Classification of longissimus lumborum muscle spindle afferents in the anaesthetized cat.
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Recordings have been made from 127 single muscle spindle afferents from the longissimus lumborum muscles of anaesthetized cats. They have been characterized by their responses to passive muscle stretch and the effects of succinylcholine (SCh) and by their sensitivity to vibration. The use of SCh permitted the assessment for each afferent of the influence of bag1 (b1) and bag2 (b2) intrafusal muscle fibres. From this, on the assumption that all afferents were affected by chain (c) fibres, they were classified in four groups: b1b2c (41.9%), b2c (51.4%), b1c (1.3%) and c (5.4%). All the afferents with b1 influence were able to respond one to one to vibration at frequencies above 100 Hz and were considered to belong to primary endings. On the basis of the vibration test, 64% of the b2c type afferents appeared to be primaries and 36% secondaries. Of the units classified as primaries, 41% were designated as b2c and would not therefore be able to respond to dynamic fusimotor activity. The significance of this relatively high proportion of b2c-type spindle primary afferents is discussed in relation to the specialized postural function of the back muscles. (+info)
Neuromuscular transmission in a mammalian preparation during exposure to enflurane.
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The effects of enflurane on motor nerve terminals and muscle endplates were studied in the rat phrenic nerve-diaphragm preparation using standard microelectrode recording techniques. Muscle endplate interaction with enflurane was suggested by depression of the amplitude of miniature endplate potentials (MEPP's) without change in frequency, increased duration of MEPP's and endplate potentials (EPP's) increased threshold for generation of muscle action potentials, and inhibition of the endplate depolarization induced by succinylcholine. Evidence of nerve terminal effects of enflurane was limited to a greater relative decline of EPP amplitude during tetanus, indicative of failure to maintain transmitter output at rapid rates of stimulation. It is concluded that the depressant effect of enflurane on indirectly elicited muscle twitch is primarily due to an impairment of the action of muscle endplate on adjacent membrane; however, the relative importance of prejunctional depression, seen only during rapid nerve stimulation, cannot be assessed from the present data. (+info)
The onset of disuse-related potassium efflux to succinylcholine.
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Disuse atrophy of skeletal muscle produces resistance to nondepolarizing relaxants and increased potassium efflux after the administration of succinylcholine. These changes appear to be due to development of perijunctional and/or extrajunctional receptors (up-regulation). In this study, the authors searched for the earliest detectable appearance of increased potassium efflux in beagles in whom disuse atrophy was simulated. Seven beagles underwent unilateral cast immobilization of a hind limb. Between 4 and 42 days, they periodically received succinylcholine 0.25 mg/kg while anesthetized with thiamylal and nitrous oxide. Sequential bilateral femoral venous samples showed that the casted limb did not manifest potassium release greater than the upper limit of normal (1 mEq/l) until cast immobilization periods of 14 days or longer. When this occurred, the increase in the potassium concentration in the femoral venous blood of the casted limb exceeded that from the noncasted limb by at least 0.7 mEq/l (P less than 0.01). The range for the onset of this response after casting was 14-42 days, the mean 27.2 days, and the standard deviation 9.8 days. These findings imply that up-regulation of skeletal muscle receptors, associated with exaggerated potassium efflux after administration of succinylcholine, is dependent on progressive development of extrajunctional receptors over surface membrane areas beyond the endplate. (+info)
Activation and inhibition of human muscular and neuronal nicotinic acetylcholine receptors by succinylcholine.
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BACKGROUND: Succinylcholine is one of the most widely used muscle relaxants in clinical anesthesia and emergency medicine. Although the clinical advantages and cardiovascular side effects are well known, its mechanism of action within the human nicotinic cholinergic receptor system remains to be understood. The aim of this study was to investigate the effect of succinylcholine on human muscle and neuronal nicotinic acetylcholine receptor (nAChR) subtypes. METHODS: Xenopus laevis oocytes were injected with human messenger RNA for muscle and neuronal nAChR subunits. Receptor activation, desensitization, and inhibition induced by the natural ligand acetylcholine or by succinylcholine was studied using a multichannel two-electrode voltage clamp setup. Responses were measured as peak current and net charge. RESULTS: Succinylcholine concentration-dependently activated the muscle-type nAChR with an EC50 value of 10.8 microm (95% confidence interval, 9.8-11.9 microm), and after the initial activation, succinylcholine desensitized the muscle-type nAChR. Succinylcholine did not activate the neuronal nAChR subtypes alpha3beta2, alpha3beta4, alpha4beta2, or alpha7 at concentrations up to 1 mm and was a poor inhibitor at these receptor subtypes, with IC50 values above 100 microm. CONCLUSION: Succinylcholine activates the muscle-type nAChR followed by desensitization. The observation that succinylcholine does not inhibit the presynaptic alpha3beta2 autoreceptor at clinically relevant concentrations provides a possible mechanistic explanation for the typical lack of tetanic fade in succinylcholine-induced neuromuscular blockade. Finally, cardiovascular side effects (e.g., tachyarrhythmias) of succinylcholine are not mediated via direct activation of the autonomic ganglionic alpha3beta4 subtype because succinylcholine does not activate the neuronal nAChRs. (+info)
Increased extrajunctional acetylcholine sensitivity produced by chronic acetylcholine sensitivity produced by chronic post-synaptic neuromuscular blockade.
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1. Anaesthetized rats were paralysed for periods of up to 3 days by chronic administration of D-tubocurarine (DTC), succinylcholine or alpha-bungarotoxin. 2. After 3 days of treatment with DTC, the phrenic nerve remained active. Neuromuscular transmission and spontaneous miniature end-plate potentials (m.e.p.p.s) were restored after removal of the DTC. Resting potentials and input resistances of muscle fibres that had been paralysed for 3 days were similar to those in denervated fibers. 3. Chronic neuromuscular blockade increased the binding of [125-I]-alpha-bungarotoxin by extrajunctional regions of muscle. The time course of the increase was similar to that seen after denervation. Binding to muscles from animals that were anaesthetized and respirated, but not paralysed, was not increased. 4. Three days of paralysis increased the sensitivity of the extrajunctional muscle membrane to acetylcholine (ACh) applied by iontophoresis. 5. Approximately the same proportion of muscle fibres from muscles paralysed for 3 days gave overshooting action potentials in the presence of tetrodotoxin 10-minus 6 g/ml. as did fibres form muscles denervated for 3 days. 6. Chronic paralysis did not change the accumulation of acetylcholinesterase above a ligation in the sciatic nerve. 7. These results are consistent with the idea that extrajunctional ACh sensitivity is normally controlled by muscle activity. (+info)
Pharmacodynamics of high-dose vecuronium in children during balanced anesthesia.
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To compare the speed of onset, intubating conditions, duration of action, and recovery from neuromuscular blockade with vecuronium to those with succinylcholine, 40 ASA physical status 1 or 2 children (ages 2-9 yr) were studied during N2O-O2-opioid anesthesia. Each child was randomly assigned to receive a bolus dose of one of the following muscle relaxants: succinylcholine 2.0 mg/kg (n = 10), vecuronium 0.1 mg/kg (n = 10), vecuronium 0.2 mg/kg (n = 10), or vecuronium 0.4 mg/kg (n = 10). The evoked electromyogram of the abductor digiti minimi to train-of-four stimulation was monitored. We found that with succinylcholine, the time to 95% twitch depression (speed of onset, mean +/- SD), 24 +/- 7 s, was significantly less than that with each dose of vecuronium: 0.1 mg/kg, 83 +/- 21 s; 0.2 mg/kg, 58 +/- 17 s; and 0.4 mg/kg, 39 +/- 11 s, respectively (P less than 0.05). The time to laryngoscopy and intubation did not differ significantly between succinylcholine (48 +/- 10 s) and vecuronium 0.4 mg/kg (57 +/- 13 s); however, both were significantly less than than with vecuronium 0.1 and 0.2 mg/kg (P less than 0.005). The intubating conditions were excellent in 100% of patients. The duration of action was least with succinylcholine (5.7 +/- 1.5 min) and increased with increasing doses of vecuronium: 0.1 mg/kg, 23.9 +/- 5.1 min; 0.2 mg/kg, 55.2 +/- 11.6 min; and 0.4 mg/kg, 74.6 +/- 9.9 min, respectively (P less than 0.001). The recovery index was most rapid with succinylcholine (1.6 +/- 0.4 min) and was slowest with vecuronium 0.4 mg/kg (22.6 +/- 2.1 min) (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
Substrate and product trafficking through the active center gorge of acetylcholinesterase analyzed by crystallography and equilibrium binding.
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Hydrolysis of acetylcholine catalyzed by acetylcholinesterase (AChE), one of the most efficient enzymes in nature, occurs at the base of a deep and narrow active center gorge. At the entrance of the gorge, the peripheral anionic site provides a binding locus for allosteric ligands, including substrates. To date, no structural information on substrate entry to the active center from the peripheral site of AChE or its subsequent egress has been reported. Complementary crystal structures of mouse AChE and an inactive mouse AChE mutant with a substituted catalytic serine (S203A), in various complexes with four substrates (acetylcholine, acetylthiocholine, succinyldicholine, and butyrylthiocholine), two non-hydrolyzable substrate analogues (m-(N,N,N-trimethylammonio)-trifluoroacetophenone and 4-ketoamyltrimethylammonium), and one reaction product (choline) were solved in the 2.05-2.65-A resolution range. These structures, supported by binding and inhibition data obtained on the same complexes, reveal the successive positions and orientations of the substrates bound to the peripheral site and proceeding within the gorge toward the active site, the conformations of the presumed transition state for acylation and the acyl-enzyme intermediate, and the positions and orientations of the dissociating and egressing products. Moreover, the structures of the AChE mutant in complexes with acetylthiocholine and succinyldicholine reveal additional substrate binding sites on the enzyme surface, distal to the gorge entry. Hence, we provide a comprehensive set of structural snapshots of the steps leading to the intermediates of catalysis and the potential regulation by substrate binding to various allosteric sites at the enzyme surface. (+info)
Heterogeneity of human mast cells and basophils in response to muscle relaxants.
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The authors studied the effects of increasing concentrations 10(-5)-10(-3) M) of four muscle relaxants (succinylcholine, d-tubocurarine, vecuronium, and atracurium) on histamine release from peripheral blood basophils and mast cells isolated from human lung parenchyma, skin tissues, and heart fragments. Basophil granulocytes released less than 5% of their histamine content when incubated with any one of the muscle relaxants tested. In contrast, mast cells showed a significant heterogeneity in response to different muscle relaxants. Succinylcholine did not induce histamine release from any type of mast cell, and only high concentrations of d-tubocurarine (10(-3) M) caused histamine release from skin and lung mast cells. Vecuronium concentration-dependently induced histamine release from skin and lung--but not from heart mast cells--to a maximum of 7.2 +/- 2.1% and 4.9 +/- 1.4%, respectively. Atracurium concentration-dependently caused significant histamine release from skin and lung mast cells to a maximum of 46.2 +/- 15.1% and 30.6 +/- 6.0%, respectively. Atracurium (5 x 10(-5) - 2 x 10(-4) M) also induced histamine release from heart mast cells. The histamine release process from both lung and skin mast cells caused by atracurium and vecuronium was extremely rapid (t1/2 = less than 1 min). The releasing activity of atracurium and vecuronium on lung and skin mast cells was not reduced, and not abolished, by lowering the temperature of the incubation buffer to 22 degrees C and 4 degrees C. Extracellular calcium did not affect the capacity of atracurium and vecuronium to induce histamine release from lung and skin mast cells.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)