BACKGROUND: The administration of high doses of glucocorticoids can produce significant side effects including skeletal muscle atrophy, weakness and aberrant pharmacology. However, available reports have yielded conflicting results ranging from facilitatory to no change to inhibitory action of glucocoticoids on neuromuscular transmission. Also, the mechanisms for such changes are not known. Therefore, this study investigated the changes in muscle contractility and pharmacology after prednisolone administration in vivo. METHODS: With institutional approval, Sprague-Dawley rats were randomly allocated to 3 treatment groups, namely prednisolone (10 mg/kg daily for 7 days), saline control (equal volume of saline daily for 7 days) and an age-matched food-restriction group which grew at the same rate as the prednisolone group. On day 8 the rats were anesthetized, mechanically ventilated and the twitch response of the tibialis muscle to supramaximal stimulation of the sciatic nerve at 2 Hz for 2 sec every 12 sec, or at 50 or 100 Hz tetanus for 5 sec were monitored. The peak twitch and tetanic tensions were measured and tetanic fade was calculated. The cumulative dose-response curves of d-tubocurarine (d-TC) in the tibialis muscles were determined. The tibialis muscle weight relative to body weight was measured (muscle index), and the tension per unit muscle mass (i.e., specific tension) was calculated. The control and treatment groups were compared by a one way ANOVA test and P>0.05 was regarded as significant. RESULTS: Prednisolone caused a decline in growth rate and the ED50 of dTC relative to saline. Food-restriction caused a decline in growth rate and an increase in muscle index relative to saline, and a decline in tension relative to prednisolone. CONCLUSIONS: These results indicate that prednisolone can alter the sensitivity of skeletal muscles to dTC even without or before changes in neuromuscular contractility become apparent. Therefore, titration of doses of nondepolarizing neuromuscular blocking agents may be indicated in patients receiving glucocorticoid therapy.
Animals ; Atrophy ; Body Weight ; Glucocorticoids ; Humans ; Muscle, Skeletal* ; Muscles ; Neuromuscular Agents* ; Neuromuscular Blocking Agents ; Pharmacology ; Prednisolone ; Rats* ; Rats, Sprague-Dawley ; Refractory Period, Electrophysiological ; Sciatic Nerve ; Tetanus ; Tubocurarine

BACKGROUND: The serotonin type 3 receptors are diffusely distributed in both the central and the peripheral nervous system. Physiological and pathophysiological processes thought to be mediated by this receptor include nausea and vomiting, peripheral nociception and central antinociception, conditioned aversion response to drugs, anxiety, and cognition. Because of the structural similarity between the nicotinic acetylcholine receptor and the 5HT3 receptor, we investigated the effects of clinically used neuromuscular blockers on the 5HT3 receptor function related with PONV. METHODS: A cDNA clone encoding the full length murine 5HT3a receptor was subcloned into an oocyte expression vector and 50 ng of cRNA transcribed in vitro injected per oocyte. After 24 72 h incubation, oocytes were placed into a recording chamber continuously perfused with frog Ringer's solution and electrophysiological recordings were obtained by the two electrode voltage clamp technique. Serotonin with or without the various drugs were bath applied by a computer controlled solenoid valve. Peak currents induced by the drug applications were measured and dose responses were obtained. RESULTS: The 5HT3 receptor expression in Xenopus oocyte was identified by the pharmacologic tools. Serotonin induced rapid inward currents, and thus was showed dose-dependent: KD = 2.5 micrometer, Hill coefficiency = 2.09. Inhibition by the neuromuscular blockers showed dose-dependence and their inhibitory potency on 5HT3 receptor (IC50) was in order of d-tubocurarine (0.046 micrometer) > vecuronium (16.32 micrometer) > gallamine (1,169 micrometer). CONCLUSIONS: There was a different inhibitory effect of nicotinic cholinergic antagonists, clinically used neuromuscular blockers, on the 5HT3 receptor and a judicious selection of them might contribute to reducing the incidence of PONV clinically.
Anxiety ; Baths ; Cholinergic Antagonists ; Clone Cells ; Cognition ; DNA, Complementary ; Electrodes ; Gallamine Triethiodide ; Incidence ; Nausea ; Neuromuscular Blockade* ; Neuromuscular Blocking Agents* ; Nociception ; Oocytes* ; Peripheral Nervous System ; Postoperative Nausea and Vomiting ; Receptors, Nicotinic ; RNA, Complementary ; Serotonin* ; Tubocurarine ; Vecuronium Bromide ; Vomiting ; Xenopus*

BACKGROUND: The serotonin type 3 receptors are diffusely distributed in both the central and the peripheral nervous system. Physiological and pathophysiological processes thought to be mediated by this receptor include nausea and vomiting, peripheral nociception and central antinociception, conditioned aversion response to drugs, anxiety, and cognition. Because of the structural similarity between the nicotinic acetylcholine receptor and the 5HT3 receptor, we investigated the effects of clinically used neuromuscular blockers on the 5HT3 receptor function related with PONV. METHODS: A cDNA clone encoding the full length murine 5HT3a receptor was subcloned into an oocyte expression vector and 50 ng of cRNA transcribed in vitro injected per oocyte. After 24 72 h incubation, oocytes were placed into a recording chamber continuously perfused with frog Ringer's solution and electrophysiological recordings were obtained by the two electrode voltage clamp technique. Serotonin with or without the various drugs were bath applied by a computer controlled solenoid valve. Peak currents induced by the drug applications were measured and dose responses were obtained. RESULTS: The 5HT3 receptor expression in Xenopus oocyte was identified by the pharmacologic tools. Serotonin induced rapid inward currents, and thus was showed dose-dependent: KD = 2.5 micrometer, Hill coefficiency = 2.09. Inhibition by the neuromuscular blockers showed dose-dependence and their inhibitory potency on 5HT3 receptor (IC50) was in order of d-tubocurarine (0.046 micrometer) > vecuronium (16.32 micrometer) > gallamine (1,169 micrometer). CONCLUSIONS: There was a different inhibitory effect of nicotinic cholinergic antagonists, clinically used neuromuscular blockers, on the 5HT3 receptor and a judicious selection of them might contribute to reducing the incidence of PONV clinically.
Anxiety ; Baths ; Cholinergic Antagonists ; Clone Cells ; Cognition ; DNA, Complementary ; Electrodes ; Gallamine Triethiodide ; Incidence ; Nausea ; Neuromuscular Blockade* ; Neuromuscular Blocking Agents* ; Nociception ; Oocytes* ; Peripheral Nervous System ; Postoperative Nausea and Vomiting ; Receptors, Nicotinic ; RNA, Complementary ; Serotonin* ; Tubocurarine ; Vecuronium Bromide ; Vomiting ; Xenopus*

Background: This study was designed to determine whether presynaptic receptor blockade could be differentiated from postsynaptic receptor blockade by examining the effect of increasing frequencies of indirect stimulation on partial twitch depression in vitro rat phrenic nerve hemidiaphragm preparations. Methods: After isolating rat phrenic nerve hemidiaphragm preparation, T200/T1 ratio (twitch height of the 200th stimuli divided by that of the 1st stimuli) at frequencies of 0.2, 0.5, 1.0, and 2.0 Hz using a drug concentration which provided approximately 20% twitch depression at 0.1 Hz was calculated. To compare T200/T1 ratios with TOF ratios, 2.0 Hz TOF response was measured immediately after 200th stimuli at either frequency of stimulation. Results: Hexamethonium caused a marked decrease in T200/T1 ratio at 0.5~2.0 Hz of stimulation, whereas alpha-bungarotoxin caused no change in T200/T1 ratios at up to 2.0 Hz of stimulation. The T200/T1 ratios produced by d-tubocurarine, vecuronium, mivacurium, and rocuronium located intermediate between alpha-bungarotoxin and hexamethonium, however significant differences among four drugs were found at 2.0 Hz. The propensity for decrease in T200/T1 ratios at 2.0 Hz might differ from this study: hexamethonium >d-tubocurarine >rocuronium >mivacurium = vecuronium >alpha-bungarotoxin. T200/T1 ratios at 2.0 Hz were not different from TOF ratios. Conclusions: When the observed effects in this study were provided with result of alpha-bungarotoxin acting predominantly at postsynaptic receptors and hexamethonium acting predominantly at presynaptic receptors, the effects of nondepolarizing muscle relaxants at each binding site could be differentiated by examining the T200/T1 ratios at 2.0 Hz.
Animals ; Binding Sites ; Bungarotoxins ; Depression* ; Hexamethonium ; Phrenic Nerve* ; Rats* ; Receptors, Presynaptic ; Tubocurarine ; Vecuronium Bromide

BACKGROUND: To elucidate the mechanism of interaction between depolarizing and nondepolarizing muscle relaxants, train-of-four (TOF) fade during onset of neuromuscular blockade of d-tubocurarine (dTC) with or without decamethonium (C10) was evaluated in a rat phrenic nerve hemidiaphragm preparation. METHODS: Phrenic nerve hemidiaphragm preparations from 250~300 g Sprague Dawley rats (n=20) were suspended in a Krebs solution bubbled with 5% CO2 in O2 at 32oC. Phrenic nerves were stimulated with supramaximal stimuli of 0.2 ms duration at 0.15 Hz single twitch and 2 Hz TOF by a Grass S88 stimulator and the contractions of the hemidiaphragm were detected by a Grass FT03 force transducer then recorded. Estimation of ED50 for the dose response data were performed by a linear regression. The statistical significance of the results was determined by Wilcoxon Rank Sum test. p<0.05 was considered significant. RESULTS: Mean ED50 values of dTC and C10 calculated from the dose response relations were 7.76 microgram/ml and 0.65 microgram/ml respectively. Compared to adminstration of 2xED50 of dTC alone, TOF ratios at 75% and 50% of twitch height were markedly decreased by combination of ED50 of C10 and ED50 of dTC with statistic significance (67 +/- 1.9% vs. 46 +/- 3.1% and 36 +/- 2.5% vs. 7 +/- 2.5%). Conclusion: If fade in response to TOF stimulation represents a prejunctional effect, the results from this study suggests that the presynaptic action of C10 has some role in the mechanism of the interaction between dTC and C10 in the rat.
Animals ; Linear Models ; Neuromuscular Blockade* ; Phrenic Nerve* ; Poaceae ; Rats* ; Rats, Sprague-Dawley ; Transducers ; Tubocurarine*

Using the planar lipid bilayer method, we investigated the effect of d-tubocurarine (dTC) on the extracellular side of large-conductance Ca2+-activated K+ channel from rat brain. When the initial open probability (Po) of the channel was relatively high, dTC decreased channel activity in a concentration dependent manner. In contrast, when the initial Po was lower, sub-micro molar dTC increased channel activity by destabilizing the closed states of the channel. Further addition of dTC up to micro molar range decreased channel activity. This dual effect of dTC implicates that there exist at least two different binding sites for dTC.
Animals ; Binding Sites ; Brain* ; Lipid Bilayers* ; Molar ; Potassium Channels, Calcium-Activated* ; Rats* ; Tubocurarine*

The conductance change evoked by step depolarization was studied in primarily cultured rat adrenal chromaffin cells using patch-clamp and capacitance measurement techniques. When we applied a depolarizing pulse to a chromaffin cell, the inward calcium current was followed by an outward current and depolarization-induced exocytosis was accompanied by an increase in conductance trace. The slow inward tail current which has the same time course as the conductance change was observed in current recording. The activation of slow tail current was calcium-dependent. Reversal potentials agreed with Nernst equation assuming relative permeability of Cs+ to K+ is 0.095. The outward current and tail current were blocked by apamin (200 nM) and d-tubocurarine (2 mM). The conductance change was blocked by apamin and did not affect membrane capacitance recording. We confirmed that conductance change after depolarization comes from the activation of the SK channel and can be blocked by application of the SK channel blockers. Consequently, it is necessary to consider blocking of the SK channel during membrane capacitance recording.
Animals ; Apamin ; Calcium ; Chromaffin Cells* ; Exocytosis ; Membranes* ; Patch-Clamp Techniques ; Permeability ; Rats* ; Tubocurarine

Non-depolarizing muscle relaxant; d-tubocurarine was introduced clinically in 1942. Thereafter depolarizing muscle relaxant; succinylcholine was introduced in 1951. Those muscle relaxants were highly contributed in modern anesthesia practice today. But, since many years ago complications of succinylcholine were reported clearly so many anesthesia practice. Complications were such as ventricular arrythmia(cardiac arrest), fasciculation, hyperkalemia, muscle pain, elevation of intragastric, intraocular & intracranial pressure, prolonged apnea, generalized muscle clonus, masseter muscle rigidity and malignant hyperthermia etc. Succinylcholine was still used in clinical practice despite of many complications reported as long as more than 45 years. Finally, FDA(USA) decleared the routine use of succinylcholine was contraindicated in children and adolescents. Many textbooks of anesthesiology shows that use of succinylcholine was contraindicated in children and adolescents those were published recently since 1994. What is the current status of succinylcholine in despite of changing current concept of succinylcholine use in Korea? Succinylcholine is still inadvertently used in Korea over 79% of resident training hospital. Intravenous dantrolene reserve was only one hospital(1.4%). Undoubtedly, amazing things were going on in Korea. Seventeen cases of malignant hyperthermia had been reported from 1971 to 1996 on Korean medical journals. It's mortality was 70.6%. Not only the reported malignant hyperthermia, there are many cardiac arrest during anesthesia reported on Korean medical journals. Etiological analysis of cardiac arrest was reviewed some of them, there are certain numbers of cardiac arrest cases confirmed by succinylcholine was guilty. What is the counterplan? Change the current concept of succinylcholine is important. Conclusions ; 1. Non-depolarizing mucle relaxant should be used for intubation &/or muscle relaxation. 2. Hot line for malignant hyperthermia should be established.. 3. Intravenous dantrolene reserve is necessary. 4. Routine monitoring during anesthesia should be blood pressure, ECG, SPO2, ETCO2, body temperature and peripheral nerve stimulator.
Adolescent ; Anesthesia ; Anesthesiology ; Apnea ; Blood Pressure ; Body Temperature ; Child ; Cognition* ; Dantrolene ; Electrocardiography ; Fasciculation ; Heart Arrest ; Humans ; Hyperkalemia ; Intracranial Pressure ; Intubation ; Korea ; Malignant Hyperthermia ; Masseter Muscle ; Mortality ; Muscle Relaxation ; Myalgia ; Peripheral Nerves ; Succinylcholine* ; Tubocurarine

Administration of a subparalytic dose of a nondepolarizing muscle relaxant prior to intubating dose hastens the onset time of neuromuscular blockade. This study was designed to investigate the influence of a priming dose of vecuronium (0.015 mg/kg) and d-tubocurarine (0.05 mg/kg) on intubating dose of vecuronium (0.085 mg/kg). The authors measured TOF ratio using neuromuscular monitoring. This monitoring was carried out by stimulation of ulnar nerve at a frequency of 2Hz every 20 seconds using Datex relaxograph to measure the compound evoked electrographic response of hypothenar muscle. The patients were randomly divided into two groups as priming dose ; vecuronium and dtubocurarine (DTC) group respectively. Mixture of two different nondepolarizing muscle relaxant may produce synergism, although the reason for this synergism is unknown. It may be the results of the action of the drugs at different sites. In our study, we found the results as follows ;1) The rapid onset was occured with d-tubocurarine(0.05 mg/kg) as priming drug than vecuronium (0.015 mg/kg) 2) The duration was longer when d-tubocurarine was used (P<0.05) The authors conclude that the onset is more rapid and the duration is longer when other species of nondepolarizing muscle relaxant is used than same agent is used as priming drug.
Humans ; Neuromuscular Blockade* ; Neuromuscular Blocking Agents ; Neuromuscular Monitoring ; Tubocurarine* ; Ulnar Nerve ; Vecuronium Bromide*

The effects of nifedipine, a dihydropyridine Ca2+ antagonist, on the eleetrically-evoked twitch response, train-of-four and tetanic stimulation were studied in the isolated rat hemidiaphragm preparation. Nifedipine, in concentrations ranging from 3 to 100 uM, increased the electrically-evoked (nerve stimulation, 0.1 Hz, 0.5 ms, 10 V) twitch response and train-of-four ratio in a dose-relat- ed fashion, and the potentiating effects were inhibited by d-tubocurarine preteratment. The effect of nifedipine was not affected by reducing the extracellular Ca2+ concentration from 2.5 mM to 1.25 mM. In cases of the direct(muscle, 0.1 Hz, 5 ms, 10 V) stimulation, nifedipine increased the twitch response in a dose-dependent manner, but the amplitudes were smaller than those in indirect stimulation. Nifedipine 30 uM potentiated the contractile response induced by 70 mM KC1 and caffeine(10 mM)-induced isometric contractile responses were markedly potentiated by nifedipine treatmeat. Nifedipine 70 upotentiated the effect of l mM caffeine on the electrically-evoked twitch response and the potentiating effect was also seen in reverse treatment. On the basis of these findings, the result of present study suggests that the potentiating contractile response by nifedipine is mediated by two distinctive mechanisms. One is the acetylcholine release from presynaptic nerve terminal and the other may be due to the releases of Ca2+ in sarcoplasmic reticulum.
Acetylcholine ; Animals ; Caffeine ; Nifedipine* ; Rats* ; Sarcoplasmic Reticulum ; Tubocurarine