Neuromuscular Blocking Actions of Hexamethonium, Rocuronium and (-)Vesamicol / 대한마취과학회지

BACKGROUND: Hexamethonium (HM) and Rocuronium (R) are nAChR antagonists. However, there is some controversy as to whether R has a selective presynaptic effect. (-)Vesamicol (V) inhibits the transport of acetylcholine into the vesicles. This study compared the neuromuscular blockade of HM, R and V. METHODS: Hemidiaphragm-phrenic nerve preparations (male Sprague-Dawley rats [150-250 g]) were bathed in a Krebs solution maintained at 32oC and aerated with a mixture of 95% O2 and 5% CO2. Isometric forces were generated in response to 0.1 Hz, and 1.9-second 50 Hz with supramaximal stimulation (0.2 ms, rectangular) of the phrenic nerve. HM, R and V were added sequentially to achieve an 80-90% decrease in the ST. The ECs for ST, PTT and TF were calculated using a probit model. The antagonism indices of calcium (5 mM) and neostigmine (N) (250 nM) were assessed at the 85+/-5% level. RESULTS: The potency of ST, PTT and TF were respectively, 5.92, 3.56 and 1.99 mM for HM, 10.81, 5.27 and 4.4 1micronM for R, and 19.4, 15.2 and 13.3micronM for V. The neuromuscular blockades of R were reversed by N but not by calcium. Those of V were not reversed by either of them. Calcium and N inhibited the decrease in ST and TF by HM, respectively. CONCLUSIONS: The mechanism for how HM and R affect the neuromuscular blockade are different. V might not affect the release of acetylcholine.

Studies of Interaction between Hexamethonium and Lidocaine, alpha-Bungarotoxin or Decamethonium in Vitro / 대한마취과학회지

BACKGROUND: Interactions of neuromuscular blocking agents are antagonistic in a combination of depolarizing and nondepolarizing agents, additive in a combination of relative two compounds or synergistic in a combination of different two nondepolarizing agents. However, the interactions of neuromuscular blocking agents with a different site of action from each other have not been studied clearly. This study was designed to examine the interaction between hexamethonium and lidocaine, alpha-bungarotoxin or decamethonium with markedly different pre and postsynaptic sites of action. METHODS: Square wave, 0.1 Hz supramaximal stimuli or 2 Hz, 0.2 ms train of four (TOF) stimuli, was applied to the rat phrenic nerve-hemidiaphragm preparation, and the twitch height response was recorded mechanomyographically. The cumulative concentration effect and TOF ratio at each point of twitch depression after hexamethonium, lidocaine, alpha-bungarotoxin or decamethonium given were measured. The EC50 and EC95 of hexamethonium, lidocaine, alpha-bungarotoxin and decamethonium were calculated using an inhibitory sigmoid Emax model. In the experiment of each combination of two drugs, three points of the isobole for hexamethonium-lidocaine, hexamethonium-alpha-bungarotoxin and hexamethonium-decamethonium were established using ratios of 1 : 3, 1 : 1 and 3 : 1 of their EC50. Points on the line of theoretical additivity and 95% confidence intervals were calculated according to Tallarida et al. TOF ratios were observed at 75, 50 and 25% of the control twitch height value during each combination ratio of their EC50. RESULTS: Significant deviations of points on the isobole from the line of additivity to the left were found at all EC50 ratios of hexamethonium-lidocaine (P < 0.05 respectively), that to the right was found at all EC50 ratios of a hexamethonium-alpha-bungarotoxin and hexamethonium-decamethonium (P < 0.05 respectively). The magnitude of TOF fade depended upon the mixed ratios for their EC50. CONCLUSIONS: The interaction was found to be synergistic in the combination of hexamethonium- lidocaine, and antagonistic in the combination of hexamethonium-alpha-bungarotoxin and hexamethonium- decamethonium.

Neuromuscular Blocking Properties of beta-Bungarotoxin, Hexamethonium and Verapamil in the Rat Phrenic Nerve-Hemidiaphragm Preparation / 대한마취과학회지

BACKGROUND: beta-Bungarotoxin irreversibly changes the presynaptic membrane, hexamethonium acts on the presynaptic nicotinic receptor, and verapamil blocks the ion channels on the presynaptic membrane. The effect of these drugs on twitch height and train of four (TOF) ratio were investigated, as well as the reversal effects of neostigmine, pyridostigmine or 4-aminopyridine (4-AP) on the partial neuromuscular blockade induced by these drugs. METHODS: Square wave, 0.1 Hz supramaximal stimuli or 2 Hz, 0.2 ms train of four stimuli, was applied to the phrenic nerve-hemidiaphragm preparation of the rat, and the twitch height response was recorded mechanomyographically. The cumulative concentration effects and TOF ratios at each point of twitch depression after beta-bungarotoxin, hexamethonium or verapamil were measured. TOF ratios were observed at 75, 50 and 25% of the control twitch height value during observation of the concentration effect. The EC50 and EC95 of beta-bungarotoxin, hexamethonium or verapamil were calculated using an inhibitory sigmoid Emax model. The reversal effect of some doses of neostigmine, pyridostigmine or 4-aminopyridine to the partial neuromuscular block produced by EC50 of beta- bungarotoxin, hexamethonium or verapamil was determined. RESULTS: The EC50 and EC95 of beta-bungarotoxin, hexamethonium and verapamil were 0.0695 and 0.1160 microgram/ml, 1267.0 and 2033.5 microgram/ml and 29.45 and 37.99 microgram/ml respectively. TOF fade was marked with hexamethonium or verapamil but small with beta-bungarotoxin. Neostigmine or pyridostigmine did not reverse the partial neuromuscular block induced by beta-bungarotoxin, hexamethonium or verapamil. However, 4-AP produced a dose-dependent recovery of the twitch response (P < 0.05). CONCLUSIONS: beta-Bungarotoxin, hexamethonium and verapamil produced different degree of TOF fade, and this may be due to different sites of action of these drugs. 4-AP reversed effectively the partialneuromuscular block induced by beta-bungarotoxin, hexamethonium and verapamil, whereas, neostigmine and pyridostigmine did not.

Evaluation of Presynaptic Action of Depolarizing Neuromuscular Blocking Agents with Single Twitch Response in Vitro / 대한마취과학회지

BACKGROUND: This study was performed to evaluate the presynaptic effects of depolarizing neuromuscular blocking drugs by using slow and fast frequencies of indirect stimulation on partial twitch depression in vitro. METHODS: A rat phrenic nerve hemidiaphragm was dissected and was mounted in an organ bath containing an oxygenated Krebs solution. The phrenic nerve was stimulated supramaximally and the twitch response (0.1 Hz) was stabilized for at least 30 minutes. T200/T1 ratio (twitch height of the 200th stimuli divided by that of the first 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, a 2.0 Hz TOF response was measured immediately after the 200th stimuli at either frequency of stimulation. RESULTS: T200/T1 ratios produced by succinylcholine (SCC) and decamethonium (C10) were located between alpha-bungarotoxin (ABX) and hexamethonium (C6), however, significant differences among the four drugs were found at 2.0 Hz. The propensity for a decrease in T200/T1 ratios at 2.0 Hz might differ from this study: C6 > C10 > SCC > ABX. T200/T1 ratios at 2.0 Hz were not different from TOF ratios. CONCLUSIONS: It is concluded that small doses of C10 have a greater presynaptic activity than that of SCC, when the observed effects in this study were compared with the result of ABX acting predominantly at postsynaptic receptors and C6 acting predominantly at presynaptic receptors.

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.

Electronmicroscopic Study of the Effect of Hexamethonium on Serous Choriretinopathy in Rabbits

Stress has been regrarded as one of the causes of central serous chorioretinopathy. We studied the effect of Hexamethonium (ganglionic blocking agent) on experimentaI serous chorioretinopathy following epinephrine injection in rabbits. In group 1, we injected the 0.1 % epinephrine into the rabbits through IV route for 10 days and in group 2, we addited Hexamethonium subcutaneously prior to injection of the epinephrine same term of gorup 1. We could find slight histological changes in gorup 2 as com paired with group 1, which produced serous chorioretinopathy, under the electronmicroscopic study so we would expect the preventive effect of Hexamethonium on the stress-induced serous chorioretinopathy.

Electronmicroscopic Study of the Effect of Hexamethonium on Serous Choriretinopathy in Rabbits

Stress has been regrarded as one of the causes of central serous chorioretinopathy. We studied the effect of Hexamethonium (ganglionic blocking agent) on experimentaI serous chorioretinopathy following epinephrine injection in rabbits. In group 1, we injected the 0.1 % epinephrine into the rabbits through IV route for 10 days and in group 2, we addited Hexamethonium subcutaneously prior to injection of the epinephrine same term of gorup 1. We could find slight histological changes in gorup 2 as com paired with group 1, which produced serous chorioretinopathy, under the electronmicroscopic study so we would expect the preventive effect of Hexamethonium on the stress-induced serous chorioretinopathy.