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Gallamine triethiodide pancuronium bromide or d-tubocurarine was infused intravenously at different rates in urethane anaesthetized rats. When given in neuromuscular blocking doses gallamine triethiodide produced significant hypotension if the rate of infusion exceeded 2 mg/min whereas neither pancuronium bromide nor d-tubocurarine produced a marked change in blood pressure in neuromuscular blocking doses.
After intravenous infusion maintaining a neuromuscular blocking concentration very little gallamine enters the cerebrospinal fluid (CSF) of the intact anesthetized cat even after several days. After a similar intravenous infusion in the decerebrate cat gallamine enters the CSF slowly over 4 days eventually reaching a concentration similar to that in the plasma. This procedure is accompanied by very strong twitching in many muscles and the occurrence of slow waves in the inferior olive in synchrony with the twitches. A large dose (4 mg) of gallamine triethiodide injected directly into the cisterna magna of an intact anesthetized cat produced twitching within 1 min and slow waves in the inferior olive in good synchrony with the twitches; the effects lasted at least 43 h. Injection of a quantity of gallamine triethiodide (about 130 micrograms) sufficient to mimic the concentration in the CSF obtained after 3-4 days of neuromuscular block in the decerebrate cat (50-120 micrograms/ml gallamine) had extremely weak effects lasting for at most 1 h. However, this weak effect is probably due to the anesthetic because injection of a similar quantity into an (unanesthetized) decerebrate cat at any time after decerebration had strong effects. After intracisternal injection of gallamine the concentration in the CSF reaches very low levels within 12 h but twitching and activity in the inferior olive persists for 1-2 days. The reasons for this prolonged action are now being investigated. The effects of gallamine are compared with the condition of reticular reflex myoclonus.
Sixty coldwater and warmwater fish ranging in weight from 2 to 35 kg were injected intramuscularly with the hypnotics alphaxalone-alphadolone and metomidate hydrochloride and the non-depolarising muscle relaxant gallamine triethiodide using a laser-aimed underwater dart gun. Alphaxalone-alphadolone produced sufficient sedation for easy netting within five to 20 minutes at doses between 0.3 and 0.5 ml/kg, with induction being somewhat faster in warmwater species. The pattern of induction was similar with metomidate but required doses of 40 to 60 mg/kg. The muscle relaxant gallamine triethiodide showed promise as a practical agent for the capture and handling of large fish by virtue of its smooth induction of paralysis at doses between 1 and 3 mg/kg and its reversible supplementation with orally administered metomidate hydrochloride.
1. The effect of natural stimulation of the limbs (usually pinching the forepaws) on the discharges of muscle spindle primary and secondary afferents and gamma motoneurones of the gastrocnemius medialis muscle were examined in the precollicular decerebrate rabbit, paralysed with gallamine triethiodide to prevent extrafusal muscle contraction. 2. The afferents showed only excitation in response to natural stimulation. The same stimulus strongly inhibited some gamma motoneurones and, at the same time, predominantly excited others. 3. Since extrafusal muscle contraction was prevented using gallamine triethiodide, intrafusal contraction was responsible for the afferent excitation, and could only have been evoked by those gamma motoneurones excited by natural stimulation. The distribution of effects from gamma motoneurones that were strongly inhibited by natural stimulation could not be deduced from afferent recordings. 4. On the basis of these afferent and efferent recordings, and the known structure of the muscle spindle, gamma motoneurones were identified as static or dynamic. 5. The results are discussed in relation to the patterns of discharge of static and dynamic gamma motoneurones.
Respiration related units ( RRU ) were recorded in the brainstem of cats with spinal transection at the C7-Th 1 level and breathing N2O. The proportion of RRU in several structures was compared in control and in 3 experimental groups: (1) paralyzed with gallamine triethiodide; (2) vagotomized; and (3) both vagotomized and paralyzed. After gallamine, RRU percentage was multiplied by 3 in the bulbo-pontine reticular formation (RF) and as much as 20 in the mesencephalic RF. Vagotomy multiplied RRU proportions by 2 in the bulbo-pontine RF, by 12 in the mesencephalic RF and by 3 in the pneumotaxic complex (nucleus parabrachialis medialis ( NPBM ) and K olliker -Fuse (KF) nucleus). The effects of gallamine and vagotomy were not additive. Gallamine still increased proportion of RRU in the RF after vagotomy showing that the gallamine effect is not vagally mediated; this was in contrast to the previously reported suppression by vagotomy of phrenic discharge facilitation induced by gallamine. The total number of firing units in the RF was not modified by gallamine or vagotomy. It is concluded that the respiratory modulation of reticular neurons is selectively enhanced by gallamine and vagotomy through two independent mechanisms.
This is a report on the resistance to block of the motor terminals on intrafusal fibres of cat soleus muscle spindles using the drug gallamine triethiodide (Flaxedil). To minimize diffusion barriers and to permit accurate measurements of time courses, rather slow rates of gallamine infusion were used (0.15 mg min-1). The main finding made was that after gallamine infusion, when extrafusal tension had dropped to half, all dynamic fusimotor effects and eight of twenty static effects had fallen to 40% or less of their control value. The remaining static effects persisted at 60-80% of their control value. Where fusimotor fibres were stimulated together with one or two skeletomotor fibres, the influence of the skeletomotor axons was significant only after spindle biasing had fallen to low levels. When gallamine infusion was stopped extrafusal tension returned to control levels within 20-75 min, depending on the length of the block, while fusimotor responses did not fully recover within the recording period of up to 150 min. The combination for some fusimotor responses of an early fall and a late recovery when compared with extrafusal tension, suggested a greater sensitivity of these endings to the drug. A comparison of spindle responses to the drug succinyl choline (SCh) and to fusimotor stimulation in the presence of gallamine showed that SCh responses were rapidly reduced by gallamine and had a long recovery time course, as were some fusimotor responses. From this it is argued that fusimotor effects with a high sensitivity to gallamine blockade were associated with nuclear bag fibre contractions and the more resistant effects with nuclear chain fibre contraction. It is generally believed that intrafusal neuromuscular junctions are more resistant to neuromuscular blockers than extrafusal junctions. The present experiments provide evidence to the contrary for some intrafusal junctions. Since muscle relaxants are often used in general anaesthesia it is interesting to speculate about the recovery of function of proprioceptive reflexes and of kinaesthesia during the immediate post-anaesthetic period, in view of the large difference in recovery time for transmission at intrafusal and extrafusal junctions.
A test for diminished neuromuscular function in animals with experimental autoimmune myasthenia gravis is described. Within minutes following an injection of gallamine triethiodide, mice exhibit a dramatic yet transient response which is dose-dependent. Mice previously inoculated with acetylcholine receptor are approximately twice as sensitive to gallamine as normal mice. Positive results have been found in over 80% of receptor-inoculated BALB/c mice and in 94% of C57Bl/6 mice.
1. Breuer's hypothesis that the vagus nerves exert a tonic control of respiratory rhythm, in addition to the phasic control, was examined.2. Closed-chest cardiopulmonary bypass was instituted in dogs weighing 20-30 kg anaesthetized with chloralose. Respiratory rhythm was recorded from a phrenic electroneurogram.3. Complete muscular paralysis induced with gallamine triethiodide produced an increase in the duration of inspiration and an increase in the amplitude of the integrated phrenic electroneurogram. There was no consistent effect on expiratory duration. Gallamine produced no effect when given after vagotomy.4. In the paralysed state, an increase in lung volume of 25-100 ml. for 30-60 sec produced a sustained increase in the duration of expiration and a decrease of respiratory rate: there was little effect on inspiratory duration, or the amplitude of the integrated phrenic electroneurogram.5. A decrease in lung volume of the same order of magnitude for the same period produced a sustained decrease in the duration of expiration and an increase of respiratory rate: there was little effect on inspiratory duration or the amplitude of the integrated phrenic electroneurogram.6. The phenomena described in (5) and (6) constitute a high gain respiratory frequency controller. They did not occur after bilateral cervical vagotomy.7. Bilateral cervical vagotomy during complete muscular paralysis produced a further increase in the duration of inspiration and in the amplitude of the integrated phrenic electroneurogram; there was no consistent effect on expiratory duration.8. The results confirmed Breuer's hypothesis and showed that inspiratory duration and expiratory duration are controlled independently.
The flow of fluid within the trachea of fetal sheep (121-135 days) has been measured using a newly developed flowmeter. The flowmeter, which is basically a miniature servo-controlled peristaltic pump, is connected in series with an extra-corporeal tracheal loop. Integrated tracheal flow was measured for periods of at least 8 h in 5 control fetuses during which we determined its relationship to fetal breathing movements detected by EMG's of inspiratory muscles or tracheal pressure fluctuations. The overall flow of fluid away from the lungs was 14.4 ml/h; on average outward flow was 5.3 times greater during episodes of breathing movements than during apnea. Interruption of the motor innervation of the larynx in 5 fetuses led to a 25% reduction in mean overall flow and, compared with control fetuses, there was a reduction in net flow associated with breathing movements and an increased flow during apnea. These findings suggest that tracheal flow is normally retarded by a laryngeal mechanism during apnea, giving rise to an elevated pressure within the trachea and probably resulting in increased pulmonary distension. Paralysis of the fetus with gallamine triethiodide reduced the flow of liquid from the lungs and abolished variations in flow rate related to fetal electrocortical states.
In an attempt to assess the universal validity of the conditioned taste aversion (CTA) paradigm, various types of poisoning (UC) were associated with the gustatory CS. Water deprived rats were habituated for two days to the drinking box, where water was available for 15 min. On Day 3, access to the CS (0.1% saccharin 15 min) was followed after 30 min by a sublethal dose of the poison (0.15 M LiCl, 4% body weight; 0.1 M sodium malonate, 1% body weight; pyrrolopyrimidine drug BW 58-271, 15 mg/kg; sodium cyanide 4 mg/kg; sodium iodoacetate 40 mg/kg; sodium fluoride 30 mg/kg; gallamine triethiodide 40 mg/kg). Rats injected with the last drug were maintained under artificial respiration until muscular paralysis disappeared. After 4 days of recovery, water deprivation schedule was resumed on Days 8 and 9. During the retention test on Day 10 saccharin consumption dropped by 60% in the LiCl poisoned rats, but not CTA developed in animals poisoned by pyrrolopyrimidine, gallamine, malonate and cyanide. CTA of intermediate intensity was evoked by iodoacetate and fluoride. The absence of CTA was not due to the amnesic effect of poisoning, since LiCl administration to NaCN poisoned rats produced CTA of usual intensity. It is concluded that CTA is not related to the overall severity of poisoning but rather to the effect of the poison on specific interoceptors.
Previous studies have shown that a special proteolipid extract from the electric organ of Electrophorus showed high affinity binding for acetylcholine and other cholinergic agents. This proteolipid has now been incorporated into ultrathin lipidic membranes, and the membrane resistance was studied. The resistance decreased from 7.27 +/- 0.82 x 10(5) ohm cm(2) in the control membrane to 1.83 x 10(5) ohm cm(2) with addition of 72 microg/ml proteolipid. The decrease in resistance followed a potential function of order four with the proteolipid concentration in the membrane-forming solution. The presence of this proteolipid determined some type of cationic selectivity which was not observed in the control. At a critical point of proteolipid concentration the conductance spontaneously fluctuated between two levels. The membrane current jumped from one state to another by way of single discrete steps, reminiscent of those obtained with the excitatory inducing material or the macrocyclic antibiotics. In membranes containing another proteolipid having no cholinergic binding properties, the increase in conductance was smaller, and had a linear function with the concentration. In this case the "flip flop" fluctuation and the cationic selectivity were not observed. The membranes containing the cholinergic proteolipid reacted to the addition of acetylcholine by a rapid and transient increase in conductance that was considerably reduced or abolished by a previous application of d-tubocurarine. These membranes also interacted with other cholinergic agents, such as gallamine triethiodide, hexamethonium, and alpha-bungarotoxin. These results suggest that this special proteolipid, when added to the artificial membranes, induces a "chemical excitability" toward cholinergic ligands.
The effects of solvent substitution on the steady-state and kinetic properties of drugs (gallamine triethiodide) and ions (nonyltriethylammonium and Ba++) known to occlude Na+ and K+ channels have been examined and compared with the effects of D2O on unmodified channels. In general, we observed large isotope effects on the kinetics of occlusion at temperatures of 5 degrees C, but only minor effects at 15 degrees C, consistent with processes involving significant solvent interaction. Steady-state behavior was not affected. In the case of gallamine, where a dual effect on INa is evident, although both processes were D2O sensitive, only the occlusion phase had a significant temperature dependence.
1. The activity of primary afferent axons was recorded in rats that had received a chronic constriction injury (CCI) to the common sciatic nerve. The CCI gives rise to a painful peripheral neuropathy that is characterized by allodynia, hyperalgesia, and, probably, spontaneous pain (or dysesthesia). In the majority of animals, these neuropathic pain symptoms begin 2 days postinjury; sciatic nerve afferents were examined just before and just after the time of symptom onset, at 1 and 3 days postinjury. 2. We used two stimulating electrodes, one proximal to the injury and the other distal, to activate the injured sciatic nerve while we recorded from individual primary afferent axons in microfilaments teased from the L4-L6 dorsal roots. Measurements of conduction velocities (calculated from the proximal electrode) and evaluation of conduction through the site of injury were made from 181 A beta, 135 A delta, and 60 C-fibers. 3. The percentage of axons that did not conduct through the injury site at 1 day postinjury was 85% for the A beta fibers and 55% for the A delta fibers, but only 9% for the C-fibers. By day 3, these percentages had increased to 89% for the A beta fibers, 87% for the A delta fibers, and 32% for the C-fibers. Some axons were activated from the distal stimulating electrode at currents greater than 5-10 times those required from the proximal electrodes, but their distally evoked responses did not have the longer latencies expected from a more distant site of activation. Control experiments confirmed that such high-threshold responses were due to current spread from the distal electrode to a site proximal to the nerve injury. 4. Spontaneous discharges were observed in 35% of A beta fibers, 15% of A delta fibers, and 3% of C-fibers (data from 1 and 3 days postinjury combined). Of the 55 A beta fibers exhibiting spontaneous discharge, 89% did not conduct through the injury site; the same was true of 65% of the A delta fibers (n = 20). Both of the two spontaneously discharging C-fibers conducted through the injury. The frequency of the spontaneous discharge of the myelinated fibers ranged from 10 to 50 Hz and was usually regular or bursting. 5. Intravenous administration of gallamine triethiodide (Flaxedil), a K+ channel blocker, either induced activity in previously silent fibers or increased the frequency of spontaneous activity in 50% (21/42) of A beta fibers and 19% (3/16) of A delta fibers.(ABSTRACT TRUNCATED AT 400 WORDS)
Substance P (SP), a neuropeptide, has been found in amacrine cells in a variety of vertebrate retinas. SP excited many of the ganglion cells we sampled in carp retina; many of these ganglion cells are directly excited by cholinergic agonists. It has been reported that SP modulates cholinergic synaptic transmission in some other neuronal systems by inhibiting or desensitizing cholinergic receptors. SP does not act in this way on the ganglion cell cholinergic receptors in isolated carp retina. Pulses of acetylcholine (ACh), applied to sensitive ganglion cells by microiontophoresis, were set to elicit consistent cellular responses. Application of SP to the retina through a nebulizing system (final concentration about 10(-6) M) did not reduce the excitation produced by the ACh pulse. In earlier work, we showed that the cholinergic receptors were nicotinic; in the present study, SP occasionally excited cells after the retina was treated with a nicotinic cholinergic antagonist, gallamine triethiodide. SP appears to excite cholinergic-sensitive ganglion cells at a postsynaptic site other than their nicotinic cholinergic receptor and via a pathway that does not require a presynaptic, SP-sensitive, ACh-releasing interneuron.
'Lissive anaesthesia', the administration of a small dose of a non-depolarising muscle relaxant to a patient breathing nitrous oxide, oxygen and an anaesthetic vapour, is a technique popularly employed for minor procedures. In this study, the effects of intravenous gallamine triethiodide (40 mg) on the blood-gas status of 20 patients under general anaesthesia with oxygen, nitrous oxide and halothane after pethidine and atropine premedication, were assessed. The results are compared with those obtained from a control group of 10 patients anaesthetised in an identical manner, but omitting the muscle relaxant drug. All patients in both the relaxant and control groups in this study developed respiratory acidaemia. The rise in mean arterial carbon dioxide tension was, however, greater after injection of gallamine. Significant hypoxia or metabolic acidaemia was not encountered, except in one grossly obese patient in the gallamine group. The implications of these findings are discussed.
1. Drugs were applied to the cerebral cortex of rats anaesthetized with pentobarbitone and changes measured in the somatosensory primary evoked response.2. Computer-derived averages of thirty-two consecutive responses yielded stable and consistent measurements of the potential changes comprising the evoked response, and comparable records from the opposite (non-drug treated) cortex provided an essential control for systemic actions of the drug.3. The modifications produced by curare and strychnine were indistinguishable. The first positive wave (peak latency 7 msec) was unaltered; the second positive wave (peak latency 11.5 msec) was variably enhanced, and the first and second negative waves (peak latencies 16 and 40 msec) were replaced by a much larger negative wave (peak latency 22 msec).4. The time of onset of the effect on the negative waves and the maximal amplitude attained by the abnormal negative wave were related to the log concentration of the drug used. Curare is approximately 10 times more potent than strychnine.5. Toxiferine I, di-allylnortoxiferine and atropine also produced this effect but were less potent than strychnine.6. Succinylcholine, dihydro-beta-erythroidine and gallamine triethiodide did not produce this effect (in concentrations up to 10(-3)M).7. The observations are consistent with an action of curare and strychnine on an intracortical cholinergic inhibitory system, but other possibilities including a "non-specific excitatory action" cannot be excluded.
Several methods have been used to bind electric organ aetylcholinesterase to the walls of phosphatidylcholine liposomes. One of these methods [Brunner, J., Skrabal, P. & Hauser, H. (1976) Biochim. Biophys. Acta, 455, 322-331] achieved complete incorporation, although some enzyme was shown to be sequestered inside the vesicles. The association was established either in the presence of high salt media or altered liposomal membrane fluidity. The reconstitution process impaired the allosteric transition of acetylcholinesterase which is thought to occur when Flaxedil (gallamine triethiodide) is present in a low ionic strength medium. It is suggested that the cholinesterase is capable of being incorporated into liposomes, possibly via hydrophobic forces. Such a system may be an adequate one for further study of the functioning of the enzyme in a defined membrane environment.
A new carbon paste electrode (CPE) for the determination of iodide ion based on a cetyltrimethylammonium iodide (CTMAI) ion pair as an electroactive material is described. The electrode shows a linear response for iodide ion over the concentration range of 4 x 10(-5) M to 1 x 10(-1) M with a lower detection limit of 4 x 10(-5) M at 25 degrees C. The electrode has a Nemstian slope of -55.0 +/- 0.4 mV/decade and a fast potential response of 45 s, which is almost constant over a pH range of 5.0 - 9.0. Selectivity coefficient data of the CTMAI-CPE for some common ions show negligible interference, and the electrode has high selectivity towards the iodide ion. An average recovery of 101.83% with a relative standard deviation of 1.53% has been achieved for the determination of iodide in Flaxedil (gallamine triethiodide) ampoules, a muscle relaxant drug. The electrode has been examined for the determination of iodide in saline water; the results were found to compare favorably with those obtained using Metrohm iodide ISE. The electrode has been utilized as an end-point indicator electrode for the determination of Hg(II) and phenylmercury(I) in their aqueous solutions using potentiometric titration with a potassium iodide standard solution.