Curare-like Action Research Articles

β-Eudesmol as an antidote for intoxication from organophosphorus anticholinesterase agents

β-Eudesmol, a sesquiterpenol present in Chinese herbs, improved the tetanic contraction impaired by diisopropylfluorophosphate in isolated mouse diaphragm preparations by an inhibition of the regenerative acetylcholine release. The antagonism was enhanced when a small concentration of obidoxime was present. Neither enzyme reactivation nor curare-like action was evident. β-Eudesmol (300 mg/kg, i.p.) elevated the LD 50 of diisopropylfluorophosphate (s.c.) in control mice from 4.2 to 6.4 mg/kg and in mice pretreated with atropine from 7.8 to 10.6 mg/kg. In mice pretreated with atropine and obidoxime, β-eudesmol showed a greater synergistic effect, increasing the LD 50 from 281 to more than 800 mg/kg. β-Eudesmol also markedly alleviated diisopropylfluorophosphate-induced muscle fasciculation, tremor and convulsion and prolonged the time to death. It is proposed that β-eudesmol may be added to the standard antidotal regimen (atropine plus obidoxime) for treating organophosphate intoxication.

Obidoxime antagonizes the neuromuscular failure induced by neostigmine and diisopropyl fluorophosphate via different mechanisms

The efficacies and mechanisms of obidoxime in antagonizing the neuromuscular failure induced by neostigmine and diisopropyl fluorophosphate (DFP) were studied in mouse phrenic nerve/diaphragm preparations. Obidoxime antagonized neostigmine-induced tetanic fade (EC(50): 300 &mgr;M) by inhibiting the regenerative and sustained depolarization during repetitive stimulation. The antagonism was associated with a depression and shortening of single endplate potentials (EPPs) and miniature EPPs (MEPPs). In contrast, the neuromuscular failure induced irreversibly after treatment with DFP and followed by washout was restored by obidoxime at concentrations (EC(50): 0.6 &mgr;M) 500-fold lower than that against neostigmine. The regenerative depolarization was abolished with no depression of single EPPs and MEPPs, and the antagonistic action persisted after washout of obidoxime. The EC(50) of obidoxime was proportionately increased in the presence of increasing concentrations of DFP. Nevertheless, the EC(50) against DFP, at a concentration (30 &mgr;M) 15-fold in excess of that which caused tetanic fade, was still 10-fold lower than that which antagonized neostigmine. In both cases, the amplitudes of train EPPs were increased. It is concluded that obidoxime antagonizes neostigmine-induced neuromuscular failure by a curare-like action but antagonizes DFP by an enzyme reactivation. Copyright 1994 S. Karger AG, Basel

Studies on the neuromuscular blocking action of MPTP in the mouse phrenic nerve-diaphragm

The peripheral neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse phrenic nerve-diaphragm preparation was studied. The inhibition of nerve-evoked twitches was dependent on the concentrations of MPTP, ranging from 1 to 200 μM, which only slightly increased the amplitude of the twitch evoked by direct stimulation of the muscle. Pretreatment with pargyline did not prevent this inhibitory action of MPTP. The inhibition of the twitch by MPTP was reversible and could be partially reversed by anticholinesterase agents such as neostigmine and physostigmine, as well as ecothiophate. Pretreatment with either 0.7 μM d-tubocurarine or 2.2 μM succinylcholine, did not affect the twitches individually but markedly potentiated the effects of MPTP, by shifting the concentrationinhibition curve of MPTP to the left. MPTP not only directly inhibited acetylcholine (O.1mM)-induced contracture of the denervated mouse diaphragm but also protected the muscle from the inhibitory action of α-bungarotoxin. Furthermore, the specific binding of [ 125I]α-bungarotoxin to the mouse diaphragm was also inhibited by MPTP. Electrophysiological studies revealed that MPTP inhibited the frequency and amplitude of the m.e.p.p., as well as the amplitude of the e.p.p. All of these findings indicate that MPTP exerts a neuromuscular blocking action through a curare-like action, by binding to the nicotinic acetylcholine receptors of the mouse diaphragm. The inhibitory action of MPTP on the contraction of the diaphragm is considered to play a role in the respiratory failure and muscle paralysis of intoxication with MPTP.

Studies on curare-like action of 2,2',2''-tripyridine in the mouse phrenic nerve-diaphragm.

1. The curare-like action of 2,2',2''-tripyridine (a synthetic by-product of the herbicide, paraquat) was studied in mouse phrenic nerve-diaphragm preparation. The inhibition by 2,2',2''-tripyridine of nerve-evoked twitches was dependent on the concentration, ranging from 1 to 100 microM, which had no significant effect on the twitch amplitudes evoked by direct muscle stimulation. 2. The twitch inhibition by 2,2',2''-tripyridine was reversible and could be antagonized by anticholinesterase agents such as neostigmine, physostigmine as well as ecothiophate. 3. Pretreatment with either 0.7 microM (+)-tubocurarine or 2.2 microM succinylcholine shifted the concentration-inhibition curve of 2,2',2''-tripyridine to the left. 4. 2,2'2''-Tripyridine inhibited not only acetylcholine-induced contracture of the denervated mouse diaphragm but also that of the chick biventer cervicis muscle. Like (+)-tubocurarine, 2,2',2''-tripyridine protected the twitches from the inhibition by alpha-bungarotoxin and also specifically inhibited the binding of [125I]-alpha-bungarotoxin to the mouse diaphragm. All of these findings indicate that 2,2',2''-tripyridine possesses curare-like action and inhibits the muscle contractions through binding to postsynaptic acetylcholine receptors. 5. The postsynaptic inhibition exhibited by 2,2',2''-tripyridine was also implicated in the tetanic fade, a decrease in the amplitude of miniature endplate potential (m.e.p.p.) and endplate potential (e.p.p.). 6. The clinical implication of these findings is that 2,2',2''-tripyridine may be involved in the cause of respiratory failure in paraquat-intoxicated workers since 2,2',2''-tripyridine is a by-product of paraquat synthesis.

喉頭の運動神経および内喉頭筋の神経筋接合部について

Morphological changes of the neuromuscular junctions were studied ultrastructurally in the denervated and reinnervated posterior cricoarytenoid (PCA) muscle of the cat. Acetylcholinesterase (AchE) activity and acetylcholine receptors (AchR) were also investigated histochemically. The left recurrent laryngeal nerve was transected at the level of the second tracheal ring and neurorraphy was done immediately after the transection. AchE activity was demonstrated by Karnovsky and Lewis method whereas AchRs were identified by snake neurotoxin (α-bungarotoxin or erabutoxin b) which had a curare-like action. Two days after denervation nerve terminals at the neuromuscular junctions almost disapeared. Three to six weeks after denervation some primary synaptic clefts were narrowed and others were flattened while the secondary synaptic clefts were relatively preserved. The intensity of AchE activity at the neuromuscular junctions was almost same as that of the nonaffected side six weeks after denervation. Fourteen weeks after denervation AchE activity decreased. The regenerating axons appeared at the neuromuscular junctions three weeks after neurorrhaphy. An evoked electromyogram was observed at this stage. Nerve terminals were small and the secondary synaptic clefts were distorted until 22 weeks after neurorrhaphy. AchRs were detected at the neuromuscular junctions of the normal PCA muscle by snake neurotoxins. Ultrastructurally AchRs were localized at the postsynaptic membrane of the neuromuscular junctions. We were also able to demonstrate ultrastructurally calcitonin gene-related peptid (CGRP) immunoreactivity in the nerve terminals of the PCA muscle. These results strongly suggest that CGRP is involved in the regulation of the contractile function of the intrinsic laryngal muscle. The motor nerve innervation of the larynx and the neuromuscular junctions in the intrinsic laryngeal muscles

Histochemical study of acetylcholine receptors at the neuromuscular junctions of the cat posterior cricoarytenoid muscle using erabutoxin B

Acetylcholine receptors (AchRs) at the neuromuscular junctions of the cat posterior cricoarytenoid muscle (PCA muscle) were demonstrated by using erabutoxin b (Eb) which has a curare-like action. Eb is one of the short-chain neurotoxins which is obtained from Laticauda-semifasciata. At the light microscopic level, the localization of the neuromuscular junctions was detected on the muscle fiber by rhodamine-labeled Eb (TMR-Eb) under a fluorescein microscopy. For the electron microscopy horseradish peroxidase-labeled Eb (HRP-Eb) was used. After incubation with HRP-Eb conjugate the tissue was fixed in a mixture of paraformaldehyde and glutaraldehyde, then embedded in Epon. The reaction products were largely restricted to the postsynaptic membrane at the neuromuscular junction. Acetylcholinesterase (AchE) activity was also demonstrated electron microscopically by Karnovsky's and Lewis' methods respectively. The reaction products were localized at the subneural apparatus of the neuromuscular junction. Both these results were compared.

川〓より得られたフタライド化合物リグスチライド類の中枢性筋弛緩作用

The present study was carried out to elucidate a centrally acting muscle relaxant effect of chloroform soluble fraction and its component, namely, ligustilide, cnidilide and senkyunolide obtained from the rhizome of Cnidium officinale Makino. These three compounds were isolated from the chloroform soluble fraction by column chromatography on silica gel. The centrally acting muscle relaxant effect was investigated on the crossed extensor reflex in anesthetized rats and these samples were suspended in 0.5% carboxymethyl cellulose solution and administered i.p. These three compounds as well as the chloroform soluble fraction depressed the reflex response. The depressive potencies among them were almost the same and their potencies were also the same or somewhat weaker as that of mephenesin. As a curare-like action was not observed, a muscle relaxation induced by these phthalide compounds is considered to be due to central origin.

Effects of a Dendroaspis neurotoxin on synaptic transmission in the spinal cord and the neuromuscular junction of the frog.

A neurotoxin from the venom of Dendroaspis jamesoni was tested at the neuromuscular junction and at a cholinergic pathway in the isolated spinal cord of the frog. The toxin reduced the amplitude and time constant of decay of miniature endplate currents in the presence of prostigmine, indicating a curare-like action. In the spinal cord it selectively blocked transmission in the cholinergic pathway and increased spontaneous activity. Partial protection against toxin action in the spinal cord was provided by atropine or carbachol. The results suggest that the toxin acts on cholinergic receptors at both sites and also provide further evidence that the pharmacology of the two sites is different.

THE NATURE OF GENTAMICIN-INDUCED NEUROMUSCULAR BLOCK

Gentamicin in concentrations of 0.05--0.2 mmol litre-1 blocked neuromuscular transmission in the toad sartorius nerve--muscle preparation by decreasing the release of transmitter. In concetnrations of 0.5--1 mmol litre-1 it decreased the amplitude of the miniature end-plate current by a curare-like action, without affecting the mean open channel lifetime.

The effect of anticholinesterase drugs on postjunctional potentials of skeletal muscle

1. 1. Quantitative detailed investigation of the effects of seven anticholinesterase (anti-ChE) drugs—organophosphorus inhibitors (OPI) (armin, GD-42, GD-7), carbamates (proserine or neostigmine, eserine), quaternary ammonium salts (ambenonium, edrophonium)—on postjunctional potentials in skeletal muscle was carried out with a reduced quantum content of end plate potentials (EPP). 2. 2. It was established by the method of elimination of other possible causes that the amplitude of miniature end plate potentials (MEPP) and the duration of EPP were increased by inhibitors as a result of their anti-ChE action only. 3. 3. Curare-like action of the inhibitors was analysed. It was found to be related neither to their effect on membrane potential or passive electrical properties of the muscle fibres nor to inhibition of cholinesterases (ChE). 4. 4. It was found that inhibitors, excepting OPI, failed to affect the EPP quantum content and MEPP frequency. OPI affected these parameters in experiments on the frog sartorius muscle but not on the rat diaphragm muscle and only at concentrations of 2 × 10 −5 M and higher. Under these conditions armin decreased the EPP quantum content and the MEPP frequency. GD-42 and GD-7 decreased the EPP quantum content as well but increased MEPP frequency. These variations of parameters were not related to inhibition of ChE activity and were reversible by washout.

Sila-Pharmaka, 9. Mitt. [1] Darstellung und Eigenschaften potentiell curarewirksamer Silicium-Verbindungen, I / Sila-Drugs, 9th Communication [1] Preparation and Properties of Silicon Compounds with Potential Curare-Like Activity, I

Abstract Organosilicon compounds 8, 9 and 10 with potential curare-like action and their precursors 5, 6 and 7 were synthesized for the first time. 5−10 were characterized by their physical and chemical properties, and their structures were confirmed by analyses, 1 H NMR and mass spectroscopy (only for 5−7). The pharmacological and toxicological data of 8, 9 and 10 are reported.

Reexamination of carbodiimide as a possible affinity label for the acetylcholine receptor at the frog neuromuscular junction.

The effects of water-soluble carbodiimide were examined at the frog neuromuscular junction. Acetylcholine sensitivity was measured using a fluid electrode technique and intracellular recording of miniature end-plate potentials. The carbodiimide blocked synaptic sensitivity by a reversible, curare-like action. Irreversible blockade was also observed, probably due to covalent binding. The conditions of reaction and irreversibility suggest that several different residues may be attacked. The inability of cholinergic antagonists to protect the receptor from attack indicates that nonspecific sites, and not the acetylcholine binding site, are involved.

A CHOLINOCEPTOR ANTISERUM: ITS PHARMACOLOGICAL PROPERTIES

1 Sera of rabbits immunized against a nocotinic receptor-rich fraction, obtained from the electric organ of Torpedo marmorata, were tested for their pharmacological activity on different in vitro preparations. 2 Sera containing antibodies against the nicotinic receptor blocked neuromuscular transmission in the phrenic-nerve hemidiaphragm preparation without affecting the muscle responses evoked by direct electrical stimulation. Complement inactivated sera were still active. Immune sera, incubated for 15 min with a receptor-rich fraction, lost their activity. 3 The immune sera antagonized the responses elicited by acetylcholine on the frog rectus abdominis. 4 The immune sera tested in vitro decreased the compound action potential evoked in the superior cervical ganglion of the rat by electrical stimulation of the preganglionic nerve. 5 The sera did not show any activity on muscarinic receptors of the guinea-pig ileum preparation. 6 It is concluded that in sera obtained from immunized rabbits a substance is present with curare-like action, and that this activity is probably due to the presence of antibodies against the nicotinic receptor.

Synthesis of a series of bisquaternary ammonium derivatives of diphenyldiaminopropane possessing curare-like action

Synthesis of a series of bisquaternary ammonium derivatives of diphenyldiaminopropane possessing curare-like action

Actions of the selective inhibitor of cholinesterase tetramonoisopropyl pyrophosphortetramide on the rat phrenic nerve-diaphragm preparation.

1. Tetramonoisopropyl pyrophosphortetramide (iso-OMPA) added for 15 min to the rat isolated phrenic nerve-diaphragm in a concentration of 30 muM, produced a complete selective and stable inhibition of cholinesterase. A concentration of 3 muM produced near complete inhibition of cholinesterase, and a concentration of 300 muM also inhibited acetylcholinesterase marginally.2. Inhibition of cholinesterase was associated with a sustained increase in the neuromuscular blocking action of exogenous butyrylcholine but not of exogenous acetylcholine. Iso-OMPA, 300 muM, in addition caused transient increases in the sensitivity of the rat diaphragm to exogenous acetylcholine and butyrylcholine. In the same concentration, it had a curare-like action on the frog rectus abdominis muscle preparation.3. Iso-OMPA, 30 muM, caused reversible increases in the amplitude of the twitch response and tetanic responses, which were of a similar magnitude in the indirectly stimulated preparation and the directly stimulated curarized preparation. Caffeine had a similar effect on the twitch response and its effectiveness was increased by iso-OMPA, and vice-versa. Amongst anticholinesterases, octamethyl pyrophosphortetramide and tetraethylpyrophosphate also enhanced the amplitude of the tetanic response, but paraoxon, dyflos, and mipafox did not.4. It is concluded that iso-OMPA, in concentrations (3 and 30 muM) which in 15 min give near maximal or maximal selective inhibition of cholinesterase, has no effect on the transmission of nerve impulses at the neuromuscular junction, but enhances reversibly the amplitude of the contractile response to stimulation by a direct action upon the muscle fibre, which involves a mechanism related to but not identical with that by which caffeine potentiates twitch tension. In higher concentrations, iso-OMPA has a curare-like action at the neuromuscular junction.

Curare-like action of monoquaternary salts containing an adamantyl group on the nitrogen atom

Curare-like action of monoquaternary salts containing an adamantyl group on the nitrogen atom

Effects of anticholinergics on the afferent discharges from the muscle spindle of the bullfrog in vitro.

Stretching of the muscle spindle produces a receptor potential (a local depolarization) in the muscle spindle which gives rise to repetitive spikes in the sensory nerve (1). In addition, it has been suggested that the dynamic component of the receptor potential is simply the result of a change in membrane capacity, and that the successive static component may be due to a change in membrane permeability (1). Henatsch and Schulte (2) found that the afferent discharges from the muscle spindle were increased by acetylcholine or succinylcholine in the muscle of frog. Ottoson (3) reported that acetylcholine (1×10-4 g/ml) had no significant effect on the sensory endings while higher concentrations caused a slight reduction of their activity. Some reports (4-6) indicated that d-tubocurarine or atropine affected the discharges from the muscle spindle. The problem thus remains whether acetylcholine or cholinesters play an essential role in the generation or transmission of spikes. It was expected that use of various anticholinergics might provide an important clue in elucidating the mechanism of static generation and transmission of spikes. Strychnine was shown to have curare-like action (7) and also depressive action on the afferent discharges from the muscle spindle (8). The present study deals with d-tubocurarine, atropine, hexamethonium, hemicholinium-3, procaine and also strychnine. It is concerned with effects on muscle spindle discharges, receptor potential, nerve conduction and muscle twitch.

Studies on the neuropharmacology of papaverine—I. The curare-like action isolated nerve-muscle preparation

The spasmolytic effect of papaverine on smooth muscle is well known. The present experiments give evidence of its effects on striated muscle and neuromuscular transmission. The isolated rat phrenic nerve-hemidiaphragm preparation was used. Papaverine in concentrations 2 × 10 −8−1 × 10 −3 g ml inhibited muscle contractility in directly stimulated muscle, but did not elicit a blockade of muscle twitches. It was possible to overcome the inhibitory action of papaverine temporarily by caffeine. On the other hand, papaverine could not cause changes in contractions evoked by caffeine. In the indirectly stimulated preparation, papaverine in a low concentration (2 × 10 −6 g ml ) inhibited, and in higher concentrations (8 × 10 −5− 1 × 10 −3 g ml ) completely blocked, the muscle twitches. For inhibition and blockade of the indirectly evoked contractions, lower doses of the drug were needed than for suppression of the directly elicited ones. Papaverine in concentrations which inhibited and blocked the indirectly evoked responses was also able to inhibit acetylcholine hydrochloride and potassium chloride contractions. The inhibitory effect of d-tubocurarine was markedly enhanced by papaverine. Inhibition and blockade caused by papaverine were readily abolished by neostigmine. It is concluded, that this curare-like action of papaverine is postsynaptic and non-depolarizing.

Acute anaphylaxis under anaesthesia.

AnaesthesiaVolume 26, Issue 3 p. 363-367 Free Access Acute anaphylaxis under anaesthesia R. P. Holmes, R. P. Holmes R. P. Holmes, FFARCS, Consultant Anaesthetist, Frenchay Hospital, Bristol; J. W. Ross, FDSRCS, Consultant Surgeon, Frenchay Hospital and United Bristol Hospitals; E. R. Williams, MRCP, Senior Registrar, United Bristol Hospitals (present address: Walsgrave Hospital, Coventry).Search for more papers by this authorJ. W. Ross, J. W. Ross R. P. Holmes, FFARCS, Consultant Anaesthetist, Frenchay Hospital, Bristol; J. W. Ross, FDSRCS, Consultant Surgeon, Frenchay Hospital and United Bristol Hospitals; E. R. Williams, MRCP, Senior Registrar, United Bristol Hospitals (present address: Walsgrave Hospital, Coventry).Search for more papers by this authorE. R. Williams, E. R. Williams R. P. Holmes, FFARCS, Consultant Anaesthetist, Frenchay Hospital, Bristol; J. W. Ross, FDSRCS, Consultant Surgeon, Frenchay Hospital and United Bristol Hospitals; E. R. Williams, MRCP, Senior Registrar, United Bristol Hospitals (present address: Walsgrave Hospital, Coventry).Search for more papers by this author R. P. Holmes, R. P. Holmes R. P. Holmes, FFARCS, Consultant Anaesthetist, Frenchay Hospital, Bristol; J. W. Ross, FDSRCS, Consultant Surgeon, Frenchay Hospital and United Bristol Hospitals; E. R. Williams, MRCP, Senior Registrar, United Bristol Hospitals (present address: Walsgrave Hospital, Coventry).Search for more papers by this authorJ. W. Ross, J. W. Ross R. P. Holmes, FFARCS, Consultant Anaesthetist, Frenchay Hospital, Bristol; J. W. Ross, FDSRCS, Consultant Surgeon, Frenchay Hospital and United Bristol Hospitals; E. R. Williams, MRCP, Senior Registrar, United Bristol Hospitals (present address: Walsgrave Hospital, Coventry).Search for more papers by this authorE. R. Williams, E. R. Williams R. P. Holmes, FFARCS, Consultant Anaesthetist, Frenchay Hospital, Bristol; J. W. Ross, FDSRCS, Consultant Surgeon, Frenchay Hospital and United Bristol Hospitals; E. R. Williams, MRCP, Senior Registrar, United Bristol Hospitals (present address: Walsgrave Hospital, Coventry).Search for more papers by this author First published: July 1971 https://doi.org/10.1111/j.1365-2044.1971.tb04797.xCitations: 4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References 1 Dundee, J. W. and Gray, T. C. (1951). Variations in response to relaxant drugs. Lancet, ii, 1015. 2 Lopert, H. (1955). Allergic reaction to gallamine triethiode. Anaesthesia, 10, 76. 3 Walmsley, D. A. (1959). Sensitivity reaction to gallamine triethiodide. Lancet, ii, 237. 4 Hainsworth, A. M. and Bingham, W. (1970). An allergic circulatory collapse following the administration of muscle relaxants. Anaesthesia, 25, 105 5. 5 Anderton, J. M. and Hopton, D. S. (1968). Thiopentone anaphylaxis. A hazard of multiple cystoscopic examinations under general anaesthesia. Anaesthesia, 23, 90. 6 Larard, D. G. (1970). Cardiac arrest following induction with propanidid. British Journal of Anaesthesia, 42, 652. 7 Mushin, W. W., Wien, R., Mason, D. F. J. and Langston, G. T. (1949). Curare-like actions of tri-(diethylaminoethoxy)-benzene triethyliodide. Lancet, i, 726. 8 Idsøe, O., Guthe, T., Willcox, R. R. and DE Weck, A. L. (1968). The nature and extent of penicillin side-reactions with particular reference to fatalities from anaphylactic shock. Bulletin of the World Health Organisation, 38, 159. 9 Welch, H., Lewis, C. N., Weinstein, H. I. and Boeckman, B. B. (1957). Severe reactions to antibiotics: a nationwide survey. Antibiotic Medicine and Clinical Therapy, 4, 800. 10 Krapin, D. (1962). Anaphylaxis with orally administered penicillin. New England Journal of Medicine, 267, 820. 11 Katz, A. M., Battit, G. E. and Wilkey, B. R. (1970). An anaphylactoid reaction to penicillin during anesthesia. Anesthesiology, 32, 84. 12 Cohen, S. B. (1963). Brain damage due to penicillin. Journal of the American Medical Association, 186, 899. 13 Fox, A. M. (1965). Anaphylactoid shock induced by oral penicillin and resulting in Gerstmann's syndrome. British Medical Journal, ii, 206. 14 Westerman, G., Corman, A., Stelos, P. and Nodine, J. H. (1966). Adverse reactions to penicillin. Journal of the American Medical Association, 198, 173. Citing Literature Volume26, Issue3July 1971Pages 363-367 ReferencesRelatedInformation

Actions of some cholinergic antagonists on fast-twitch and slow-twitch skeletal muscle of the cat.

1. The anticholinergic drug N-ethyl-2-pyrrolidylmethylcyclopentylphenyl glycollate (PMCG) has been studied for its effects on the contraction of fast-twitch (flexor hallucis longus, FHL) and slow-twitch (soleus) muscles in the cat.2. In both muscles lower doses (0.25 to 10 mg intra-arterially) potentiated and higher doses (10 mg and above) depressed twitches produced by indirect stimulation. Similar effects were obtained in directly stimulated muscles.3. The effects of the drug on muscles stimulated repetitively were dependent on both dose and frequency of stimulation. Doses which potentiated twitches also potentiated low frequency tetani (5-30 Hz for soleus; 10-50 Hz for FHL). There was a depression and non-maintenance of higher frequency tetani (80 Hz and above for soleus; 150 Hz and above for FHL).4. Both atropine and caramiphen had similar dose dependent potentiating and depressant actions. Hyoscine acted similarly in some cats; in others it had only a depressant action.5. It is suggested that the potentiating actions of PMCG, caramiphen, atropine and hyoscine are due to a direct musculotropic action. The depressant actions resulting from higher doses are due, in part, to a curare-like action and in part to a direct action on the muscle fibres.