Ketamine (KTM), a N-methyl-D-aspartate (NMDA) receptor antagonist, was found to has an anti-inflammatory effect, but some patients suffered from exacerbated pro-inflammatory reactions after anesthesia with KTM. The present study was aimed to examine the underlying mechanism of pro-inflammatory effects of KTM. In this study, RAW264.7 cells were exposed to KTM and NMDA alone or combined for 30 min before lipopolysaccharide (LPS) stimulation. The expression levels of IL-6 and TNF-α were detected by RT-PCR and ELISA, and those of NMDA receptors by RT-PCR in RAW264.7 cells. Additionally, the TLR4 expression was determined by RT-PCR and flow cytometry, respectively. The results showed that in RAW264.7 cells, KTM alone promoted the TLR4 expression, but did not increase the expression of IL-6 or TNF-α. In the presence of LPS, KTM caused a significantly higher expression of IL-6 and TNF-α than LPS alone. NMDA could neither alter the IL-6 and TNF-α mRNA expression, nor reverse the enhanced expression of IL-6 and TNF-α mRNA by KTM in LPS-challenged cells. After TLR4-siRNA transfection, RAW264.7 cells pretreated with KTM no longer promoted the IL-6 and TNF-α expression in the presence of LPS. In conclusion, KTM accelerated LPS-induced inflammation in RAW264.7 cells by promoting TLR4 expression, independent of NMDA receptor.
Anesthetics, Dissociative ; pharmacology ; Animals ; Cell Survival ; drug effects ; Gene Expression Regulation ; Inflammation Mediators ; pharmacology ; Interleukin-6 ; genetics ; Ketamine ; pharmacology ; Lipopolysaccharides ; pharmacology ; Macrophages ; drug effects ; metabolism ; Male ; Mice ; N-Methylaspartate ; pharmacology ; RAW 264.7 Cells ; Signal Transduction ; drug effects ; Toll-Like Receptor 4 ; genetics ; metabolism ; Tumor Necrosis Factor-alpha ; genetics

Acute Coronary Syndrome ; chemically induced ; Anesthetics, Dissociative ; adverse effects ; Humans ; Ketamine ; adverse effects

OBJECTIVE: To explore the effect of ketamine on adrenal pheochromocytoma (PC12) cell proliferation inhibition and induction of apoptosis and its mechanism. METHODS: PC12 cells of rats were models for dopaminergic neuron. PC12 cells were cultured with ketamine at concentrations of 0.9, 1.2, 1.5, 1.8 and 2.1 mmol/L, respectively. The cell viability was measured by MTT method after incubation at 12, 24, 48 and 72h. Hoechst stain was used to observe the morphological changes of apoptosis. PC12 cells cultured after 48 h with different concentrations of ketamine were selected to detect apoptotic rate using flow cytometry and detect the expression of bax and bcl-2 proteins using Western blotting. RESULTS: For different concentrations of ketamine, vitality of PC12 cells significantly decreased with increase of the incubation time. Apoptosis was obviously observed using Hoechst staining. Flow cytometry showed that apoptosis rates significantly increased with increasing ketamine concentrations. CONCLUSION Ketamine can inhibit the proliferation of PC12 cell by inducing apoptosis of the PC12 cell in a concentrations-dependent manner. The underlying mechanism may be related to promoting the expression of bax and inhibiting the expression of bcl-2 in the cells.
Anesthetics, Dissociative/pharmacology* ; Animals ; Apoptosis/drug effects* ; Blotting, Western ; Cell Proliferation/drug effects* ; Dose-Response Relationship, Drug ; Flow Cytometry ; Gene Expression Regulation/drug effects* ; Ketamine/pharmacology* ; PC12 Cells ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Rats ; Time Factors ; bcl-2-Associated X Protein/metabolism*

The effects of ketamine on transient outward potassium current (I(to)) of isolated human atrial myocytes were investigated to understand the mechanism of part of its effects by whole-cell patch-clamp. Atrial myocytes were enzymatically isolated from specimens of human atrial appendage obtained from patients under going cardiac valve displacing. Ito is recorded in voltage-clamp modes using the patch-clamp technique at room temperature. Currents signals were recorded by an Axopatch 200B amplifier with the Digidata 1322A-pClamp 9.0 data acquisition system. Ketamine decreased I(to) of human atrial myocytes in a dose-dependent manner. The current-voltage curve was significantly lowered, 30, 100, 300, and 1000 micromol x L(-1) ketamine decreased respectively I(to) current density about (13.62 +/- 0.04)%, (38.92 +/- 0.05)%, (72.24 +/- 0.10)% and (83.84 +/- 0.05)% at the potential of 50 mV, with an IC50 of 121 micromol x L(-1). The I(to) activation curve, inactivation curve and the recovery curve were not altered by ketamine. So, ketamine concentration-dependently decreased I(to) of human atrial myocytes.
Adolescent ; Adult ; Aged ; Anesthetics, Dissociative ; administration & dosage ; pharmacology ; Dose-Response Relationship, Drug ; Female ; Heart Atria ; cytology ; Humans ; Ketamine ; administration & dosage ; pharmacology ; Male ; Middle Aged ; Myocytes, Cardiac ; cytology ; drug effects ; physiology ; Patch-Clamp Techniques ; Potassium Channels ; drug effects ; Young Adult

OBJECTIVE: To investigate the toxicokinetics profiles of ketamine and its main metabolite norketamine in rabbits. METHODS: The rabbits were administered orally the hydrochloride of ketamine with a dose of 0.15 g/kg. The serum and urine samples were collected before administration and at different time points after drug administration. The concentrations of ketamine and norketamine were determined by GC-NPD and GC-MS. Compartment model and toxicokinetics parameters were simulated and calculated by WinNorLin program. Changes of important vital signs of rabbits were recorded during the experiment. RESULTS: The mean serum concentration-time profile of ketamine and norketamine were fitted to a two-compartment open model with first order kinetics. The kinetic equation of ketamine and norketamine were p(t) = 121.760 e(-0.0025t) +0.980 e(-0.002t) +4.579 e(-0.021 t) and p(t) = 640.919 e(-0.03 t) +1.023 e(-0.001 t) +9.784 e (-0.031 t), respectively. The peak time and the peak concentration of ketamine in serum were (40.950 +/- 12.098) min and (9.015 +/- 1.344) microg/mL, respectively. The elimination half-time of ketamine in rabbits was (430.370 +/- 28.436) min. The serum and urine showed a middle relation in concentrations of ketamine during 30-240 min after drug administration. After oral administration ketamine to rabbits, the toxic symptom on the rabbits occurred at 30 min and disappeared after 120 min. CONCLUSION The toxicokinetics parameters and kinetic equation of ketamine and norketamine in rabbits may provide the theoretical basis for forensic identification of reasonable specimen collection and inferring the time of oral administration ketamine from the ketamine concentration in serum.
Administration, Oral ; Anesthetics, Dissociative/toxicity* ; Animals ; Blood Pressure/drug effects* ; Gas Chromatography-Mass Spectrometry/methods* ; Heart Rate/drug effects* ; Ketamine/urine* ; Male ; Perceptual Disorders/etiology* ; Rabbits ; Random Allocation ; Time Factors

OBJECTIVETo study the psychedelic effects in healthy volunteers when given subanesthetic dose of ketamine.

METHODSThirteen male healthy volunteers aged 24-39 years were enrolled. All subjects received subanesthetic doses of ketamine using target control infusion. A stepwise series of target plasma concentrations (0, 100, 200, and 300 ng/ml) were maintained for 20 minutes each. Visual analogue scale (VAS) of mechanical pain by von Frey hair was evaluated, and then the volunteers completed a VAS rating of 13 symptom scales. Pictures were shown to them at the same time. Heart rate, mean blood pressure, and SpO2 were monitored throughout the infusion.

RESULTSDuring the process of analgesia, ketamine produced dose-related analgesic effects. With the increase of ketamine dose, some psychedelic effects became more obvious and the memory impairment became worse stepwisely.

CONCLUSIONTarget control infusion of subanesthetic doses of ketamine produce obvious psychedelic effects in healthy volunteers.

Adult ; Anesthetics, Dissociative ; administration & dosage ; adverse effects ; pharmacology ; Dose-Response Relationship, Drug ; Hallucinations ; chemically induced ; Humans ; Ketamine ; administration & dosage ; adverse effects ; pharmacology ; Male

OBJECTIVETo observe the effect of orexin-A on the recovery and cognitive function of aged rats after ketamine anesthesia.

METHODSFifty-five aged rats were divided randomly into control group, model control group, 1 nmol/L Orexin-A group, and 4 nmol/L Orexin-A group. In the latter 3 groups, the rats received an intraperitoneal injection of ketamine at 100 mg/kg, and normal saline was injected in the control group. Ten minutes after the injections, the rats received intraventricular injections of artificial cerebrospinal fluid (control and model control group) or of 10 microl 1 or 4 nmol/L Orexin-A as indicated. The behavioral changes of the rats were assessed by the duration of loss of righting reflex (LORR). Electroencephalogram (EEG) recordings were used to evaluate the changes in rat brain activity by comparison of the percent of sigma wave in EEG before and after the intraventricular injections. Morris water maze was used to test the learning and spatial localization abilities of the rats.

RESULTSKetamine resulted in obvious impairment of learning and memory abilities of the aged rats. Orexin-A at 4 nmol/L induced significant decrease in the duration of LORR and marked reduction of sigma activities in anesthetic rats (P<0.05), and obviously improved the learning and spatial localization abilities of the rats after anesthesia (P<0.05).

CONCLUSIONOrexin-A can promote the recovery and improve the cognitive function of aged rats after ketamine anesthesia.

Aging ; Anesthesia Recovery Period ; Anesthetics, Dissociative ; Animals ; Cognition ; drug effects ; Delayed Emergence from Anesthesia ; prevention & control ; Intracellular Signaling Peptides and Proteins ; pharmacology ; Ketamine ; Male ; Neuropeptides ; pharmacology ; Orexins ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo summarize the anesthetic management in fetal lamb cardiac bypass.

METHODSFive ewes at 120-140 days of gestation were anesthetized intramuscularly with katamine hydrochloride, intubated and ventilated with a respirator. Anesthesia was maintained with fentanyl and vecuronium. Lactated Ringer's solution and magnesium sulfate were infused to maintain the mean blood pressure (MAP) over 70 mmHg and uterine relaxation. The fetal lambs received anesthesia with fentanyl and vecuronium intramuscularly via the uterine wall. Fetal cardiac bypass was established with pulmonary artery and right atrium cannulation, lasting for 30 min. The hemodynamic and blood gas data of the ewes and fetal lambs were recorded before bypass, at 30 min during bypass, and at 1 and 2 h after cessation of bypass. The pulse index of the umbilical artery (PIua) and the ewe's uterine artery (PIeu) were monitored simultaneously.

RESULTSThe MAP and heart rate (HR) of the fetus remained normal during the anesthesia. PIua increased significantly after cessation of bypass (P<0.05). Although the fetal oxygen tension in the axillary artery remained normal, the fetal lambs showed hypercarbia and acidosis after cessation of bypass (P<0.05). The maternal MAP and HR remained normal. The PIeu decreased significantly during bypass (P<0.05) and recovered the normal level after cessation of bypass. The arterial blood gas of the ewes was normal during the experiment.

CONCLUSIONMaintaining high hemodynamics in the ewes, application of uterine relaxation and intensive care during anesthesia are crucial in anesthetic management of cardiac bypass in fetal lambs.

Anesthetics, Dissociative ; Animals ; Cardiopulmonary Bypass ; methods ; Female ; Fentanyl ; administration & dosage ; Fetal Heart ; surgery ; Goats ; surgery ; Ketamine ; administration & dosage ; Pregnancy ; Vecuronium Bromide ; administration & dosage

Ketamine is a phencyclidine derivative acting primarily as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) excitatory glutamate receptors. As a common intravenous anaesthetic in clinic, it is also increasingly abused because of its hallucination and addiction effects. Based on the pharmacological and toxicologic characteristics of ketamine and the acknowledged addiction mechanism of other abused drugs, this article reviews the possible addiction mechanism of the ketamine in the aspects of its enhanced effects and reward systems, the anatomic structures, the related receptors and the individual differences.
Anesthetics, Dissociative/adverse effects* ; Animals ; Brain/drug effects* ; Humans ; Illicit Drugs ; Ketamine/adverse effects* ; Mental Disorders/chemically induced* ; Rats ; Receptors, Dopamine/drug effects* ; Receptors, N-Methyl-D-Aspartate/drug effects* ; Substance-Related Disorders

The aim of the present study was to examine the effects of ketamine, a dissociative anesthetics, on secretion of catecholamines (CA) secretion evoked by cholinergic stimulation from the perfused model of the isolated rat adrenal gland, and to establish its mechanism of action, and to compare ketamine effect with that of thiopental sodium, which is one of intravenous barbiturate anesthetics. Ketamine (30~300 micrometer), perfused into an adrenal vein for 60 min, dose- and time-dependently inhibited the CA secretory responses evoked by ACh (5.32 mM), high K+ (a direct membrane- depolarizer, 56 mM), DMPP (a selective neuronal nicotinic NN receptor agonist, 100 micrometer) and McN-A-343 (a selective muscarinic M1 receptor agonist, 100 micrometer). Also, in the presence of ketamine (100 micrometer), the CA secretory responses evoked by veratridine (a voltage-dependent Na+ channel activator, 100 micrometer), Bay-K-8644 (an L-type dihydropyridine Ca2+ channel activator, 10 micrometer), and cyclopiazonic acid (a cytoplasmic Ca2+-ATPase inhibitor, 10 micrometer) were significantly reduced, respectively. Interestingly, thiopental sodium (100 micrometer) also caused the inhibitory effects on the CA secretory responses evoked by ACh, high K+, DMPP, McN-A-343, veratridine, Bay-K-8644, and cyclopiazonic acid. Collectively, these experimental results demonstrate that ketamine inhibits the CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors and the membrane depolarization from the isolated perfused rat adrenal gland. It seems likely that the inhibitory effect of ketamine is mediated by blocking the influx of both Ca2+ and Na+ through voltage-dependent Ca2+ and Na+ channels into the rat adrenal medullary chromaffin cells as well as by inhibiting Ca2+ release from the cytoplasmic calcium store, which are relevant to the blockade of cholinergic receptors. It is also thought that, on the basis of concentrations, ketamine causes similar inhibitory effect with thiopental in the CA secretion from the perfused rat adrenal medulla.
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride ; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ; Adrenal Glands ; Adrenal Medulla ; Anesthetics ; Anesthetics, Dissociative ; Animals ; Barbiturates ; Calcium ; Catecholamines ; Chromaffin Cells ; Cytoplasm ; Dihydropyridines ; Dimethylphenylpiperazinium Iodide ; Indoles ; Ketamine ; Membranes ; Neurons ; Rats ; Receptor, Muscarinic M1 ; Receptors, Cholinergic ; Thiopental ; Veins ; Veratridine