments

Nine analogues of the azasteroid muscle relaxant chandonium have been tested for neuromuscular blocking activity, ganglion blocking activity, inhibitory effects on cardiac muscarinic receptors, and for effects on noradrenergic transmission. Experiments were performed in anaesthetized cats and in isolated preparations. The two bisquaternary compounds HS-626 and HS-627, choline and acetylcholine-like analogues of chandonium respectively, were approximately equipotent with chandonium as neuromuscular blocking agents in the cat, but HS-672 possessed slightly more vagal blocking action. No evidence was obtained for ganglion block. The monoquaternary analogues, HS-408 and HS-465 and two 4-aza-androstanes, (HS-522 and HS-523) were more than 100 times less active than the bisquaternary compounds as neuromuscular blocking agents, and produced vagal blockade and ganglion blockade at sub-neuromuscular blocking doses. pA₂ determinations in the chick biventer cervicis muscle, the guinea-pig atria and guinea-pig ileum showed that the bisquaternary compounds chandonium, HS-626 and HS-627 were much more potent in blocking cardiac than intestinal muscarinic receptors and that HS-626 possessed the widest margin between concentrations blocking the nicotinic receptors at the neuromuscular junction and the cardiac muscarinic receptors. Evidence for the three bisquaternary compounds blocking neuronal noradrenaline reuptake was obtained only at very high concentrations. HS-626 possessed a slightly more desirable spectrum of activities than chandonium, but the degree of improvement over the parent compound is insufficient to merit extensive clinical testing.     

Contribution of Single-Fiber Evaluation on Monitoring Outcomes Following Injection of Botulinum Toxin-A: A Narrative Review of the Literature

Botulinum toxin-A (BoNT-A) blocks acetylcholine release at the neuromuscular junction (NMJ) and is widely used for neuromuscular disorders (involuntary spasms, dystonic disorders and spasticity). However, its therapeutic effects are usually measured by clinical scales of questionable validity. Single-fiber electromyography (SFEMG) is a sensitive, validated diagnostic technique for NMJ impairment such as myasthenia. The jitter parameter (µs) represents the variability of interpotential intervals of two muscle fibers from the same motor unit. This narrative review reports SFEMG use in BoNT-A treatment. Twenty-four articles were selected from 175 eligible articles searched in Medline/Pubmed and Cochrane Library from their creation until May 2020. The results showed that jitter is sensitive to early NMJ modifications following BoNT-A injection, with an increase in the early days’ post-injection and a peak between Day 15 and 30, when symptoms diminish or disappear. The reappearance of symptoms accompanies a tendency for a decrease in jitter, but always precedes its normalization, either delayed or nonexistent. Increased jitter is observed in distant muscles from the injection site. No dose effect relationship was demonstrated. SFEMG could help physicians in their therapeutic evaluation according to the pathology considered. More data are needed to consider jitter as a predictor of BoNT-A clinical efficacy.     

Block of potassium channels and facilitation of acetylcholine release at the neuromuscular junction by the venom of the scorpion, Pandinus imperator

Venom from the scorpion Pandinus imperator potently and selectively blocks voltage-gated K+ channels in bullfrog neurones (Pappone, P. A. and Cahalan, M. D. 1987, J. Neurosci. 7, 3300-3305). Its effects on neuromuscular transmission have now been assessed. Twitch tension studies on chick biventer cervicis preparations showed that the venom (1 microgram/ml and above) significantly augmented responses to nerve but not muscle stimulation; there was little change in postjunctional sensitivity to cholinoceptor agonists or K+-induced depolarization. Electrophysiological studies on mouse triangularis sterni preparations revealed that the venom had no effect on spontaneous transmitter release, but increased evoked transmitter release. Extracellular recordings of nerve terminal action potentials showed that the venom selectively reduced the component of the waveform associated with K+ currents. These results confirm that this venom can selectively block neuronal K+ currents, and they show that this can facilitate the release of acetylcholine at the neuromuscular junction.     

Single fiber electromyographic jitter and detection of acute changes in neuromuscular function in young and adult rats

IntroductionExposure to irreversible cholinesterase (ChE)-inhibiting compounds, such as organophosphates may produce neuromuscular dysfunction. However, less is known about changes in neuromuscular transmission after treatment with reversible ChE-inhibitors. These studies adapted single fiber electromyography (SFEMG) techniques to quantify neuromuscular jitter in adult and juvenile rats after treatment with agents that alter cholinergic neurotransmission.MethodsAnesthetized adult and juvenile rats were tested using stimulation SFEMG, recorded in the gastrocnemius muscle, after stimulation in the sciatic notch region. The influence of electrode placement, treatment with decamethonium (to disrupt neuromuscular transmission) or physostigmine (reversible ChE inhibitor), and the impact of varied stimulation frequency were quantified.ResultsNo significant effects of needle placement or criterion amplitude were observed when calculating the mean consecutive difference (MCD). Treatment with decamethonium did not alter MCD values in adult or juvenile rats. However, decamethonium produced an increased blocking of muscle action potentials (MAP) in juveniles. Also, when stimulated at 9.09 Hz, both adult and juvenile animals had a greater decrease in MAP amplitude between the first and fourth responses (T₁–T₄ decrement) after treatment with decamethonium. Prior to treatment with decamethonium, the T₁–T₄ decrement averaged about 3 fold greater in juveniles than adults, and was larger at 3.03 and 9.09 Hz than with 0.91 Hz stimulation. Treatment with physostigmine resulted in at least 50% inhibition of muscle ChE activity, but produced minimal changes in the MCD values in adults or juveniles. Combined over treatments and stimulation frequencies, the median MCD for juveniles (11.6 µs) was less than that for of adults (18.8 µs). In juveniles, the median MCD increased from 9.3 µs to 13.9 µs as the stimulation rate was increased from 0.91 to 9.09 Hz. This stimulus-dependant change was more evident in juveniles than in adults.DiscussionA technique was developed to record stimulation SFEMG and neuromuscular jitter, in vivo, in adult and juvenile rats. The method was sufficiently sensitive to detect age-related differences, potentially allowing developmental processes to be examined. Based on the literature and the current data, the technique appears to be more sensitive to prolonged inhibition of ChE enzymes than the reversible inhibition produced by physostigmine.     

Assessment of neuromuscular blockade produced by atracurium in the rat diaphragm preparation. Measurements of tetanic fade, depression and recovery profile

The effect of atracurium, a relatively new muscle relaxant, on neuromuscular transmission, in the rat diaphragm preparation, was studied, by analysing the characteristic features of tetanic fade and recovery pattern following a blocking concentration of atracurium (10 microns). Tetanic fade (TF) and peak tetanic tension (Tp) and its depression by atracurium, were analysed and the results were interpreted in terms of atracurium action at the neuromuscular junction. Atracurium reduced the sustained tetanic tension, elicited at 50 Hz for 0.5 s duration, and produced a marked tetanic fade in 38 s. Atracurium also reduced the peak tetanic tension by 40%, of the control value, in 38 s. Maximum tetanic tension was 5.7 g tension, and the time taken to completely block the tetanus was 4.75 +/- 0.15 min (means +/- SE, n = 8). Recovery from atracurium-induced blockade occurred in 30s (tetanic fade) and in 3-4 min (peak tetanic tension). It was concluded that atracurium produces a profound tetanic fade, at a time when the peak tetanic tension is reduced by only 40%. The data presented indicate that atracurium has a rapid onset of blockade, intermediate duration and a quick recovery profile at the rat neuromuscular junction.     

Effects of emetine and dehydroemetine at the frog neuromuscular junction

Emetine and dehydroemetine caused concentration-dependent reduction of the quantal content of the endplate potential (EPP) at the frog neuromuscular junction. At lower concentrations, the drugs had presynaptic action only, as they decreased the amplitude of the EPP without significantly affecting that of the spontaneous miniature EPP (MEPP). At higher concentrations, the drugs had postsynaptic effects as well. Studies of low frequency facilitation indicated that although at low concentrations the effect of emetine on quantal content was independent of frequency of stimulation, at higher concentrations the effect became markedly frequency-dependent and many of the stimuli (at 4 and 8 Hz) failed to evoke EPPs. In the voltage-clamped transected cutaneous pectoris muscle emetine (10(-4) M) depressed the peak amplitude of the endplate current (EPC). Emetine markedly shortened the time constant of decay of the EPC (tau) at more negative holding potentials but did not change the single exponential character of the decay. The results indicate that the acute effects of emetine involve blocking neuromuscular transmission by acting prejunctionally at low concentrations and pre- as well as postjunctionally at higher concentrations. The prejunctional effect is due to interference with evoked release and probably, mobilization of acetylcholine. The postjunctional effect is due to blockade of the acetylcholine-activated ionic channel.     

Telithromycin blocks neuromuscular transmission and inhibits nAChR currents in vitro

Telithromycin, a ketolide antibiotic, is reported to exacerbate myasthenia gravis, potentially leading to respiratory failure and death. However, telithromycin is not associated with neuromuscular effects in animal toxicity studies. The objective of this study was to examine the effect of telithromycin on the neuromuscular junction in the isolated rat phrenic nerve-diaphragm preparation and to investigate its postsynaptic effects on the muscle-like nicotinic acetylcholine (ACh) receptors expressed on human TE671 cells. Telithromycin decreased the twitch contraction force of the rat diaphragm muscle in response to phrenic nerve stimulation in a concentration-dependent manner with an IC₅₀ of 22.3 μM and a maximal inhibition of ∼70%. The trans-membrane current from the ACh receptors expressed in the TE671 neuromedulloblastoma cells was recorded in the whole-cell patch-clamp configuration. When applied to the TE671 cells, telithromycin caused a dose-dependent inhibition of the nicotinic ACh current with an IC₅₀ of 3.5 μM and maximal inhibition of nearly 100%. These results indicate that telithromycin inhibits postsynaptic nicotinic ACh receptors in vitro and partially blocks neuromuscular transmission in the isolated rat phrenic nerve-diaphragm preparation. Based on these findings, we propose that exacerbation of myasthenia gravis reported in some patients taking telithromycin results in part from postsynaptic neuromuscular transmission block.     

Effects of atropine and glycopyrrolate on neuromuscular transmission in the rat phrenic nerve-diaphragm preparation

1. The effects of atropine and glycopyrrolate on neuromuscular transmission and on muscle contraction, were studied, in the rat diaphragm preparation, by analyzing their effects on the indirectly (and directly)-elicited twitch (0.2 Hz), tetanic (50 Hz for 20 sec duration), post-tetanic twitch responses (at 5 sec after the tetanus), and on the phenomenon of post-tetanic twitch potentiation (PTP), which is thought to be of a presynaptic origin, i.e. due to increased transmitter release. 2. Atropine (0.001-10 microM) increased the indirectly-elicited twitch tension by 22 +/- 2.1% (control 0.9 +/- 0.1 g, P less than 0.02), the tetanus by 15 +/- 1.1% (control 3.9 +/- 0.7 g, P less than 0.05), the post-tetanic twitch response by 33 +/- 3.1% (control 1.2 +/- 0.1 g, P less than 0.01) and the PTP value by 36 +/- 1.9% (control 33 +/- 2.3%, P less than 0.01, means +/- SEM = 6). 3. Atropine (0.001-10 microM) had little effect on the directly-elicited twitch tension, but in high concentrations (e.g. 20 microM), it blocked the twitch tension. 4. In contrast, glycopyrrolate (0.1-100 microM) had little effect on the twitch tension (direct or indirect), but it significantly reduced the tetanus (by 38 +/- 3.5%, P less than 0.01), the post-tetanic twitch response (by 17 +/- 1.2%, P less than 0.05) and the PTP values (by 24 +/- 3.1% P less than 0.02). 5. In the presence of hemicholinium (1.3 microM) the responses to atropine and glycopyrrolate were altered (decreased), indicating a possible action on presynaptic mechanism of transmission. 6. It is concluded that atropine and glycopyrrolate produce different (opposite) effects at the rat neuromuscular junction, atropine enhances whereas glycopyrrolate depresses neuromuscular transmission. The effects of these two antimuscarinic drugs may be exerted at the presynaptic nerve terminals, i.e. on presynaptic muscarinic receptors, which are involved in the feedback mechanism of transmitter release.