The Effect of Nicorandil on the Pharmacodynamics of Rocuronium / 대한마취과학회지

BACKGROUND: Some investigators have shown that nicorandil, a K(ATP) channel opener, depresses the neuromuscular transmission contraction of the skeletal muscle. However, others have reported that it improves the recovery of vecuronium relaxation and the myotonic activity of muscle. This study investigated the effect of nicorandil on rocuronium relaxation. METHODS: Hemidiaphragm-phrenic nerve preparations were obtained from male Sprague-Dawley rats (150-250 g). The preparations were bathed in Krebs' solution containing in (mM): NaCl 118, KCl 5, CaCl2 2.5, NaHCO3 30, KH2PO4 1, MgCl2 1 and glucose 11. The preparations were, then maintained at 32 degrees C and aerated with a mixture of 95% O2 and 5% CO2. Isometric forces that were generated in response to 0.1 Hz, and, 50 Hz for 1.9 seconds with supramaximal electrical stimulation (0.2 msec, rectangular) to the phrenic nerve were measured using a force transducer. The single twitch tension (ST) and peak tetanic tension (PTT) were calculated as % inhibition of the control, and the tetanic fade (TF), as % increase in the PTT. Each preparation was exposed to one of the 6 nicorandil concentrations (0.0, 0.625, 1.25, 2.5, 5, 10 micrometer), and the adequate volume of the rocuronium solution was cumulatively added to the tissue bath for a desired rocuronium concentration until there was an 80-90% decrease in the ST. The effect of rocuronium at each concentration was allowed to reach a steady state before the tension parameters were measured. The EC5, EC25, EC50, EC75, and EC95 of rocuronium for the ST, PTT and TF were calculated using a probit model. The differences between the EC50 of rocuronium according to the nicorandil concentrations were tested using a t-test and a Bonferroni's correction. RESULTS: 1.25 and 2.5 micrometer nicorandil shifted the cumulative concentration-response curves for the TF of rocuronium to the right. 5 and 10 micrometer nicorandil shifted the cumulative concentration-response curves for the ST of rocuronium to the left. CONCLUSIONS: Lower concentration of nicorandil may help maintain the tetanic contraction during rocuronium relaxation.

The Effect of Kanamycin on Rocuronium Neuromuscular Blockade in Rat Hemidiaphragm-phrenic Nerve Preparations / 대한마취과학회지

BACKGROUND: Kanamycin has been shown to block neuromuscular transmission by reducing acetylcholine can release or blocking postsynaptic receptors. This study was undertaken to investigate whether kanamycin can potentiate rocuronium neuromuscular block. METHODS: Hemidiaphragm-phrenic nerve preparations were obtained from male Sprague-Dawley rats (150-250 g). Preparations were bathed in Kreb's solution of (mM): NaCl 118, KCl 5, CaCl2 2.5, NaHCO3 30, KH2PO4 1, MgCl2 1 and glucose 11 maintained at 32oC and aerated with a mixture of 95% O2 and 5% CO2. Isometric forces generated in response to 0.1 Hz and 50 Hz for 1.9 seconds with supramaximal electrical stimulation (0.2 msec, rectangular) to the phrenic nerve, were measured using a force transducer. The effects of drugs on single twitch tension (ST) and peak tetanic tension (PTT) were calculated as % inhibition of control and tetanic fade (TF), as % increase. Each preparation (n = 20) was exposed to one of 4 kanamycin concentrations (0.0, 1.0, 2.0, 4.0 mM), and an adequate volume of rocuronium solution was cumulatively added to the tissue bath to achieve a 80-90% reduction in ST. An adequate volume of kanamycin solution was cumulatively added to the other 5 preparations to achieve a 80-90% reduction in ST. The effect of kanamycin or rocuronium at each concentration was allowed to reach a steady state before tension parameters were measured. EC5, EC25, EC50, EC75, and EC95 of rocuronium and kanamycin for ST, PTT and TF were calculated using a probit model. Drug interactions were drawn using Berenbaum's additive isobole at 25% isobole, 50% isobole, and 75% isobole. Differences between EC50's of rocuronium at different kanamycin concentrations were tested using one way ANOVA with Tamhane post hoc analysis, P values of < 0.05 were regarded significant. RESULTS: Kanamycin shifted cumulative concentration-response curves to the right. The interactions of these drugs varied from additive to antagonistic or synergistic according to the magnitude of neuromuscular block, concentration of the drugs and the frequency of the stimulation. CONCLUSIONS: Kanamycin lowered the effective concentration of rocuronium, but the interaction between rocuronium and kanamycin was variable.

The Effect of Pefloxacin on Rocuronium-Induced Neuromuscular Blockade in Rat Phrenic Nerve-Hemidiaphragm Preparations / 대한마취과학회지

BACKGROUND: At the neuromuscular junction, pefloxacin (P) may exacerbate myasthenia gravis and reduce the tau of MEPC. So here we investigated the effect of P on the neuromuscular blocking action of rocuronium (R). METHODS: Hemidiaphragm-phrenic nerve preparations were obtained from male Sprague-Dawley rats (150-250 g). Preparations were bathed in Kreb's solution (in (mM): NaCl 118, KCl 5, CaCl2 2.5, NaHCO3 30, KH2PO4 1, MgCl2 1 and glucose 11), maintained at 32oC and then aerated with a mixture of 95% O2 and 5% CO2. Isometric forces generated in response to 0.1 Hz, and, 50 Hz for 19 seconds with supramaximal electrical stimulation(0.2 msec, rectangular) to the phrenic nerve, were measured with a force transducer. Single twitch tension (ST) and peak tetanic tension (PTT) were calculated as % reduction versus the control, and tetanic fade (TF), as a % increase. Each preparation was exposed to one of 4 P concentrations of Krebs' solution (0, 0.25, 0.5, 1.0 mM), and enough R solution was added to the tissue bath to achieve the desired R concentration. The effects of P and R were allowed to stabilize before measuring tension parameters. EC5, EC25, EC50, EC75, and EC95 of R for ST, PTT and TF were calculated using a probit model. The interactions between the two drugs were drawn with Berenbaum's additive isobole at 25% isobole, 50% isobole, and 75% isobole. Differences between EC50's of R according to P concentrations were tested by one way ANOVA with Tamhane for post hoc; P <0.05 was regarded as significant. RESULTS: The cumulative concentration-effect curves shifted to the right in ST, and to the left in TF as the concentration of P was increased. The interactions between these two drugs varied from additive to antagonistic according to the magnitude of relaxation effect, drug concentration, and the frequency of stimulation. CONCLUSIONS: P augmented the TF of R. Our results suggest that simultaneous 0.1 Hz and 50 Hz stimulations allow the neuromuscular blocking action of a drug to be correctly evaluated.

The Effect of Magnesium on the Verapamil Neuromuscular Blockade in Rat Phrenic Nerve-Hemidiaphragm Preparations / 대한마취과학회지

BACKGROUND: At the neuromuscular junction, magnesium acts on the release of acetylcholine and on the excitability of sarcolemma. Verapamil inhibits acetylcholine release and enhances the autodesensitization of acetylcholine receptor ion channels. So, we studied the effect of magnesium on the neuromuscular blocking action of verapamil. METHODS: Hemidiaphragm-phrenic nerve preparations were obtained from male Sprague-Dawley rats (200-300 g). Preparations were bathed in Kreb's solution of (mM): NaCl 118, KCl 5, CaCl2 2.5, NaHCO3 30, KH2PO4 1, MgCl2 1 and glucose 11, then maintained at 32 degrees C, and aerated with a mixture of 95% O2 and 5% CO2. Isometric forces generated in response to 0.1 Hz and 50 Hz for 1.9 seconds with supramaximal electrical stimulation (0.2 msec, rectangular) to the phrenic nerve, were measured with a force transducer. Single twitch tension (ST) and peak tetanic tension (PTT) were calculated as % reduction versus the control, and tetanic fade (TF) as a % increase. Each preparation was exposed to one of 4 magnesium concentrations of Krebs' solution (0.5, 1.0, 2.0, 3.0 [mM]), and the adequate volume of verapamil stock solution was added to the tissue bath to achieve the desired verapamil concentration. The effects of magnesium and verapamil were allowed to reach a steady state before tension parameters were measured. EC5, EC25, EC50, EC75, and EC95 of verapamil for ST, PTT and TF were calculated using a probit model. Differences between the EC50's of verapamil according to magnesium concentrations were tested using the Mann-Whitney U test with the Bonferroni correction, P < 0.05 was regarded as significant. RESULTS: The effective concentration of verapamil reduced at magnesium concentrations of 0.5, 2.0 and 3.0 (mM). CONCLUSIONS: The neuromuscular action of verapamil was found to be potentiated at either lower or higher magnesium concentrations.

Effect of Diltiazem on Pancuronium - and Vecuronium - induced Neuromuscular Blockade / 대한마취과학회지

The effects and interactions of pancuronium and vecuronium with diltiazem on the electri- cally-evoked twitch response, train-of-four and tetanic stimulation were studied in the isolated rat hemi-diaphragm preparation. Pancuronium(3 X 10(-7) -10(-5) M) and vecuronium(3 X 10(-6)-15 X 10(-6) M) decreased the electrically evoked(nerve stimulation, 0.1Hz, 0.5ms, 10V) twitch response, train-of-four and tetanus ratio in a dose-related fashion and pancuronium was more potent than vecuronium. The inhibitory effects of pancuronium and vecuronium were potentiated by pretreatment with 5 & 10 uM diltiazem, a Ca++-channel blocker, in which the concentration of diltiazem has no obvious effects on the twitch response itself. Furthermore, it is noteworth that the inhibitory effects of pancuronium and vecuronium were markedly potentiated by 150 uM hemicholinium pretreatment. In cases of the direct(muscle, 0.1 Hz, 5 ms, 10 V) stimulation, pancuronium and vecuronium decreased the electrically evoked twitch response dose dependently, but the amplitudes of inhibition were less than those in indirect(nerve) stimulation. The inhibitory effects were not affected by diltiazem pretreatment except low doses of vecuronium. On the basis of these findings, the result of the present study suggests that the muscle relaxation by pancuronium and vecuronium is mediated by pre- and post-junctional receptor blockade, and that diltiazem intensifies neuromuscular blockade produced by muscle relaxants. The potentiating effect of diltiazem may be due to blocking influx of calcium and/or release of acetylcholine from presynaptic nerve terminals.

Effect of Diltiazem on Pancuronium - and Vecuronium - induced Neuromuscular Blockade / 대한마취과학회지

The effects and interactions of pancuronium and vecuronium with diltiazem on the electri- cally-evoked twitch response, train-of-four and tetanic stimulation were studied in the isolated rat hemi-diaphragm preparation. Pancuronium(3 X 10(-7) -10(-5) M) and vecuronium(3 X 10(-6)-15 X 10(-6) M) decreased the electrically evoked(nerve stimulation, 0.1Hz, 0.5ms, 10V) twitch response, train-of-four and tetanus ratio in a dose-related fashion and pancuronium was more potent than vecuronium. The inhibitory effects of pancuronium and vecuronium were potentiated by pretreatment with 5 & 10 uM diltiazem, a Ca++-channel blocker, in which the concentration of diltiazem has no obvious effects on the twitch response itself. Furthermore, it is noteworth that the inhibitory effects of pancuronium and vecuronium were markedly potentiated by 150 uM hemicholinium pretreatment. In cases of the direct(muscle, 0.1 Hz, 5 ms, 10 V) stimulation, pancuronium and vecuronium decreased the electrically evoked twitch response dose dependently, but the amplitudes of inhibition were less than those in indirect(nerve) stimulation. The inhibitory effects were not affected by diltiazem pretreatment except low doses of vecuronium. On the basis of these findings, the result of the present study suggests that the muscle relaxation by pancuronium and vecuronium is mediated by pre- and post-junctional receptor blockade, and that diltiazem intensifies neuromuscular blockade produced by muscle relaxants. The potentiating effect of diltiazem may be due to blocking influx of calcium and/or release of acetylcholine from presynaptic nerve terminals.

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.

Effect of Nifedipine on the Contractile Response in the Isolated Rat Phrenic - Hemidiaphragm / 대한마취과학회지

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.