Effects of previous curare-immobilization on Pavlovian conditioned heart decelerations in the curarized rat.
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Adaptation, Physiological↗
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The regional curare test in myasthenia gravis.
30 subjects without disturbance of neuromuscular transmission and 18 patients with myasthenia gravis were used in conducting the regional curare test. The adductor pollicis and the hypothenar muscles were studied with the 3/sec stimulation test. With three different dosages of curare one could find no reliable border between "normal" and "pathological". In the patients with myasthenia no definite relation could be found between the findings with the regional curare test and the clinical picture. The curare concentration reaching the muscle is probably quite variable from case to case as regards diffusion and volume in the tissue. The 3/sec stimulation test with registration from the deltoid muscle, and in certain cases the systemic curare test, appear more suitable than the regional curare test for routine diagnosis as well as indication for thymectomy. But for cases of ocular myasthenia showing no further weakness by the systemic curare test, the regional curare test can be put to use. The advantage lies in the higher concentration of curare which can thereby be brought to the muscle. The precautionary measures should be similar to those taken with the systemic curare test.
Adolescent↗
Effect of curare on responses to different putative neurotransmitters in Aplysia neurons.
We have studied the effects of curare on responses resulting from iontophoretic application of several putative neurotransmitters onto Aplysia neurons. These neurons have specific receptors for acetylcholine (ACh), dopamine, octopamine, phenylethanolamine, histamine, gamma-aminobutyric acid (GABA), aspartic acid, and glutamic acid. Each of these substances may on different specific neurons elicit at least three types of response, caused by a fast depolarizing Na+, a fast hyperpolarizing Cl-, or a slow hyperpolarizing K+ conductance increase. All responses resulting from either Na+ or Cl- conductance increases, irrespective of which putative transmitter activated the response, were sensitive to curare. Most were totally blocked by less than or equal to 10-4 M curare. GABA responses were less sensitive and were often only depressed by 10-3 M curare. K+ conductance responses, irrespective of the transmitter, were not curare sensitive. These results are consistent with a model of receptor organization in which one neurotransmitter receptor may be associated with any of at least three ionophores, mediating conductance increase responses to Na+, Cl-, and K+, respectively. In Aplysia nervous tissue, curare appears not to be a specific antagonist for the nicotinic ACh receptor, but rather to be a specific blocking agent for a class of receptor-activated Na+ and Cl- responses.
Acetylcholine↗
Presynaptic action of curare.
1. As a result of a conditioning phrenic nerve stimulus, end-plate currents (e.p.c.s) in a voltage clamped uncurarized cut diaphragm show a facilitation which reaches its maximum at 30-40 msec and subsequently decays with a time constant from 150 to 200 msec. In curarized (cut or uncut) diaphragms, however, the conditioning stimulus causes a depression which reaches its maximal value at 10 msec and then decays slowly with a time constant of about 3 sec. This indicates that curare strongly interferes with the process of transmitter release. 2. The presynaptic action of curare is also evident if short tetanic trains are given. In uncurarized preparations e.p.c.s decay in size much more slowly than in curarized preparations, and usually show a transient facilitation. 3. These results can be explained in terms of a model where curare blocks presynaptic depolarizing action of ACh. As a result of this presumed curare action a small increase in Ca permeability and subsequent entry of Ca associated with depolarization are also blocked, and the facilitation resulting from that entry of Ca is abolished.
Animals↗
Study of sensitivity to curare in certain neurological disorders using a regional technique.
A regional technique for the study of curare sensitivity has been applied to patients with Duchenne type muscular dystrophy, myotonic disorders, certain lower motor neurone disorders, to patients with weakness in the arm after hemiplegia, to patients with hyper-reflexia and hypertonia without weakness, and to Parkinsonism. In the dystrophy patients, sensitivity to curare differs from normal controls in that the neuromuscular block persists. The possibilities that this latent defect of neuromuscular transmission is the result of acetylcholine deficiency due to a prejunctional defect or the result of alterations in the property of the postjunctional membrane are discussed. In the myotonic and lower motor neurone disorders, curare sensitivity was similar to that of normal controls. After hemiplegia, the affected side shows resistance to curare when compared with the unaffected side. In states of hyper-reflexia and hypertonia, however, the sensitivity to curare is greater than in normal controls. In Parkinsonism, sensitivity is similar to that of the controls. The results in upper motor neurone lesions are discussed in relation to the dependence of neuromuscular transmission upon the motor neurone, which, in turn, is dependent upon descending impulses.
Action Potentials↗
[Variations in the activity of various curarizing substances as a function of the time of administration].
This experiment was carried out upon the male-adulte-AF SPF-Wister Rat, anesthetized by the use of pentobarbital-Na at the only dosage of 40 mg/kg/IP and put under artificial ventilation. The animals were divided into two groups: Group I, "diurnal animals" curarized between 10 a.m and 4 p.m; Group 2, "nocturnal animals" curarized between 9 and 12 p.m. Four drugs of the curarimimetic (pachycurare, non-depolarizing) type: gallamine, D-tubocurarine, pancuronium and AH-8165 were studied at doses presenting the same activity. The total curarizing effect measured by the surface defined by the curve of curarization within ten mns was constantly and significantly lowered in "nocturnal animals": a 25 p. 100 diminution with gallamine, 20 p. 100 diminution with D-tubocurarine, 27 p. 100 diminution with pancuronium, 19 p. 100 diminution with AH-8165. The hypothesis is that this diminution in the action of curarizing substances may be, to a great extent, in keeping with the rise of their metabolism -- the hepatic enzymatic activity being, in the rat, a nocturnal animal, definitely increased during the night.
Animals↗
Quantitative analysis of d-tubocurarine chloride in curare by column liquid chromatography.
An improved quantitative analysis of d-tubocurarine chloride in the plant extract curare is presented. Gradient high-performance liquid chromatography on a hydrophobic stationary phase was found to be very suitable for the analysis of quaternary ammonium bases such as the complex mixture of curare alkaloids. Owing to the residual free silanol groups on the modified silica surface, the curare alkaloids are eluted from a reversed-phase column only if an electrolyte is added to the mobile phase. In order to optimize the separation, the effects of pH, the nature of the cation in the buffer and the concentration of the buffer of the retention of the alkaloids were investigated. Using a tetramethylammonium phosphate buffer at pH 4 in a gradient of water-methanol, undesirable retardation effects on the reversed-phase column could be suppressed sufficiently. As a result, an accurate method for the determination of d-tubocurarine chloride in curare was obtained. The coefficient of variation of this analysis is only 1.3%.
Chromatography, High Pressure Liquid↗
Electrophysiologic diagnosis of myasthenia gravis and the regional curare test.
Two hundred and fifty consecutive patients were evaluated for myasthenia gravis with repetitive supramaximal stimulation of peripheral nerves and regional curare administration when necessary. Among patients with definite generalized myasthenia gravis, 72 percent had abnormal responses to repetitive supramaximal stimulation alone and another 17 percent had abnormal responses after regional curare administration. Among those with possible generalized myasthenia gravis, 15 percent had abnormal responses to repetitive supramaximal stimulation and another 12 percent had abnormal responses after regional curare administration. Of those with only ocular symptoms, 46 percent had abnormal responses to repetitive supramaximal stimulation before or after regional curare administration, suggesting generalized involvement. Myasthenia gravis has not developed subsequently in any of the equivocal patients with negative electric tests. We have found these electric procedures to be simple, safe, and at least as effective as other methods in diagnosing myasthenia gravis.
Curare↗
Changes in motor commands, as shown by changes in perceived heaviness, during partial curarization and peripheral anaesthesia in man.
1. The centrally generated ;effort' or direct voluntary command to motoneurones required to lift a weight was studied using a simple weight-matching task when the muscles lifting a reference weight were weakened. This centrally generated input to motoneurones was increased when the lifting muscles were partially paralysed with curare or decamethonium as judged by the increased perceived heaviness of a reference weight lifted by the weakened muscles.2. If subjects were asked simply to make matching isometric contractions when the lifting muscles were weakened the isometric tension produced by a weakened muscle was over-estimated.3. When subjects matched weights by flexing the distal joint of the thumb the perceived heaviness of a reference weight during a control partial curarization was compared with its perceived heaviness during a similar partial curarization when the thumb was also anaesthetized. At any level of maximal strength during curarization the perceived heaviness (which reflects the motor command to lifting motoneurones) was increased when the thumb was anaesthetized.4. This increased voluntary command to lifting motoneurones may be required because automatic reflex assistance provided by apparent servo action from the long flexor of the thumb is suppressed by anaesthesia of the thumb (Marsden, Merton & Morton, 1971, 1973, 1976a; Dyhre-Poulsen & Djørup, 1976).
Anesthesia, Local↗
A new regional curare test of the elbow flexors in myasthenia gravis.
Electrical and mechanical responses of the elbow flexors (EFs) and the adductor pollicis muscle (ADP) were evoked in 31 patients with myasthenia gravis (MG). Thirteen patients with moderate or severe involvement showed a decrement during trains of repetitive stimuli in both muscle types, greater in the proximal ones than in the distal one. Seven of 18 patients with mild generalized or ocular MG showed abnormalities in the EFs, and 4 patients showed abnormalities in the ADP. A regional curare test was performed in the EFs of 11 patients with borderline or no abnormalities in the EFs and the ADP. All patients were more sensitive to curare than were control subjects; in 2, a decrement outside the range of controls could only be provoked in the partly curarized muscle during posttetanic exhaustion. Excitation-contraction coupling, as evidenced by the staircase phenomenon and after correction for blackade of fibers, was abnormal in 5 of 31 patients in the EFs, and in 11 patients in the ADP. In both muscles, the action potential was a more sensitive criterion of abnormality than the mechanical response. The decrement in the action potentials during 3/sec stimuli gave the largest diagnostic yield.
Action Potentials↗
Curare has a voltage-dependent blocking action on the glutamate synapse.
The skeletal muscle of members of Orthoptera and Diptera receives an innervation which is probably glutaminergic. Recent study of the ventral muscle fibres in the larvae of the beetle, Tenebrio molitor, has revealed that the transmitter action can be mimicked by the iontophoretic application of L-glutamate to the junctional sites at which the extracellular excitatory postsynaptic potentials (e.p.s.ps) could be recorded (D.Y. and H.W., unpublished observation). Contrary to the evidence favouring glutamate as a transmitter of junctional excitation in insects, some investigators have found that curare (+)tubocrarine, TC), a classic acetylcholine (ACh) antagonist, suppresses the neurally evoked muscle potentials in the fly Sacophaga, and Tenebrio. Here, we have analysed the action of curare on the neuromuscular junction of Tenebrio larvae and found that curare blocked the glutaminergic transmission by antagonising the transmitter at the postsynaptic site.
Action Potentials↗
A re-examination of curare action at the motor endplate.
Recent evidence indicates that curare, in addition to its competitive' interference with endplate receptors, can block open ionic channels by a 'non-competitive' action on the activated acetylcholine-receptor complex. These findings called for further study of the kinetic behaviour of endplate channels and their modification by curare. Examining impulse-evoked endplate currents and acetylcholine-induced current fluctuations, it is found that the lifetime of the open channel is shortened by relatively high concentrations of curare (greater than 5 micrometer), an effect which shows up most strikingly at hyperpolarized levels of membrane potential (-130 mV and above). No shortening of this kind is observed when a neuromuscular block of equal or greater intensity is produced by a dose of alpha-bungarotoxin. Two other neuromuscular blocking agents, gallamine and pancuronium are shown to have an action on channel kinetics which cannot be explained by competitive receptor binding, but conforms to the hypothesis of rapidly repeated blocking and unblocking of individual ion channels, which had been proposed originally to account for the endplate action of local anaesthetics.
Acetylcholine↗
[Comparative study of the neuromuscular effects of 3 curare-like agents in children].
The authors studied the effect of three curare-like agents in 92 children anesthetised with halothane (1 to 2 p. 100). The method used was to give increasing doses of d-tubocurarine, metocurine and pancuronium bromide by injection until a block of approximately 95 p. 100 of the contraction of the thumb was obtained. This was checked by electrostimulation. Each of the three groups of children who were treated with one of the three curare-like agents were subdivided according to age and dose-response curves were obtained. The time required to recover 10 and 25 p. 100 of a control contraction was also studied. The authors conclude that from the point-of-view of activity, metocurine and pancuronium are respectively twice and five times more powerful than d-tubocurarine. The recovery time for pancuronium is twice as short as that for metocurine and d-tubocurarine. Furthermore, even though they are more resistant than adults, children recover more quickly than them. There is no difference in sensitivity in children that could be related to age, and this was so in the three curare-like agents studied. However, individual differences were more marked in neo-natal infants of less than 10 days than in other groups.
Age Factors↗
[The second electromyographic study of surgical curarization with AH.8165, a new pachycurare derivative of azobis-arylimidazo(1-2a) pyridinium].
This second electromyographic study of AH-8165, a product derived from azobis-arymilidazo-(1-2a) pyridinium, carried out with a special apparatus which both stimulates and records, specifies the characteristics of the neuro-muscular block induced by this new non-depolarizing type curarizing substance while taking into account the usual factors of the curarimimetic variability of action. After an initial dose of 1 mg per kg of bodyweight, we notice particularly: -the lapse of time required for a complete block (90 s), its intensity and duration (normally total during at least one hour) -the morphology of the electromyogram during the curarization and the decurarization either spontaneous or induced by Neostigmin with in particular -the muscular fatigability after repeated stimulation following curarization and chiefly during decurarization, chronological data und electro-myographic aspects which are found as well after a reinjection of AH-8165 equivalent to the half of the previous one.
Action Potentials↗
The regional curare test and electrophysiologic diagnosis of myasthenia gravis: further studies.
Five hundred consecutive patients were evaluated for myasthenia gravis with repetitive stimulation of the median and ulnar nerves. Axillary nerve stimulation and repeated stimulation of wrist nerves following regional curare administration to the hand were performed when necessary. Abnormal responses were seen in 95% of 297 patients with generalized disease and in 35% of 54 patients with ocular disease, all of whom were clinically responsive to anticholinesterases. Identical responses were also seen in 32% of 124 patients with possible generalized disease, all of whom lacked clinical responsiveness to anticholinesterases. Abnormalities occurred following regional curare administration in 29% of 224 patients with normal responses during repetitive stimulation alone. This program for evaluating patients with suspected myasthenia gravis continues to be successful, safe, and practical.
Curare↗
Activation of membrane Na+/K+-ATPase of mouse skeletal muscle by acetylcholine and its inhibition by alpha-bungarotoxin, curare and atropine.
The effect of acetylcholine and of three cholinolytic compounds (alpha-bungarotoxin, curare and atropine) on electrogenic Na+/K+ pump and activity of the membrane Na+/K+-ATPase of mouse skeletal muscles was studied. It was found that acetylcholine potentiated both the muscle electrogenic ionic pump and the Na+/K+-ATPase activity of crude membrane fractions. The cholinolytic drugs had inhibitory effects on both parameters, with the exception of curare which was ineffective in blocking the electrogenic ionic pump.
Acetylcholine↗
Membrane surface potential changes may alter drug interactions: an example, acetylcholine and curare.
Curare is known to be less effective as an acetycholine antagonist when the divalent cation concentration of the extracellular solution is increased. This observation can be accounted for by the negative surface potential on the end plate; an increase in divalent cation concentration decreases the negativity of the surface potential and thereby lowers the concentrations of cations at the membrane-solution interface. The concentration of divalent cations, such as curare, will be reduced more than the concentration of univalent cations, such as acetylcholine. The observations can be accounted for by a surface potential of about -50 millivolts. The same principle can explain the reported actions of divalent cations on the affinity of receptors for acetylcholine. The effects of surface potential on concentrations at active sites may play an important role in drug interactions.
Acetylcholine↗
Audiogenic seizures in curarized mice.
Previous experiments have indicated that interference with somatosensory feedback from convulsive movements may lessen the severity of audiogenic seizures in susceptible rodents. For further investigation of this phenomenon, mice were partially immobilized with tubocurarine chloride to attenuate convulsive movements and somatosensory input associated with such movements. In Experiment 1, seizures of mice injected with .15 mg/kg were evaluated behaviorally and compared with seizures of saline-injected litter-mates. The likelihood of clonic-tonic seizures in curarized mice was as high as that of control mice, although convulsive movements were somewhat less violent and seizure fatalities were markedly reduced. In Experiment 2, seizures of mice given .25 mg/kg were evaluated with electroencephalography, and records were compared with those of controls. Despite the near absence of behavioral signs of convulsions, electroencephalograms of curarized mice showed that audiogenic seizures readily occurred. The findings suggest that audiogenic seizures are centrally "programmed" and do not require feedback from convulsive movements. However, it may be possible to disrupt the central "program" by introducing appropriate somatosensory input not normally encountered during audiogenic seizures.
Acoustic Stimulation↗