The Neuromuscular Effects of Glucocorticoid Administration on the Skeletal Muscle of Rats / 대한마취과학회지

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.

Inhibitory Effects of Structurally Different Neuromuscular Blockers on the Serotonin Type 3 Receptor Expressed in Xenopus Oocytes / 대한마취과학회지

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.

Inhibitory Effects of Structurally Different Neuromuscular Blockers on the Serotonin Type 3 Receptor Expressed in Xenopus Oocytes / 대한마취과학회지

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.

Dual action of d-tubocurarine on large-conductance Ca2+-activated K+ channels from rat brain reconstituted into planar lipid bilayer

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.

Influence of Various Muscle Relaxants on the Plasma Cholinesterase Activity / 대한마취과학회지

BACKGROUND: The reduction in the plasma cholinesterase (PChE) level results in slow to hydrolysis of succinylcholine (SCC) and mivacurium (MIV). The factors altering the level of the normal enzyme in human could be considered under the several conditions. We investigated in the present study whether the drugs induced decreases in normal PChE activity after administration of various muscle relaxants during anesthesia are evident and how these results should be influenced to the time course of neuromuscular blockade produced by SCC and MIV. METHODS: Young adult patients of ASA class I or II scheduled for elective surgery requiring muscle relaxation were premedicated and anesthesia was maintained with nitrous oxide in oxygen with increment of thiopentone or fentanyl as required. In the neuromuscular monitoring, surface electrodes were applied on the ulnar nerve at wrist. Supramaximal transcutaneous single twitch stimulation (1 Hz) during onset and 0.1 Hz during recovery of neuromuscular blockade induced by various muscle relaxants delivered by a peripheral nerve stimulator was applied. Twitch response of thumb adductor was measured mechanomyographically using 2 kg Load Cell Strain Gauge with thumb piece modification. Recordings were made on a Gould recorder. PChE levels were measured by the modified Garry method after induction of anesthesia and, at 3, 10, 20 and 30 min following administration of 2 x ED95 of pancuronium (PAN), vecuronium (VEC) and atracurium (ATR). Neuromuscular recordings were measured with onset time defined as lag time and manifest time, and recovery time defined as clinical duration, recovery index and total duration. RESULTS: The levels of PChE were significantly reduced after administration of PAN and VEC (p<0.05). Onset times were significantly shorten but recovery time in the group given MIV pretreated by small dose of PAN was significantly prolonged (p<0.05). And there were a evidence to prolong recovery time in the group pretreated by small dose of VEC but not significant. CONCLUSIONS: It is concluded that aminosteroidal derivative neuromuscular blocking agents have presumably evidence induced decreases in PChE activity rather than benzylisoquinolinium derivative neuromuscular blocking agents.

Influence of Decamethonium on the Neuromuscular Blocking Action of d-Tubocurarine in the Rat Phrenic Nerve Hemidiaphragm Preparation / 대한마취과학회지

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.

The Effect of Frequency of Stimulation on Partial Twitch Depression in a Rat Phrenic Nerve Hemidiaphragm Preparation / 대한마취과학회지

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.

A Study on the Blocking Effect of Diltiazem and Verapamil in the Isolated Rat Phrenic - Hemidiaphragm / 대한마취과학회지

The effects of diltiazem and verapamil on the electrically-evoked twitch response, train-of- four and tetanic stimulation were studied in the isolated rat hemidiaphragm preparation. Diltiazem(3-150 pM) and verapamil(3-100 pM) increased the electrically-evoked(nerve stimulation, 0.1 Hz, 0.5 ms, 10 V) twitch responses in a dose-related fashion and diltiazem was more potent than verapamil. But, the large doses of diltiazem(150-300 uM) and verapamil(100-300 uM) decreased the twich responses. And the effects of diltiazem and verapamil were not effected by reducing the extracellular calcium from 2.5 to 1.25 mM. Diltiazem and verapamil decreased the train-of-four and tetanus ratio as well as the d-tubocurarine in a dose-related fashion. d-Tubocurarine, a specific nicotinic antagonist, decreased twitch response, and the potentiating twitch response of diltiazem was significantly inhibited by pretreatment of d-tubocura- rine. Furthermore, it is noteworth that the inhibitory effects of d-tubocurararine were markedly potentiated by diltiazem. In cases of the direct(muscle, 0.1 Hz, 5 ms, 10 V) stimulation, diltiazem and verapamil decreaaed the electrically-evoked twitch response with dose dependently. These results indicate that diltiazem and verapamil elicited two distinctive types of twitch response in the rat phrenic-hemidiaphragm preparation. The potentiating effect of twitch response is mediated by the acetylcholine release from the prejunctional nerve terminal and the inhibiting effect may be due to blcking influx of calcium and/or release of acetylcholine from presynaptic nerve terminals.

Hemodynamic Changes by Speed of Injection of d-Tubocurarine under General Anesthesia / 대한마취과학회지

d-Tubocurarine(d-TC) causes hypotension, probably as a result of the liberation of histamine; in larger doses, it produces ganglionic blockade. An increase of histamine levels in plasma to 200 to 300 percent of baseline causes a brief decrease in arterial blood pressure(1 to 5 minutes) and the increase in heart rate. The amount of histamine released by d- TC is dose related and is also related to speed of injection. Therefore histamine release can be minimized by the slow administration, light level of surgical anesthesia, and the use of smaller doses. Thus, the purpose of this study was to prevent the cardiovascular effect of d-TC by the slow administration undergoing general anesthesia. The study population was from 40 patients scheduled for elective surgery at Yeungnam University Hospital, who belonged to physical status I or II of ASA classification. Patients were divided into 4 groups by speed of injection of 10, 30, 60 and 120 seconds(group 1, 2, 3 and 4, respectively). All patients were premedicated with hydroxyzine 1mg/kg, glycopyrrolate 0.2mg, and fentanyl 1 ug/kg IM 30 minutes before anesthesia. Patients were induced with thiopental sodium 4-5 mg/kg until the disappearance of lid-reflex. Succinylcholine 1.0 mg/kg IV was used to facilitate endotracheal intubation. As soon as relaxafion was complete, laryngoscopy was initiated. After the completion of intubation, nitrous oxide and 50% oxygen with 0.6% halothane was administrated. The blood pressure and heart rate were measured using noninvasive automatic blood pressure manometer for 60 minutes per 1 minute. Data were analyzed with one-way ANOVA test within the groups. p<0.05 was considered significant. The results were as follows, The changes of blood pressure was decreased in rapid injection groups(Group 1 & 2) compared with slowly injection groups(Group 3 & 4) at 2 min, 5 min after d-TC administration. The changes of heart rate was significantly increased(p<0.05) at 1min, 2 min after d-TC administration in rapid injection groups compared with slow injection groups. These results show that the cardiovascular effect of d-TC might be prevented by slowly administration undergoing general anesthesia.

The Effect of Small Dose of Nondepolarizing Muscle Relaxant Administered Prior to Succinylcholine on Intubating Condition / 대한마취과학회지

Subparalyzing dose of nodepolarizing relaxants prior to injection of succinylcholine has been used to prevent various adverse effects induced after succinylcholine. For investigating interactions between succinylcholine and small doses of four non-depolar-izing agents, the 112 subjects that were ASA class 1-2 and no existing neuromuscular conduction system disorder were divided into 5 groups that were control group(only succinylcholine 1 mg/kg) and pretreated group d-tubocurarine 0.5 mg/kg, atracurium 0.08 mg/kg, vecuronium 0.01 mg/kg and pancuronium 0.01 mg/kg. In each group, the plasma concentration of K+ and PChE before and after use of succinylcholine, fasciculation, onset and recovery time of succinylcholine block and intubating conditon were observed. The results are as follows; In the pretreated group, there were no significant changes of plasma concentration of K+ and plasma cholinesterase(Table 3) but diminished the incidence of fascieulation, delayed the onset time and shorted the recovery time of succinylcholine block(Table 4), and worse in intubating condition(Table 5) except pancuronium treated group. It was concluded that these seem to make worse condition of intubation, while small doses of nondepolarizing muscle relaxants except pancuronium antagonize depolarizing muscle relaxant.

The Effect of Small Dose of Nondepolarizing Muscle Relaxant Administered Prior to Succinylcholine on Intubating Condition / 대한마취과학회지

Subparalyzing dose of nodepolarizing relaxants prior to injection of succinylcholine has been used to prevent various adverse effects induced after succinylcholine. For investigating interactions between succinylcholine and small doses of four non-depolar-izing agents, the 112 subjects that were ASA class 1-2 and no existing neuromuscular conduction system disorder were divided into 5 groups that were control group(only succinylcholine 1 mg/kg) and pretreated group d-tubocurarine 0.5 mg/kg, atracurium 0.08 mg/kg, vecuronium 0.01 mg/kg and pancuronium 0.01 mg/kg. In each group, the plasma concentration of K+ and PChE before and after use of succinylcholine, fasciculation, onset and recovery time of succinylcholine block and intubating conditon were observed. The results are as follows; In the pretreated group, there were no significant changes of plasma concentration of K+ and plasma cholinesterase(Table 3) but diminished the incidence of fascieulation, delayed the onset time and shorted the recovery time of succinylcholine block(Table 4), and worse in intubating condition(Table 5) except pancuronium treated group. It was concluded that these seem to make worse condition of intubation, while small doses of nondepolarizing muscle relaxants except pancuronium antagonize depolarizing muscle relaxant.

The Effect of Succinylcholine on the Intracranial Pressure in Cats / 대한마취과학회지

Succinylcholine (1.5mg/kg) without pretreatment, or succinylcholine (1.5mg/kg) with pretreatment by vecuronium (0.015 mg/kg, 0.045 mg/kg, 0.15 mg/kg) or d-tubocurarine (0.1 mg/kg, 0. 3 mg/ kg, 1mg/kg) was given to cats of the same genus (body weight 2.5-3.5kg) under subcutaneous urethane anesthesia to determine the effect of the intracrainal pressure increase in each method. The results are summarized as follows: 1) The intracranial pressure was significantly increased (0.005< p< 0.01)with the administration of succinylcholine(1.5mg/kg). 2)The intracranial pressure was not increased with the administration of vecuronium. 3)As the dosage of d-tubocuraine administration increased, the intracranial pressure was increased. 4)The increase of the intracranial pressure by succinylcholine was depressed dose-dependently by vecuronium pretreament. 5)The increase of the intracranial pressure by succinylcholine was depressed by d-tubocurarine(0.3mg/kg)pretreatment.

Circulatory Changes during Laryngoscopy and Tracheal Intubation with Prior Administration of Lidocaine , d-Tubocurarine and Diazepam / 대한마취과학회지

Direct laryngoscopy and endotracheal intubation is accompanied by mechanical stimulation of the laryngopharynx & by sympathetic timulation, as reflected by an increase in heart rate and blood pressure. The purpose of this study is to evaluate effects of certain drugs on blood pressure and heart rate during intubation. We intravenously administered some drugs prior to laryngoscopy and endotracheal intubation in adult patients with ASA class 1-2. Seventy-two patients were devided into four groups as follows: Group 1: Control group (none, n=18). Group 2: Lidocaine only (n=18). Group 3: Lidocaine (1 mg/kg) and d-Tubocurarine (3mg)(n=18). Group 4: Lidocaine (1mg/kg), d-Tubocurarine (3mg) and diazepam (0.1mg/kg)(n=18). Blood pressure, heart rate, mean arterial pressure, rate-pressure product, aterial blood gas were measured before induction, after induction, immediately after intubation and at 1, 2, 3 & 5 minutes after intubation. The results were as follows: 1) There were no significant differences in preinduction values of blood pressure, heart rate, rate-pressure product, arterial blood gas. 2) Systolic blood pressure increased significantly 2 minutes after the intubation in all groups and rapidly returned to the preinduction level in group 4, group 3 and then group 2 in that order compared to group l. 3) Diastolic and mean arterial pressure elevated significantly during intubation and rapidly retur- ned to the preinduction level in group 4, group 3 and then group 2 in that order compared to group l. 4) Heart rate increased significantly after the intubation in all groups and more rapidly returned to the preinduction levels 3 minutes after the intubation in group 4. 5) Rate-pressure product following the intubation was over 15,000 mmHg. beat/min in all groups, and more rapidly decreased 15,000 mmHg. beat/min at 2 minutes after the intubtion in group 4, 5 minutes after the intubation in group 3. 6) pH, PaCO2and PaO2values were within normal range following the intubation in all groups. In conclusion, it is suggested that the administration of lidocaine, d-tubocurarine and diazepam prior to the intubation is ideal for those patients with cardiovascular disease & increased intracranial pressure.