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At least 19 recordsLinked to original sources
PubMed1989

Curare binding and the curare-induced subconductance state of the acetylcholine receptor channel.

The curare-induced subconductance state of the nicotinic acetylcholine receptor (AChR) of mouse skeletal muscle was examined using the patch-clamp technique. Two mechanisms for the generation of subconductance states were considered. One of these mechanisms entails allosteric induction of a distinct channel conformation through the binding of curare to the agonist binding site. The other mechanism entails the binding of curare to a different site on the protein. Occupation of this site would then limit the flow of ions through the channel. The voltage dependence and concentration dependence of subconductance state kinetics are consistent with curare binding to a site within the channel. The first order rate constant for binding is 1.2 X 10(6) M-1s-1 at 0 mV, and increases e-fold per 118 mV of membrane hyperpolarization. The rate of curare dissociation from this site is 1.9 X 10(2)s-1 at 0 mV, and decreases e-fold per 95 mV hyperpolarization. The equilibrium constant is 1.4 X 10(-4) M at 0 mV, and decreases e-fold per 55 mV hyperpolarization. This voltage dependence suggests that the fraction of the transmembrane potential traversed by curare in binding to this site is 0.46 or 0.23, depending on whether one assumes that one or both charges of curare sense the electric field. Successive reduction and alkylation of the AChR agonist binding sites with dithiothreitol (DTT) and N-ethyl maleimide (NEM), a treatment which results in the loss of responsiveness of the AChR to agonists, produced no change in curare-induced subconductance events, despite the fact that after this treatment most of the channel openings occurred spontaneously. Mixtures of high concentrations of carbamylcholine (CCh) with a low concentration of curare, which produce channel openings gated predominantly by CCH, resulted in subconductance state kinetics similar to those seen in curare alone at the same concentration. Thus displacement by CCh of curare from the agonist binding sites does not prevent curare from inducing subconductances. The results presented here support the hypothesis that curare induces subconductance states by binding to a site on the receptor other than the agonist binding sites, possibly within the channel pore. It is the occupation of this site by curare that limits the flow of ions through an otherwise fully opened channel.

Animals↗
PubMed1977

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↗
PubMed1992

[Curare and its successors. A 50-year's evolution].

The introduction of curare into clinical anaesthesia by Griffith and Johnson in 1942 contributed to the termination of the era where anaesthesia was a reversible intoxication rather than the result of controlled drug action. Curare allowed general anaesthesia to be reduced to a lighter level, thereby conferring a significant safety factor to the patient. Both the shortage in supply of crude curare and its variable composition led the search for synthetic curare analogues conferring well defined pharmacodynamic and pharmacokinetic properties. Based on the chemical structure of tubocurarine which has been known since 1935 the efforts concentrated on bisquaternary ammonium compounds. Gallamine was the only synthetic curare analogue to contain three quaternary ammonium groups. This drug had significant undesired vagolytic effects. In 1951 succinylbischoline appeared to be the ideal muscle relaxant, particularly with respect to its fast onset and short duration of action. The disadvantages of its depolarising mechanism of action which were appreciated during the years to follow prevented the concept of depolarising neuromuscular blockade to be pursued further. With other muscle relaxants, including curare itself, histamine release, vagal blockade and ganglionic blockade were undesired effects to be eliminated in future compounds. Improved understanding of structure-activity relationships turned out to be an indispensable tool for future research. This in turn required more elaborate methods in chemical analysis, in electrophysiology of the motor endplate, and in ultrastructural research. As a result, alcuronium and pancuronium became available in the late sixties and early seventies. Both muscle relaxants had a non-depolarising mechanism of action with reduced side effects relative to curare. From now on better techniques for pharmacodynamic and pharmacokinetic research became available resulting in research activity with particular emphasis in this field. Researchers became aware that new muscle relaxants should be designed for larger volumes of distribution and more rapid biodegradation than those currently available. Concurrently, anaesthesia techniques had changed in a way to use intubation and mechanical ventilation as a routine procedure. The risk of intraoperative hypoventilation and hypoxemia was eliminated, yet, due to the lack of adequate monitoring techniques the slow recovery from curare, alcuronium or pancuronium neuromuscular blockade was hardly appreciated.(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthesiology↗
PubMed1975

The effect of curare on the release of acetylcholine from mammalian motor nerve terminals and an estimate of quantum content.

Curarized and non-curarized rat hemidiaphragm muscles were indirectly stimulated in vitro. 2. The fluid bathing the active curarized muscles was eluted through a dextran gel (Sephadex G-10), effecting a complete separation of ACh from curare. The acetylcholine fraction was then assayed on an isometric leech muscle preparation. 3. Prostaglandin (PGE1) in a concentration fifteen times that estimated to be released from the skeletal muscle preparation did not affect the response of leech muscle to ACh. 4. The amount of ACh released by curarized muscles (4-9 X 10(-18) mole/impulse-junction) was not significantly different from that released by non-curarized muscles (4-6 X 10(-18) mole/impulse-junction). These quantities are similar to those obtained by previous workers. It is concluded that curare in a paralytic dose does not affect the output of ACh from motor nerve terminals stimulated at low frequencies. 5. Spontaneous release of ACh from non-curarized muscles was estimated at 0-45-0-65 p-mole/min. hemidiaphragm. It is calculated that only 2% of this amount could give rise to post-synaptic electrical events, the remainder having a non-synaptic source. 6. The number of molecules of 'quantal' ACh released by stimulated muscle is calculated as 2-5 X 10(6)/impulse-junction, taking account of the non-synaptic release. The number of ACh molecules in one quantum was estimated to be 6250, an amount that could be easily accommodated in one synaptic vesicle.

Acetylcholine↗
PubMed1989

Activation by curare of acetylcholine receptor channels in a murine skeletal muscle cell line.

Curare action on nicotinic acetylcholine receptors has a number of facets, of which the best known is competitive antagonism. Here we describe the weak agonist action of 10(-5) M curare on the murine skeletal muscle cell line, G8. Although curare induces no depolarization in G8 cells, single-channel recordings reveal short-lived curare-induced currents. A feature of these brief events is the multiplicity of conductance levels (of the four levels with conductances of 48, 37, 14, and 6 pS, none had a lifetime greater than 1.5 ms). Most well-resolved events (about 17% of which are to a subconductance) last less than 0.5 ms, with activation occurring predominantly as isolated events rather than in bursts. Agonism is not, however, a high probability action for curare: calculations based on the frequency of events at half-saturating conditions suggest that curare-induced channel openings occur during less than 1% of acetylcholine receptor-curare binding episodes. The outcome is (a) an agonist action too feeble to perturb the membrane voltage and (b) a powerful competitive antagonist action.

Animals↗
PubMed1977

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↗
PubMed1987

The cerebrovascular effects of curare and histamine in the rat.

The effects of histamine and curare on cerebral blood flow (CBF) were measured in rats with an intact blood-brain barrier (BBB) and in rats in which the BBB was disrupted by hypertonic urea. Using radioactive microspheres cortical and subcortical CBF were measured in paralyzed ventilated rats anesthetized with 70% N2O, 30% oxygen. Blood gas tensions were controlled by mechanical ventilation. In rats with an intact BBB, neither histamine infusion (10 micrograms X kg-1 X min-1) nor curare (1 and 5 mg/kg) increased CBF. Twenty minutes after the BBB was disrupted by 2 M urea, histamine (10 micrograms X kg-1 X min-1) produced an increase in cortical (180-210 ml X 100 g-1 X min-1) and subcortical CBF (103 to 124 ml X 10 g-1 X min-1). Twenty minutes after BBB disruption, curare also produced a significant increase in cortical CBF (1 mg/kg: 176-201 ml X 100 g-1 X min-1, 5 mg/kg: 190-209 ml X 100 g-1 X min-1). The increases in CBF produced by curare were completely blocked by pretreatment with 30 mg/kg cimetidine, a histamine H2 receptor antagonist, 3 min before curare. The results indicate that curare may produce cerebrovasodilation and increases in CBF by release of histamine and stimulation of central nervous system H2 receptors. These effects occur only when the BBB is disrupted and circulating histamine has access to brain perivascular tissue.

Animals↗
PubMed1971

Does curare affect transmitter release?

1. The effect of curare on the amount of transmitter released by a nerve stimulus was studied in frog and rat nerve-muscle preparations using electrophysiological techniques.2. When the frog sartorius nerve-muscle preparation was exposed to low doses of curare, the amplitudes of spontaneous miniature end-plate potentials and end-plate currents (e.p.c.s, measured under ;voltage clamp' conditions) were reduced to the same extent, suggesting that the drug did not alter the number of transmitter quanta released by nerve stimulation.3. With higher doses of curare in frog muscle treated with glycerol to abolish twitching, quantum content was estimated from the coefficient of variation (CV) of e.p.c.s. The measured CV increased slightly in curare; this increase probably resulted from a relatively greater contribution of random noise to the observed fluctuations when the e.p.c. was reduced by curare.4. In the rat diaphragm, muscle fibres were cut to block twitching. This procedure produced, among other changes, a reduction in the muscle fibre space constant, so that junctional signals were distorted by the cable properties of the muscle fibre when, as often occurred, micro-electrodes were more than 100-200 mu from the end-plate focus. This produced errors in estimates of quantum content; when these errors were accounted for, it appeared that curare did not significantly alter quantum content.5. It is concluded that if curare affects transmitter release at all, its effect must be much smaller than its well known post-synaptic blocking action.

Animals↗
PubMed1979

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↗
PubMed1987

Muscle blood flow and fiber activity in partially curarized rats during exercise.

We previously reported that low doses of d-tubocurarine attenuated glycogen loss in red muscles of rats during treadmill walking but that the initial hyperemia in the muscles was normal. The present studies were performed to 1) determine with electromyography (EMG) whether red muscle fiber activity is reduced in walking, curarized rats and 2) study muscle blood flow and glycogen loss during running with different doses of curare (dose response). At 0.5 min of treadmill walking (15 m/min), integrated EMG in vastus intermedius (VI) muscle was reduced by an average of 18% in curarized (60 micrograms/kg) rats, although blood flow (measured with microspheres) was the same as in saline control rats. Comparison of blood flows and glycogen loss in quadriceps muscles at 1 min of treadmill running (30 m/min) with different curare doses (20-60 micrograms/kg) demonstrated that red muscle glycogen loss was inversely related to curare dose but that blood flows in the same muscles were unaffected by curare. These findings provide support for our previous conclusion that at the initiation of low to moderate treadmill exercise, red muscle blood flow is not proportional to the activity or metabolism of the muscle fibers.

Animals↗
PubMed1975

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↗
PubMed1985

Muscle blood flow patterns during exercise in partially curarized rats.

We studied the distribution of blood flow within and among muscles of partially curarized (40-100 micrograms/kg body wt) rats during preexercise and at 1 min of low-speed treadmill exercise (15 m/min). Glycogen loss in the deep red muscles and parts of muscles was significantly reduced in the curarized animals during exercise, indicating the fibers in these muscles were recruited to a lesser extent and/or had lower metabolisms than fibers in the same muscles of control rats. However, elevations in blood flow in the red muscles of the curarized rats were as great or greater than those in the control rats. Thus reduced recruitment and/or metabolism of the deep red muscle fibers of the curarized animals was not accompanied by reduced blood flow. These findings suggest a dissociation between red fiber metabolism and blood flow in the curarized rats during the 1st min of slow treadmill exercise and indicate that release of vasodilator substances or local physical factors associated with muscle fiber activity are not solely responsible for the initial hyperemia during exercise.

Animals↗
PubMed1975

[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↗
PubMed1992

War and hunting poisons of the New World. Part 1. Notes on the early history of curare.

The history to about 1850 of the muscle-relaxant poison curare is discussed, especially the developments leading to the botanical identification of the plants that yield the alkaloidal active principles: Loganiaceae (Strychnos species) and Menispermaceae (Abuta, Chondrodendron, and Curarea species). One of the earliest encounters with the poison appears to have been during the exploration of the Lake Maracaibo region in Colombia by Alonso Pérez de Tolosa in 1548. It is pointed out (yet again) that Sir Walter Ralegh did not bring back the poison to Europe in 1595 and that it was Keymis who first came across the word ourari when exploring the lower reaches of the Orinoco in 1596. Gumilla, La Condamine, Ulloa, Veigl, and others gave much additional information about the poison during the 18th century. Scientific studies began in the latter part of the century when Schreber listed the botanical identities of four of the plant components entering into the curare prepared by the Akawai Indians of Surinam. As far as is known, none of these people actually saw curare being made. Thereafter, progress was rapid. Humboldt and Bonpland were the first trained scientists to witness the preparation of the poison, at the very beginning of the 19th century. Subsequent exploration by Martius and Spix, Poeppig, Youd, the Schomburgk brothers, De Castelnau and Deville, Spruce, and others, up to the middle of the century, extended and deepened botanical and ethnological knowledge of curare. Study of its physiology started at about that time with the classical experiments of Rudolf von Koelliker and Claude Bernard.

Curare↗