Inhibitory Effects of the Anesthetics Propofol and Sevoflurane on Spontaneous Lymphatic Vessel Activity in Rats

Background: The effects of propofol and sevoflurane on lymphatic vessel activity are unknown. This study aimed to clarify the effects of these anesthetics on lymphatic vessel activity in rats by the use of a technique for mechanical removal of the endothelium.

Methods: The authors first examined the effects of propofol (8 mg/kg) and sevoflurane (2.0%) on in vivo lymphatic flow by injection of dye into the femoral regions of rats. In the in vitro study, the ends of the vessel segments of rat thoracic duct were connected to a syringe and stopcock, respectively. Spontaneous changes in diameter of each segment were monitored, and the extraluminal side of each segment was exposed to propofol (1 x 10-6 ~ 3 x 10-5 M) or sevoflurane (0.5~2.0%). Endothelial function was eliminated by perfusion of air into the lumen.

Results: In the dye uptake study, 80% of iliac lymphatic nodes were positively stained in a control group, whereas only 10% and 20% were positively stained in propofol and sevoflurane groups, respectively. In the in vitro study, both of the anesthetics significantly decreased the amplitude of spontaneous activity of lymphatic vessels with or without endothelial function. Sevoflurane inhibited the frequency of lymphatic vessel activity but propofol had no effect on it. When the endothelial function was eliminated, both anesthetics decreased the frequency of spontaneous activity of lymphatic vessels.     

Possible Mechanism of Irreversible Nerve Injury Caused by Local Anesthetics: Detergent Properties of Local Anesthetics and Membrane Disruption

Background: Irreversible nerve injury may result from neural membrane lysis due to the detergent properties of local anesthetics. This study aimed to investigate whether local anesthetics display the same properties as detergents and whether they disrupt the model membrane at high concentrations.

Methods: Concentrations at which dodecyltrimethylammonium chloride and four local anesthetic (dibucaine, tetracaine, lidocaine, and procaine) molecules exhibit self-aggregation in aqueous solutions were measured using an anesthetic cation-sensitive electrode. Light-scattering measurements in a model membrane solution were also performed at increasing drug concentrations. The concentration at which drugs caused membrane disruption was determined as the point at which scattering intensity decreased. Osmotic pressures of anesthetic agents at these concentrations were also determined.

Results: Concentrations of dodecyltrimethylammonium chloride, dibucaine, tetracaine, lidocaine, and procaine at which aggregation occurred were 0.15, 0.6, 1.1, 5.3, and 7.6%, respectively. Drug concentrations causing membrane disruption were 0.09% (dodecyltrimethylammonium chloride), 0.5% (dibucaine), 1.0% (tetracaine), 5.0% (lidocaine), 10.2% (procaine), and 20% (glucose), and osmotic pressures at these concentrations were 278, 293, 329, 581, 728, and 1,868 mOsm/kg H2O, respectively.     

静脉麻醉药对原代培养大鼠心肌细胞的毒性作用

目的 :探讨静脉麻醉药对原代培养大鼠心肌细胞的直接作用。方法 :将经原代培养成活 4天后的大鼠心肌细胞分为 9组 ,每组 6孔 ,对照组为C组 ,其余 8组分别为小剂量与大剂量硫喷妥钠组 (TL ,1× 10 -5mol/L与TH ,1×10 -4 mol/L) ;小剂量与大剂量氯胺酮组 (KL ,1× 10 -5mol/L与KH ,1× 10 -4 mol/L) ;小剂量与大剂量γ 羟基丁酸钠组(HL ,3× 10 -3mol/L与HH ,3× 10 -2 mol/L) ;小剂量与大剂量异丙酚组 (PL ,3× 10 -5mol/L与PH ,3× 10 -4 mol/L)。各组均于实验开始后 8小时评定心肌细胞搏动功能、观察细胞形态学改变、测定心肌细胞酶及电解质变化。结果 :与对照组相比 ,KL组心肌细胞搏动频率加快 (P <0 0 5 ) ,TL、KH及PH组搏动频率明显减慢 (P <0 0 5和P <0 0 1) ,TH组可见心肌细胞呈部分搏动或无搏动。细胞形态学亦有相应变化。LDH、AST与CK释放量增加 (P <0 0 5和P <0 0 1) ,ALP活性下降。而HL、HH、KL及PL组对上述指标无明显影响。各组间电解质变化未见显著差异。结论 :低浓度的硫喷妥钠以及高浓度的氯胺酮、异丙酚均有直接的心肌抑制作用 ,高浓度的硫喷妥钠尤为明显。而γ 羟基丁酸钠及低浓度的氯胺酮、异丙酚几无心肌细胞毒性作用 ,事实上 ,低浓度的氯胺酮表现出正性变时性和变力性作用     

Effects of Intravenous Anesthetics on Renal Ischemia/Reperfusion Injury

Background. Renal ischemia/reperfusion (I/R)-induced tubular epithelial cell injury, called ischemic acute renal failure, is associated with high mortality in humans. Protecting the kidney against I/R injury is very important during complicated renal operations, transplantation surgery, and anesthesia. Aim. The purpose of this study was to investigate and compare the efficiency of ketamine, thiopental, propofol, etomidate, and intralipid in reducing the injury induced by free radicals in a rat model of renal I/R. Method. Forty-two Wistar rats were divided into seven groups in our study. Rats in the sham group underwent laparotomy and waited for 120 minutes (min) without ischemia. Rats in the control group were given nothing with ischemia-reperfusion. Rats in the I/R groups were given ketamine (20 mg/kg), thiopental (20 mg/kg) propofol (25 mg/kg), etomidate (10 mg/kg) and 10% intralipid (250 mg/kg) intraperitoneally 15 min prior to the ischemia for 60 min, followed by reperfusion for 60 min. The blood samples and kidney tissues of the rats were obtained under anesthesia at the end of the reperfusion period. Biochemical malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), blood urea nitrogen (BUN), creatine (Cr), aspartate aminotransferase (AST) were determined, and histopathological analysis was performed with these samples. Results. MDA level was increased significantly in the control group (p < 0.05). Histopathological findings of the control group confirmed that there was renal impairment by tubular cell swelling, interstitial edema, medullary congestion, and tubular dilatation. MDA levels were lower in the ketamine, thiopental, and propofol groups compared to the control group (p < 0.05). In the thiopental and propofol groups, the levels of histopathological scores were significantly lower than control and etomidate groups in ischemia-reperfusion. Conclusion. Our results demonstrated that I/R injury was significantly reduced in the presence of propofol and thiopental. The protective effects of these drugs may belong to their antioxidant properties. These results may indicate that propofol and thiopental anesthesia protects against functional, biochemical, and morphological damage better than control in renal I/R injury.     

7种常用静脉麻醉药对血流动力学影响的比较

比较常用静脉麻醉药对血流动力学的影响。方法：８０９例拟行全麻醉患者随机分成八组,分别给予生理盐水１０ｍｌ、硫喷妥钠６ｍｇ／ｋｇ、异丙酚２．５ｍｇ／ｋｇ咪唑安定０．３ｍｇ／ｋｇ,依托咪酯丙二醇制剂０．３ｍｇ／ｋｇ,依托咪酯乳剂０．３ｍｇ／ｋｇ、氯胺酮２ｍｇ／ｋｇ和芬太尼５μｇ／ｋｇ。用Ｕｌｔｉｍａ监测仪和阻抗法记录并计算血液动力学有关参数。结果：ＢＰ而言,其降幅排序为异丙酚〉咪唑安定〉硫喷妥钠〉硫喷     

Intravenous Anesthetics Inhibit Capacitative Calcium Entry in Pulmonary Venous Smooth Muscle Cells

Background: The authors have previously demonstrated that propofol attenuates capacitative calcium entry (CCE) via the protein kinase C signaling pathway in pulmonary artery smooth muscle cells (PVSMCs). The current goals were to determine whether CCE exists in PVSMCs; to assess the roles of the protein kinase C, tyrosine kinase (TK), and [rho]-kinase signaling pathways in regulating CCE; and to investigate the extent and cellular mechanisms by which intravenous anesthetics (thiopental, midazolam, ketamine, and propofol) alter CCE.

Methods: Primary cultures of fura-2-loaded canine PVSMCs were placed in a dish (37[degrees]C) on an inverted fluorescence microscope. Intracellular Ca2+ concentration ([Ca2+]i) was measured as the 340/380 fluorescence ratio in individual PVSMCs. Thapsigargin, a sarcoplasmic reticulum Ca2+-adenosine triphosphatase inhibitor, was used to deplete intracellular Ca2+ stores after removing extracellular Ca2+. CCE was then activated by restoring extracellular Ca2+ (2.2 mm).

Results: Thapsigargin caused a transient increase in [Ca2+]i (160 +/- 6%). Restoring extracellular Ca2+ caused a rapid peak increase in [Ca2+]i (155 +/- 7% of baseline), followed by a sustained increase in [Ca2+]i (129 +/- 5% of baseline), i.e., CCE was stimulated in PVSMCs. Neither protein kinase C activation nor inhibition had an effect on CCE. [rho]-Kinase inhibition also had no effect on CCE, whereas TK inhibition attenuated both peak and sustained CCE. Thiopental, midazolam, ketamine, and propofol each attenuated both peak and sustained CCE. TK inhibition abolished the thiopental-, midazolam-, and ketamine-induced, but not the propofol-induced, decreases in CCE.     

Effect of Intravenous Anesthetics on Inward Rectifier Potassium Current in Rat and Human Ventricular Myocytes

Background: Inhibition of the inward rectifying potassium current (IK1) may cause cardiac dysrhythmias by decreasing resting membrane potential or prolonging action potential.

Methods: The effects of thiopental, ketamine, and propofol on IK1 conductance were evaluated in rat ventricular myocytes. The effect of thiopental on IK1 conductance was also evaluated in human ventricular myocytes. Currents were recorded using the nystatin-perforated whole-cell patch-clamp technique (holding potential, -50 mV; test potentials, -140 to -40 mV). Pipette solution contained 130 mM KCl, 5 mM MgCl2, 5 mM HEPES, and 5 mM EGTA, pH 7.2. Bath solution (32 [degree sign] Celsius) contained 134 mM NaCl, 4 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 0.3 mM CdCl2, 5 mM HEPES, and 5 mM d-glucose, pH 7.4. Drug concentrations examined encompassed the range of clinically relevant unbound plasma concentrations. Currents were normalized for cell capacitance. Conductance was calculated as current density/Delta mV from -140 to -100 mV. Analysis of variance was used to test for changes in conductance as a function of drug concentration.

Results: Thiopental reduced IK1 conductance in a concentration-dependent manner (P < 0.0001). Thiopental-induced changes in IK1 conductance in rat ventricular myocytes were fit to an inhibitory Emax model, with a median inhibitory concentration of 10.5 micro Meter. The effect of thiopental on IK1 conductance in human ventricular cells was comparable to that observed in rat ventricular myocytes. Neither ketamine nor propofol altered IK1 conductance.     

Effect of Intravenous Anesthetics on Spontaneous and Endotoxin-stimulated Cytokine Response in Cultured Human Whole Blood

Background: Various anesthetics have been suggested to interfere with the immune system. The ability of leukocytes to express surface receptors and mediators is fundamental to a successful host defense. Therefore, the effects of intravenous anesthetics on cytokine release by leukocytes and expression of surface molecules known to modulate this response were determined.

Methods: Concentration-dependent effects of thiopentone, etomidate, propofol, ketamine, midazolam, and fentanyl on spontaneous and endotoxin (lipopolysaccharide; 1 [micro sign]g/ml)-stimulated cytokine release were studied in whole blood from volunteers (n = 6) cultured for 25 h. In addition, expression of the lipopolysaccharide-recognition molecule CD14 and the major histocompatibility complex class II molecule human leukocyte locus A system-DR (HLA-DR) on monocytes were assessed using flow cytometry.

Results: All anesthetics studied elicited only minor effects on spontaneous cytokine release even at pharmacologic concentrations. However, expression density of CD14 was reduced in the presence of thiopentone, etomidate, and propofol, whereas HLA-DR was unaffected. lipopolysaccharide-stimulated tumor necrosis factor response was inhibited by thiopentone (12.8% [median]; 7.6-18.8 [25-75 percentile]) of control, and ketamine (46.4% [median]; 44.4-56.4 [25-75 percentile]), at pharmacologic concentrations, whereas it was augmented even in the presence of low concentrations of propofol (172.3% [median]; 120.5-200.7 [25-75 percentile]). Ketamine additionally decreased the concentration of interleukin (IL)-1 [small beta, Greek] (14.8% [median]; 12.0-18.0 [25-75 percentile]). Release of IL-1 receptor antagonist (IL-1ra) was inhibited by thiopentone, etomidate, and propofol, whereas the same anesthetics increased IL-10 concentration simultaneously. Midazolam and fentanyl did not alter the concentrations of any cytokine.     

Minimum Alveolar Concentration of Volatile Anesthetics in Rats during Postnatal Maturation

Background: Although neonatal rats have become widely used as experimental laboratory animals, minimum alveolar concentration (MAC) values of volatile anesthetics in rats during postnatal maturation remain unknown.

Methods: We determined MAC values of volatile anesthetics in spontaneously breathing neonatal (2-, 9-, and 30-day-old) and adult Wistar rats exposed to increasing (in 0.1-0.2% steps) concentrations of halothane, isoflurane, or sevoflurane (n = 12-20 in each group), using the tail-clamp technique. MAC and its 95% confidence intervals were calculated using logistic regression and corrected for body temperature (37[degrees]C).

Results: In adult rats, inspired MAC values corrected at 37[degrees]C were as follows: halothane, 0.88% (confidence interval, 0.82-0.93%); isoflurane, 1.12% (1.07-1.18%); and sevoflurane, 1.97% (1.84-2.10%). In 30-day-old rats, the values were as follows: halothane, 1.14% (1.07-1.20%); isoflurane, 1.67% (1.58-1.76%); and sevoflurane, 2.95% (2.75-3.15%). In 9-day-old rats, inspired MAC values were as follows: halothane, 1.68% (1.58-1.78%); isoflurane, 2.34% (2.21-2.47%); and sevoflurane, 3.74% (3.64-3.86%). In 2-day-old rats, inspired MAC values were as follows: halothane, 1.54% (1.44-1.64%); isoflurane, 1.86% (1.72-2.01%); and sevoflurane, 3.28% (3.09-3.47%).     

Intravenous Anesthetics Attenuate Phenylephrine-induced Calcium Oscillations in Individual Pulmonary Artery Smooth Muscle Cells

Background: The authors investigated the effects of intravenous anesthetics on alpha-adrenergic-induced oscillations in intracellular free calcium concentration ([Ca2+]i) in individual pulmonary artery smooth muscle cells (PASMCs).

Methods: PASMCs were cultured from explants of canine intrapulmonary artery. Fura-2-loaded PASMCs were continuously superfused with phenylephrine (10 micro Meter) at 37 [degree sign] Celsius on the stage of an inverted fluorescence microscope. Measurement of [Ca2+] sub i was via a dual wavelength spectrofluorometer. Intravenous anesthetics were added to the superfusate to assess their effects on the phenylephrine-induced [Ca2+]i oscillations.

Results: Resting [Ca2+]i was 103 +/- 6 nM. Phenylephrine stimulated [Ca2+]i oscillations, reaching a peak concentration of 632 +/- 20 nM and a frequency of 1.53 +/- 0.14 transients/min. The effects of phenylephrine were dose-dependent. The effects of intravenous anesthetics on phenylephrine-induced [Ca2+]i oscillations were dose-dependent. Ketamine (100 micro Meter) reduced the amplitude (221 +/- 22 nM) but not the frequency (1.48 +/- 0.11/min) of the oscillations, whereas thiopental (100 micro Meter) decreased the amplitude (270 +/- 20 nM) and the frequency (1.04 +/- 0.10/min). Propofol (100 micro Meter) and the Intralipid[registered sign] vehicle inhibited the amplitude (274 +/- 11 nM) but not the frequency (1.39 +/- 0.11/min) of the oscillations. The effects of ketamine and thiopental, but not propofol, were evident at clinically relevant concentrations.     

Inhibition of Nitric Oxide Synthase Decreases Anesthetic Requirements of Intravenous Anesthetics in Xenopus laevis

Background: Acute inhibition of nitric oxide synthase (NOS) has been demonstrated to reduce the anesthetic requirements of volatile anesthetics. Recent data suggest that not only volatile but also intravenous anesthetic agents interact with nitric oxide (NO) metabolism. The aim of this study was to examine the effect of NOS inhibition by nitro sup G -L-arginine-methyl-ester (L-NAME) on the anesthetic action of the intravenous anesthetics thiopental, propofol, and ketamine.

Methods: The anesthetic potencies of thiopental, propofol, and ketamine were determined in Xenopus laevis tadpoles in the absence and presence of L-NAME. Anesthesia was defined as loss of righting reflex for 5 s. A nonlinear logistic regression curve was fitted to the data and half-maximal effective concentrations (EC50) were calculated. A second set of experiments was performed with different concentrations of L-NAME in the presence of the previously determined the EC50 of the intravenous anesthetics.

Results: The EC50 S of the anesthetics thiopental, propofol, and ketamine were determined to be 25.5 +/- 2.0 micro Meter, 1.9 +/- 0.1 micro Meter, and 59.7 +/- 0.7 micro Meter, respectively. The addition of L-NAME shifted the concentration-response curves to the left in a concentration-dependent manner. In the presence of 1 mM L-NAME, the EC50 of thiopental was reduced by 43%, the EC50 of propofol by 26%, and the EC50 of ketamine by 63%. The addition of D-NAME did not change the EC50 values of the three anesthetics. In the presence of L-arginine, the effect of L-NAME on the EC50 of thiopental was reversed. When administered by itself in a concentration range from 0.1 micro Meter to 10 mM, L-NAME did not alter the behavior of the tadpoles.     

Intravenous Lidocaine as a Suppressant of Persistent Cough Caused by Bronchoscopy

The effect of intravenous lidocaine in the treatment of persistent cough occurring after diagnostic bronchoscopies performed under general anaesthesia was investigated in a controlled clinical trial. The study comprised 28 adults patients, all of whom had regained consciousness after anaesthesia. Fifteen patients were treated with lidocaine (1.5 mg/kg body weight) and 13 patients with placebo (saline). In each patient the intravenously injected dose was repeated once after 5 min.
In 11 of the 15 patients (73%) who received lidocaine coughing ceased, while it continued in all 13 patients in the placebo group. The difference is highly significant ( P< 0.001).
None of the patients developed side effects such as hypotension, arrhythmias, central nervous system symptoms or respiratory depression after injection of lidocaine. It is therefore concluded that intravenous lidocaine in man is a safe and useful cough-suppressant.     

Effects of Intravenous Anesthetics on Ca2+ Sensitivity in Canine Tracheal Smooth Muscle

Background: Halothane and other volatile anesthetics relax airway smooth muscle in part by decreasing the amount of force produced for a particular intracellular calcium concentration (the Ca2+ sensitivity) during muscarinic receptor stimulation. In this study, ketamine, propofol, and midazolam were evaluated to determine whether the inhibitory effect of volatile anesthetics on this signal transduction pathway is a general property of other types of anesthetic drugs.

Methods: A [beta]-escin permeabilized canine tracheal smooth muscle preparation was used. Ketamine, propofol, and midazolam, in concentrations producing near-maximal relaxation in intact airway smooth muscle (200 [mu]M, 270 [mu]M, and 100 [mu]M, respectively), were applied to permeabilized muscles stimulated with calcium in either the absence or the presence of muscarinic receptor stimulation provided by acetylcholine. The effect of halothane also was evaluated.

Results: Confirming previous studies, halothane (0.75 mM) decreased calcium sensitivity during muscarinic receptor stimulation. None of the intravenous anesthetics studied affected Ca2+ sensitivity, either in the absence or the presence of muscarinic receptor stimulation.     

Interaction of Intravenous Anesthetics with Human Neuronal Potassium Currents in Relation to Clinical Concentrations

Background: Neuronal voltage-dependent potassium (K) currents are crucial for various cellular functions, such as the integration of temporal information in the central nervous system. Data for the effects of intravenous anesthetics on human neuronal K currents are limited. It was the authors' aim to evaluate the concentration-related effects of three opioids (fentanyl, alfentanil, sufentanil) and seven nonopioids (thiopental, pentobarbital, methohexital, propofol, ketamine, midazolam, droperidol) used in clinical anesthesia on neuronal voltage-dependent K currents of human origin.

Method: K currents were measured in SH-SY5Y cells using the whole cell patch-clamp technique. Currents were elicited by step depolarization from a holding potential of -80 to -50 mV through +90 mV, and their steady state amplitudes were determined.

Results: All drugs inhibited the K currents in a concentration-dependent and reversible manner. Because time dependence of inhibition differed among the drugs, effects were measured after 54-64 ms of the test pulse. The IC50 values (concentration of half-maximal inhibition) for current suppression ranged from 7 [mu]M for sufentanil to 2 mM for pentobarbital. Suppression of the K currents by the opioids occurred at 10-fold lower IC50 values (concentration of half-maximal inhibition) than that by the barbiturates. As estimated from the concentration-response curves, K-current suppression at clinical concentrations would be less than 0.1% for the opioids and approximately 3% for the other drugs.     

Effects of Intravenous Anesthetics on Normal and Passively Sensitized Human Isolated Airway Smooth Muscle

Background: General anesthetics may modify airway responsiveness. The authors investigated the effect of thiopental, propofol, and etomidate on airway smooth muscle.

Methods: Contraction experiments were done in human airway rings that were either normal or passively sensitized with asthmatic serum. The effect of propofol and etomidate was also studied on both [Ca sup +] sub i increase measured by microspectrofluorimetry in isolated myocytes and isometric contraction in the rat trachea.

Results: In human bronchi, thiopental (10 sup -7 to 10 sup -4 M) induced a concentration-dependent contraction. Neither propofol nor etomidate altered baseline tone, but both anesthetics reduced histamine-induced contraction. In human immunologically sensitized isolated bronchi, propofol (3 x 10 sup -4 M) reduced histamine reactivity (Delta Fmax in %) to a greater degree than in nonsensitized tissues (64.4 +/- 15.7% and 16.4 +/- 8.5%, respectively; n = 6, P < 0.05), whereas the effect of etomidate (10 sup -4 M) was similar in both types of tissue (24.1 +/- 6% and 22.3 +/- 15%, respectively, n = 6). In rat isolated tracheal myocytes, propofol (3 x 10 sup -4 M) and etomidate (10 sup -4 M) altered the [Ca2+]i signal in response to the depolarizing agent potassium chloride and the muscarinic agonist acetylcholine. Accordingly, the two anesthetics also reduced the mechanical response of rat tracheal rings to these agonists.