国产维库溴铵神经肌肉阻滞效应及对心血管的影响

目的：评价国产维库溴铵的神经肌肉阻滞效应及对心血管的影响。方法：选择择期手术病人２０例，随机分为国产维库溴铵组（１０例）和进口维库溴铵组（１０例）。每组均注射维库溴铵０．１ｍｇ／ｋｇ后测定肌松药的起效时间和维持时间，并观察心血管反应。结果：国产维库溴铵和进口维库溴胺在神经肌肉阻滞效应的各项指标和对心血管的影响方面均无明显差异。结论：国产维库溴铵的肌松效果满意且不明显影响心血管系统。     

Cardiac effects of non-depolarizing neuromuscular blocking agents pancuronium,vecuronium, and rocuronium in isolated rat atria.

Pancuronium, vecuronium, and rocuronium produce different cardiac effects. Using spontaneously beating right and electrically stimulated left rat atria, while measuring developed force, effective refractory period, and heart rate, we determined and compared the concentration-dependent cardiac effects of the compounds. The preparations were exposed to five progressively increasing concentrations of these compounds (10(-9), 10(-8), 10(-7), 10(-6), and 10(-5) mol/L). Pancuronium increased heart rate; vecuronium and rocuronium produced positive inotropic effects; and vecuronium shortened refractoriness. These effects may be the result of a blockade of the M2 muscarinic receptors. However, the concentrations required to produce changes were higher than those observed in patients under neuromuscular blockade.     

The neuromuscular blocking action of spectinomycin on the mouse hemidiaphragm preparation

1. The mechanism of action of the muscle paralysing property of the antibiotic spectinomycin has been investigated on the isolated mouse phrenic nerve-hemi-diaphragm preparation. 2. Spectinomycin produced a neuromuscular blockade that was poorly reversed by neostigmine (3 μmol/l) but well reversed by both calcium (5 mmol/1) and 3,4-diaminopyridine (0.1 mmol/1). 3. Intracellular techniques were used to record endplate potentials and miniature endplate potentials from hemidiaphragms paralysed by spectinomycin. Miniature endplate potentials were reduced both in frequency and in amplitude. The quantal content of the endplate potential during spectinomycin paralysis calculated by the method of variance was 14, a value similar to that found in preparations paralysed by the prejunctionally active magnesium. 4. Thus spectinomycin possesses weak neuromuscular blocking activity by a predominant action on acetylcholine release.     

Blocking effect of diltiazem in the isolated rat phrenic hemidiaphragm

The effects of diltiazem on indirectly and directly elicited twitch were studied in the isolated rat phrenic hemidiaphragm preparation. Diltiazem (30-500 microM) blocked the indirectly elicited twitch response and this effect was not affected by reducing the extracellular calcium from 2.5 to 1.25 mM. An effect on the directly elicited twitch was also observed (100-300 microM). Diltiazem (30-300 microM) blocked the peak tetanic tension and tetanic fade was present. The results were consistent with an action of diltiazem on the nicotinic receptor-ion channel complex.     

Neuromuscular blocking action of cadmium and manganese in isolated frog striated muscles.

In isolated frog sciatic nerve--gastrocnemius muscle preparations, exposure for 60 min to Cd2+ (0.1-2 mM) caused a marked attenuation of the twitch tension developed by stimulation of nerves but no or only a slight inhibition of the tension produced by direct stimulation at maximum twitch height. The inhibitory effect was partially reversed by 1 mM cysteine. In frog sartorius muscles, the addition of Cd2+ (0.1 mM) alos abolished the end-plate potential evoked by nerve stimulation but did not suppress potential changes induced by iontophoretically applied acetylcholine. The addition of Mn2+ (2 and 5 mM) attenuated the response of muscles to both direct and indirect stimulation; a greater attenuation of the latter was observed. The inhibition was not reserved by cysteine but was partially reversed by excess Ca2+. Contractile responses of frog rectus abdominis muscles to acetylcholine were not significantly affected by Cd2+ and Mn2+ but were attenuated by d-tubocurarine in a dose-dependent manner. Impulse conduction along sciatic nerves was not impaired by Cd2+ and Mn2+ but was by procaine. It appears that Cd2+ interferes with the release of acetylcholine from motor nerve terminals by reducing the transmembrane influxes of Ca2+, the influx possibly relating to SH groups of membrane constituents.     

The effect of nickel chloride on the isolated hemidiaphragm of the rat

• 1.1. NiCl₂ (cumulative concentrations of 0.56–1.91 mmol 1⁻¹) produced concentration-dependent depression of tension developed (Td) and the maximum rate of rise of tension (dT/dt) max) of isometric contraction of the isolated rat hemidiaphragm, during direct subtetanic (DST) electrical stimulation, only. EC₅₀ values for NiCl₂-induced depression of Td and dT/dt max were 0.88 ± 0.06 and 0.83 ± 0.13 mmol 1⁻¹, respectively. NiCl₂ did not significantly change either parameter of the isometric contraction during direct single-pulse (DSP) electrical stimulation.
• 2.2. Maximal depression of Td and dT/dt max, produced by a single concentration of NiCI₂ (1 mmol 1⁻¹) during DST electrical stimulation was obtained 20 min after addition of the drug in the bathing medium.
• 3.3. In the normal Tyrode solution, addition of CaCl₂ (final concentration of 5.86 mmol 1⁻¹) almost completely antagonized the depressant effect of NiCl₂ (1 mmol l⁻¹) on Td and dT/dt max during DST electrical stimulation. In the calcium-free solution, the depression both of Td and dT/dt max produced by NiCl₂ (1 mmol 1⁻¹) was significantly more pronounced in comparison with the effect of NiCl₂ in the normal Tyrode solution.
• 4.4. l-calcium channel activator, Bay K 8644 (25 μmol 1⁻¹), significantly potentiated both Td and dT/dt max during DST electrical stimulation, but NiC1₂ (1 mmol 1⁻¹) decreased both parameters of the isometric contraction even in the presence of this concentration of Bay K 8644. On the other hand Bay K 8644 (25 μmol 1⁻¹) did not antagonize NiCl₂-induced depression of Td and dT/dt max.
• 5.5. Verapamil (2.5 μmol l⁻¹; 45 min of incubation) and lidocaine (0.10 mmol l⁻¹; 30 min of incubation) significantly potentiated the depression of Td and dT/dt max, produced by NiCl₂ (1 mmol l⁻¹), during DST electrical stimulation. The addition of CaCl₂ (final concentration of 7.20 mmol 1⁻¹) in the bathing medium only partially antagonized the depressant synergistic action of both verapamil or lidocaine and NiCl₂ on Td and dT/dt max.
• 6.6. Forskolin (cumulative concentrations of 2.60–44.20 μmol 1⁻¹) fully antagonized NiC1₂-induced depression of both Td and dT/dt max; propranolol (1 μmol l⁻¹) did not abolish this antagonizing action of forskolin. Also, NiCl₂ (cumulative concentrations of 0.56–1.54 mmol 1⁻¹) did not change potentiating effect of forskolin (23.4 μmol 1⁻¹).
• 7.7. In conclusion, NiCl₂-induced depression of both Td and dT/dt max of the isolated rat hemidiaphragm, during DST electrical stimulation could be specific in part, due to the block of calcium influx, and partially non-specific.

     

The effect of imidazole on the isometric contractility of the isolated hemidiaphragm of the rat.

Imidazole (0.73-15.9mM) was found to increase both tension developed Td and the maximum rats of rise of tension, dT/dtmax, in the isolated hemidiaphragm of the rat during indirect stimulation. Similar effects were obtained during direct stimulation and in the presence of d-tubocurarine. Imidazole (0.73-22 mM) antagonized the action of d-tubocurarine. This effect was particularly pronounced in preparations pretreated with imidazole. Propranolol did not significantly change the action of imidazole on Td and dT/dtmax during direct stimulation. Similarly, propranolol did not affect the action of low concentrations of imidazole during indirect stimulation. When present in the bath for periods of time longer than 15 min, propranolol significantly depressed the effect of even high concentrations of imidazole on Td and dT/dtmax during indirect stimulation. Histamine (0.18-0.91 mM) did not affect either Td or dT/dtmax. In the experiments in vivo, imidazole (12.5-100 mg/kg) produced a small increase both in Td and dT/dtmax of the gastrocnemius muscle during sciatic nerve stimulation. The available evidence indicates that the action of imidazole on Td and dT/dtmax is not connected with its action on phosphodiesterase, but it is most probably due to a direct action on the muscle.     

Neuromuscular blocking activity of two fractions isolated from the venom of the seasnake, Laticauda semifasciata

Two components (0·06 M and 0·09 M fractions) have been isolated from the venom of the seasnake, Laticauda semifasciata. Both are similar polypeptides, each with about 100 amino acids and a mol. wt of approximately 10,000. When tested on the isolated chick biventer cervicis nerve-muscle preparation, both fractions were post-junctional cholinoceptor antagonists, although about 100 times less active than erabutoxin b from the same venom. The fractions chemically resemble venom phospholipase A, but they differed from the enzyme in some effects at the neuromuscular junction. The fractions were very slowly and only partially reversible, whereas the effects of phospholipase A were reversed rapidly on washing.     

Interaction of halothane and aminophylline on the isolated hemidiaphragm of the rat

Halothane itself (1--3 vol percent) produced no significant changes in either Td or dT/dt max of the isolated hemidiaphragm during direct electrical stimulation. On the other hand, halothane significantly potentiated the effect of aminophylline on the resting tension of the muscle, both in a resting non-stimulated muscle and during direct electrical stimulation. Diethyl-ether did not affect the action of aminophylline on the resting tension. The interaction between halothane and aminophylline can be taken as a model for malignant hyperpyrexia. Procaine regularly produced further potentiation of the halothane-aminophylline interaction. There was no halothane-aminophylline interaction in a calcium-free medium. Verapamil was found to potentiate the halothane-aminophylline interaction, whereas di-Na-EDTA depressed it. Halothane did not significantly affect the actions of isoprenaline and adrenaline on Td and dT/dt max during direct electrical stimulation. So far, there is no obvious molecular basis for the action of halothane, but the available evidence indicates that its action is taking place both on the cell membrane and inside the cell, probably by blocking the reaccumulation of calcium in the sarcoplasmic reticulum and thus increasing the amount of free calcium in the cell.     

The effect of forskolin on the isometric contraction of the isolated hemidiaphragm of the rat.

The effects of forskolin on the parameters of the isometric contraction alone and in combination with aminophylline and isoprenaline were studied on the isolated hemidiaphragm of the rat during direct electrical stimulation. Forskolin (2.6 - 18.2 mumol l-1) produced a concentration-dependent increase in tension developed (Td) and, to a lesser extent, in the maximum rate of rise in tension (dT/dt max). The dose-response curve for the action of forskolin (2.6 - 18.2 mumol l-1) on Td was shifted to the left in the presence of a standard concentration of aminophylline (0.32 mmol l-1). Forskolin (5.2 mumol l-1) produced a further and significant increase in both Td and dT/dt max in the presence of isoprenaline (0.24 mumol l-1) in the bath. In a calcium-free medium, the effects of forskolin (7.80 and 18.2 mumol l-1) on Td and dT/dt max were significantly weaker than in a medium containing calcium. These data indicate that forskolin increases the isometric contraction of the isolated hemidiaphragm probably by activating the adenosine 3':5'-cyclic monophosphate (cyclic AMP) generating system. These effects are possible only in the presence of calcium.     

Neuromuscular blockade with vecuronium in paediatric patients with burn injury.

1. The effect of body surface area (BSA) burn injury on neuromuscular pharmacodynamics of vecuronium was evaluated. 2. The neuromuscular responses of 15 burned children were compared with those in five controls. 3. The effective dose for 50% suppression of twitch tension (ED50) was 34 micrograms kg-1 for patients with less than 40% BSA burn, 55 micrograms kg-1 for 40-60% BSA burn, and 65 micrograms kg-1 for patients with greater than 60% BSA burn. These values were significantly higher than the value for control patients, which was 18 micrograms kg-1. 4. Burn injury induces a resistance to the neuromuscular effects of vecuronium, the magnitude of which is related to burn size.     

NG-nitro-L-arginine methyl ester potentiates the effect of aminophylline on the isolated rat hemidiaphragm

The effects of different concentrations of N(G)-nitro-L-arginine methyl ester (L-NAME) (0.3, 1, 3, and 10 mM), a non-selective inhibitor of NOS, on the effect of aminophylline on the isometric contraction of the isolated rat hemidiaphragm were investigated. The muscle contractions were induced by direct subtetanic electrical stimulation. Aminophylline (0.36 - 3.60 mM) produced a typical concentration-dependent increase in both parameters of the isometric contraction: tension developed (Td) and the maximum rate of rise of tension (dT/dt max). The second series of additions of aminophylline produced a more pronounced effect. L-NAME (0.3, 1, 3, and 10 mM, 30 min of incubation without stimulation) itself did not change Td and dT/dt max. However, L-NAME (1, 3, and 10 mM) produced a statistically significant potentiation of the effect of aminophylline on Td and dT/dt max.     

Effect of some benzodiazepines on peripheral neuromuscular function in the rat in-vitro hemidiaphragm preparation

The effect of equimolar cumulative concentrations of 11 different benzodiazepines on the indirectly evoked twitch contraction was investigated in the rat in-vitro phrenic nerve-hemidiaphragm preparation. Depending on the pattern of the concentration-response curves two groups of benzodiazepines can be distinguished: (i) a first group with a biphasic action, e.g. potentiation of twitch tension in low concentrations and depression of twitch tension in high concentrations, and (ii) a second group with primary depression of twitch tension with increasing concentrations. All of the tested compounds ultimately caused a 100% depression of twitch tension at concentrations ranging from 0.175 to 0.35 mmol litre-1. Although this peripheral effect of benzodiazepines on neuromuscular function is not the main site of action of these compounds, there are enough arguments to state that it is not a simple toxic effect. There is some evidence from this study that the peripheral component of the benzodiazepine effect on muscle relaxation may involve a multi- rather than one single receptor system.     

Effects of pancuronium and vecuronium on creatine phosphokinase in rat isolated heart, liver, kidney and diaphragm.

1. The effects of two muscle relaxants, namely, pancuronium and vecuronium, on creatine phosphokinase (CPK) release from four different types of tissues, namely, heart, liver, kidney and diaphragm, were studied in the rat in vitro. 2. The total, neat and CPK levels (units/ml), released by muscle relaxants were measured using spectrophotometric determination at 340 nm. 3. The results showed that both muscle relaxants, in low concentrations, i.e. 0.34 or 0.32 microM, close to a clinical dose of 0.1 mg/kg, had no significant effect on CPK leakage in all four types of tissues studied. However, in concentrations 12-122 times clinical dose, the two muscle relaxants produced differential adverse effects in the tissues studied. 4. In most concentrations, pancuronium and vecuronium produced significant increases in the CPK release in the kidney and diaphragm. In contrast, pancuronium had no significant effect on CPK release in the liver and the lowest effect in the heart. Similar results were obtained with vecuronium. 5. The clinical relevance and/or implications of the present results are discussed and the results are compared to those previously reported by other workers in other preparations.     

Neuromuscular facilitation induced by muscarinic antagonists in the rat isolated diaphragm

• 1.1. Atropine (EC₅₀ = 87 μM), pirenzepine (447 μM), and AF-DX 116 (95.5 μM), but not 4-DAMP (at concentrations of up to 110 μM), produced neuromuscular facilitation and antagonized the oxotremorine-induced neuromuscular blockade in the rat isolated diaphragm.
• 2.2. Atropine, pirenzepine, and AF-DX 116 did not change the responses of curarized diaphragms to direct stimulation, or the twitch tension produced by retrograde injection of acetylcholine.
• 3.3. These results indicate that neuromuscular facilitation induced by muscarinic antagonists may depend on drug interaction with the M2 subtype of muscarinic autoreceptors to increase acetylcholine output in the neuromuscular junction.

     

Characterization of the isolated rat mesenteric vascular-intestinal loop preparation.

The isolated mesenteric vascular-intestinal loop preparation has been shown to be an important model of resistance vessel hemodynamics reflective of both physiological and pathological conditions. The present experiments were performed to characterize the isolated rat mesenteric vascular-intestinal loop preparations. The mesenteric vasculature with intestine was perfused with modified Krebs-Ringer bicarbonate solution at a constant flow of 5 mL/min. To examine spontaneous norepinephrine overflow, the perfusate and superfusate were collected for 4-min periods from 36 to 60 min after the start of the perfusion. The norepinephrine overflow from the mesenteric vasculature was also determined in response to field stimulation (FS). Basal spontaneous endogenous norepinephrine overflow was relatively constant. The spontaneous norepinephrine overflow was increased by guanethidine (10(-5) M) but was not influenced by tetrodotoxin (3 x 10(-7) M), cocaine (10(-6) M), or prazosin (10(-6) M) treatment. Field stimulation (4-12 Hz) caused frequency-dependent pressor responses and increases in norepinephrine overflow. When norepinephrine overflow was expressed as amount/stimulus (picogram/stimulus), it was frequency independent. The pressor responses to FS were abolished by guanethidine (10(-5) M), tetrodotoxin (3 x 10(-7) M), and prazosin (3 x 10(-8) M). Prazosin at 10(-6) M significantly augmented the FS-induced endogenous norepinephrine overflow. Thus, these results indicate that the isolated rat mesenteric vascular-intestinal loop preparation is an excellent model for demonstrating resistance changes in isolated vascular beds while simultaneously measuring endogenous catecholamine overflow.