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PubMed1979

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↗

PubMed1975

A comparison of memory under three methods of anaesthesia with nitrous oxide and curare.

Sixty-three volunteer patients participated in an investigation disigned to evaluate memory of the surgical experinece with three different methods of balanced nitrous oxide-curare anaesthesia. Two of the methods (Liverpool and Roosevelt protocols) used thiopentone for induction but did not utilize any neuroleptic drug, while the third (Diazepam protocol) used the tranquilizer diazepam in combination with morphine for both premedication and induction. In general, the results suggest that all three variations are successful in producing anaesthesia and that patients have no recall of the major portion of the surgical procedure. The major differences among the groups were exhibited in the post-operative periods. These findings suggest that diazepam affects the emotional quality associated with memory and thus aids the patients by reducing both the incidence of noxious psychological reactions and the possibility of severe emotional trauma. Finally, the findings also suggest the importance of using a narcotic analgesic as part of nitrous oxide-curare anaesthesia.

Adjuvants, Anesthesia↗

PubMed1979

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↗

PubMed1975

Regional curare test in evaluation of ocular myasthenia.

In 7 of 14 patients with clinically restricted ocular myasthenia gravis, the regional curare test showed latent peripheral involvement. The test consisted of the intravenous administration of 0.2 mg d-tubocurarine into an ischemic arm followed by repetitive supramaximal percutaneous electrical stimulation of the median or ulnar nerves. This produced a decrease in the amplitude of the initial evoked potential and a decrement of greater than 10% in the amplitude of the succeeding three to five potentials at rates of 3, 5, or 15 stimuli/sec. Three patients underwent transcervical thymectomy with subsequent improvement in both electrical and clinical findings. Evaluation of all patients with ocular myasthenia gravis should include regional curare testing of clinically uninvolved peripheral nerves. Thymectomy should be considered for patients with abnormal results.

Adult↗

PubMed1977

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↗

PubMed1975

Regional curare for the reduction of the safety factor in human motor end-plates studied with single fibre electromyography.

A method employing six minutes of regional curarization with 0.5 mg D-tubocurarine and single fibre electromyographic measurements (SFEMG) was used in order to study the effect of an additional small dose of D-tubocurarine. The effect of the additional dose was most pronounced in terms of increased jitter, on motor end-plates with the initially highest jitter. The combination of regional curarization and SFEMG jitter recordings offers a sensitive technique for detecting mild effects of various drugs on neuromuscular transmission not detectable with decrement investigations.

Action Potentials↗

PubMed1977

Critical assessment of the local curare test in myasthenia gravis.

In a group of 60 patients of which 30 were affected by myasthenia, we used the regional curare test. The results were evaluated from a critical point of view and were then compared with the results obtained by the repetitive stimulation of the circumflex nerve, deriving from deltoid muscle. We considered too the specificity of the regional curare test for the evaluation of ocular myasthenia.

Action Potentials↗

PubMed1975

[The effect of 1-adamantyl radicals on curare-like activity].

In the series of polymethylene bis-ammonium salts R(CH3)2N(CH2)NN(CH3)2R . 2I--(R=CH3 or Ad) a study was made of the significance of hydrophobic 1-adamantyle radicals (1--Ad) for curare-like activity. Administration of 1-ad radicals into the cation groups of depolarizing agents (n-9--11) altered their mechanism of action and diminished their activity. Attachmeni of 1-Ad radicals to the both quarternary nitrogen atoms of the antidepolarizing agents (n=5 and 6) sharply increased their curare-like activity. The data obtained pointed to the presence of hydrophobic zones in the cholinoreceptors of skeletal muscles.

Adamantane↗

PubMed1979

[Modification of curarization after acute administration of 2 antiepileptic drugs].

In rats anaesthetised with sodium pentobarbital the previous administration of a single dose of an anti-epileptic agent (carbamazepine or sodium valproate) significantly increases the curarising action of two short-action curare-like agents--pancuronium bromide and fazadinium bromide. It seems that this potentialisation of curare action might be the result of either a pharmacokinetic interference (competion for plasma protisen receptor sites), or due to a summation of depressor actions at the neuromuscular level, especially through changes in the levels of GABA and/or cAMP.

Animals↗

PubMedDate not supplied

[Myotonic seizures; the action of curare or related compounds on myotonia (author's transl)].

Myotonic seizures with apnea are alarming but temporary incidents occurring during curaization of a myotonic patient. Experience with regional curaization in myotonia shows that it is induced only by suxamethonium and it is only an exaggeration of the fasciculations produced by this compound. In contrast, however, competitive curare compounds have no effect on myotonia. The myotonic seizure, which is specific to myotonia, is radically different from the other respiratory accidents common to muscular dystrophies.

Adolescent↗

PubMed1978

O2 uptake and developed tension during and after fatigue, curare block, and ischemia.

The purpose of this study was to investigate the effect of changes in developed tension on the ratio between O2 uptake and isometric developed tension in the in situ dog gastrocnemius-plantaris muscle group. O2 uptake and isometric developed tension of the muscle were measured during contractions at 1 twitch/s before and after fatigue with both single and twin impulses (6.5 V, 0.2-ms duration; the twins were separated by 10--20 ms). Twin impulses prior to fatigue raised developed tension to two times the tension developed with single impulses. Fatigue was obtained by stimulation at 10--20 impulses/s for 30--40 min. Twin impulses after fatigue returned developed tension to the level of single impulses before fatigue. O2 uptake and developed tension were also measured during the slower development of fatigue produced by continuous stimulation (3, 4, 5, and 6 impulses/s) as well as during "fatigue" induced by partial neuromuscular block with curare or ischemia. In all cases, there was no change in the O2 uptake per unit of tension developed, indicating a constant coupling between O2 uptake and developed tension.

Animals↗

PubMed1978

Hofmann elimination with diazomethane on curare bases and selected quaternary tetrahydroisoquinoline alkaloids.

Use of a large excess of alkali-free diazomethane resulted in a Hofmann elimination with selected curare bases and some other quaternary tetrahydroisoquinoline alkaloids. (+)-Tubocurarine chloride provided a monostilbene methine, O,O-dimethyltubocurinemethine, and a monostilbene--monostyrene compound, O,O-dimethyltubocurinedimethine. The major elimination products of (+)-isotubocurarine chloride and (+)-carnegine methiodide were monostyrene methines, O,O-dimethyltubocurineisomethine and carneginemethine, respectively. Treatment of (+)-laudanosine methiodide with potassium hydroxide, under the conditions of Hofmann degradation, or alkali-free diazomethane solution provided the same stilbene compound, laudanosinemethine. The structures of the elimination compounds were further confirmed by catalytic reduction and quaternization with methyl iodide.

Alkaloids↗

PubMed1976

Hypothalamic chemostimulation and autonomic changes in curarized rats.

Rats previously implanted with chronic double walled cannulae aimed at the lateral hypothalamic area (LHA) ate and drank reliably after minute injections of norepinephrine and carbachol respectively. Later on the rats were curarized and artificially respirated. After an habituation period during which rectal temperature, cardiac rate and peripheral vasomotor activity were continuously recorded, half of the subjects were injected with 1 mul of norepinephrine (40 x 10(-9) moles) and the other half with 1 mul of carbachol (2.4 x 10(-9)moles). Both drugs elicited hypothermia, bradycardia and vasodilatation. Bradycardia after carbachol was significantly greater than after norepinephrine and hypothermia and vasodilatation after norepinephrine were significantly greater than after carbachol. When the treatments were reversed essentially the same effects were observed.

Animals↗

PubMed1978

Origin of the neocortically monitored theta rhythm in the curarized rat.

An array of epidural electrodes was acutely implanted in locally anesthetized, curarized rats in order to map the surface distribution of rhythmic slow activity (RSA) which appears within the neocortex. Peak amplitudes (of about 122 muV) were centered over the dorsal hippocampus outline. A laminar profile of RSA recorded within the neocortex indicated no shifts in phase relative to a homotopic, epidural electrode. RSA increased slightly in amplitude (mean increase = 53%) at the deepest level or neocortex, but it did not approximate an amplitude peak or null within the neocortex. Multiple-unit activities within the neocortex were not phase-locked to RSA. On the other hand, all of these manifestations of an RSA generator were observed as electrodes passed into the dorsal hippocampus. A unilateral cortical spreading depression (CSD) treatment, which markedly attenuated barbiturate spindles in all subjects (N = 10), usually (N = 7 of 10) had no effect on the neocortically monitored RSA. Dissociations between depressed and non-depressed hemispheres, and between neocortical and hippocampal RSA, were obtained in some subjects during CSD. However, concurrent dissociations were also apparent between recording sites within the hippocampus. It is concluded that the neocortical RSA of rats is passively spread from the underlying hippocampus, and dissociations in neocortical and hippocampal RSA in the rat are secondary to changes in the organization of multiple generators of hippocampal RSA.

Animals↗

PubMed1976

Peripheral heat as a reward for heart rate response in the curarized rat.

It is generally assumed that the mechanical perception of shivering is necessary for the perception of cold discomfort. Shivering of rats in a cool environment was eliminated by curarization. The rats were kept alive by artificial respiration. Heart rate was proportional to rectal temperature in a group of controls. One group of rats was conditioned to increase heart rate to trigger an infrared lamp; another group was conditioned to decrease heart rate to obtain heat. When compared with the results of the control group without infrared heat reward, the results obtained from the two heart-rate-modifying groups show that shivering is not a necessary signal to determine thermoregulatory behavior in rats and, presumably, cold discomfort in man.

Animals↗

PubMed1975

Evaluation of RX 72601 as an anti-curare agent.

RX 72601, a new and potent anticholinesterase, has been evaluated for its ability to reverse the neuromuscular blockade induced by non-depolarizing muscle relaxants. In rats RX 72601 10 mug/kg i.v. proved effective in reversing the effects of alcuronium gallamine, pancuronium or tubocurarine and the drug exhibited a wide margin of safety. RX 72601 proved equally effective in reversing the effects of tubocurarine in both cats and baboons. In dogs and cats, effective anti-curare doses had little action on the cardiovascular or respiratory systems. Overall the results obtained indicate that RX 72601 may be a safe antagonist of non-depolarizing muscle relaxants and that it will be possible to use RX 72601 without prior administration of atropine.

Animals↗

PubMed1975

Interaction of competitive antagonists: the anti-curare action of hexamethonium and other antagonists at the skeletal neuromuscular junction.

1. In the rat isolated diaphragm preparation hexamethonium and other low potency competitive antagonists of acetylcholine (ACh), including gallamine and hyoscine butylbromide, reverse block by the potent antagonists tubocurarine, pancuronium and alcuronium. 2. In the presence of tubocurarine, hexamethonium increases the amplitude of the end-plate potential without increasing the quantal content. It enhances the response to ACh applied iontophoretically to the end-plate but does not enhance the response to ACh applied in the bath. 3. The anti-curare effect of hexamethonium is abolished in the diaphragm of the rat, guinea-pig and mouse by inhibitors of acetylcholinesterase. The effect is not observed in the indirectly stimulated toad sartorius muscle. 4. The effect is explained if tubocurarine does not dissociate appreciably in the time taken for ACh to achieve high occupancy of receptors, so that a fraction of receptors is completely excluded from occupation by ACh. Equilibration with hexamethonium reduces the fraction excluded by tubocurarine and the transmitter now competes with hexamethonium for more receptors and produces a larger response. 5. On the basis of this explanation the half-time for dissociation of tubocurarine must be about 1 millisecond. It follows that tubocurarine does not act competitively with ACh at synapses when transmitter action is sufficiently brief, and that its binding to the receptor is probably diffusion-limited.

Acetylcholine↗

PubMed1979

Effects of 2,4-dinitrophenol amylobarbitone and certain other drugs on the rate of oxygen consumption and force of contraction of isolated curarized diaphragm muscle of the rat.

1 A technique has been developed for studying over periods of 10 min or longer the effects of drugs on both the force of electrically-induced contractions and the oxygen consumption of an isolated, curarized, mammalian, skeletal muscle preparation.2 The resting oxygen consumption of the muscle was increased substantially by 2,4-dinitrophenol in concentrations (0.02 mM and higher) that eventually produced contracture. Two other uncoupling agents, 4,6-dinitro-o-cresol and carbonylcyanide-p-trifluoromethoxyphenylhydrazone, behaved similarly.3 The oxygen consumption over 10 min of the stimulated muscle was also increased by 2,4-dinitrophenol (0.05 mM), although the strength of the ;maximal' contractions was lessened.4 Amylobarbitone increased the strength of contraction at a concentration (0.2 mM) that did not affect oxygen consumption significantly. Amylobarbitone and pentobarbitone also increased it at a concentration (1 mM) that depressed oxygen consumption. They decreased both strength of contraction and oxygen consumption at a concentration of 5 mM. Phenobarbitone had a weaker action.5 S-n-decyl-thiouronium increased oxygen consumption when given at a concentration (1 mM) that diminished strength of contraction and eventually produced contracture of the muscle.6 Both S-methyl-thiouronium (1 mM) and 4-aminopyridine (0.1 mM and 0.5 mM) increased strength of contraction without increasing oxygen consumption. Neither strength of contraction nor oxygen uptake was affected by ouabain (up to 0.01 mM) or by phenformin (0.1 mM).7 It is concluded that the response to 2,4-dinitrophenol is due mainly, if not wholly, to its known ability to uncouple oxidative phosphorylation; that the response to the barbiturates is due to a combination of a known metabolic action (viz., blocking of the respiratory chain) and a stimulant action on muscle; and the response to S-n-decyl-thiouronium to a disruptive action on cell membranes. The disproportionate actions of 4-aminopyridine and S-methyl-thiouronium on strength of contraction relative to oxygen consumption are also attributed to a non-metabolic action.

Amobarbital↗