Lipofundin mediates major inhibition of intravenous propofol on phorbol myristate acetate and Escherichia coli-induced neutrophil extracellular traps.

BACKGROUND: Neutrophil extracellular traps (NETs) consist of chromatin DNA networks that are studded with cytosolic and granular antimicrobial proteins to trap or kill an infected microorganism. A lipid emulsion, the solvent of pure propofol for intravenous application, is given to clinical patients who require intravenous feeding of fatty acids and fat for energy. Intravenous propofol is widely used to sedate critically ill patients. Both intravenous propofol and its lipid emulsion have immunomodulatory activity. However, the role of lipid emulsion of intravenous propofol on NET induction remains unclear. METHODS: In this study, neutrophils were stimulated with phorbol myristate acetate (PMA) or Escherichia coli (E. coli) in the absence or presence of intravenous propofol (Propofol-Lipuro®), its solvent lipid emulsion (Lipofundin) or pure propofol, and NETs were stained with SYTOX Green for visualization and quantification. Total HOCl was determined by measuring the taurine-chloramine complex, and intracellular HOCl was evaluated with BioTracker™ TP-HOCl 1 dye. RESULTS: PMA-induced NETs were not efficiently inhibited when Propofol-Lipuro® was added after PMA stimulation. Clinically relevant concentrations of Lipofundin exerted a significant reduction in PMA-induced NETs and total reactive oxidative species (ROS), which was comparable to that observed for Propofol-Lipuro®. Lipofundin transiently reduced intracellular HOCl production and the phosphorylation level of extracellular regulated kinase (p-ERK) but did not scavenge HOCl. Moreover, Lipofundin decreased E. coli-induced NETs in a ROS-independent pathway, similar to Propofol-Lipuro®. CONCLUSIONS: All data agree that Lipofundin, the major component of Propofol-Lipuro®, inhibits intracellular HOCl and p-ERK to suppress PMA-induced NET formation but reduces E.coli-induced NETs in a ROS-independent pathway.

Edaravone Alleviated Propofol-Induced Neurotoxicity in Developing Hippocampus by mBDNF/TrkB/PI3K Pathway.

BACKGROUND: To investigate the neuroprotective effect of edaravone on excessive-dose propofol-induced neurotoxicity in the hippocampus of newborn rats and HT22 cells. METHODS: Cell proliferation was investigated by assessing ki67 expression in the neural stem of the hippocampus of newborn rats and by cell counting kit-8 (CCK8) assay in HT22 cells. Cell apoptosis was assessed in vivo by caspase 3 detection in Western blots and measurement of apoptosis in neurons and glial cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Apoptosis was analyzed by flow cytometry in HT22 cells. The Morris water maze was used to evaluate the long-term learning and memory ability of rats. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The expression of mBDNF/TrkB/PI3K pathway-related proteins was detected by Western blot and quantitative reverse transcription-polymerase chain reaction (q-RT PCR). RESULTS: In neonatal rat hippocampus and HT22 cells, edaravone increased cell proliferation and decreased cell apoptosis after excessive propofol-induced neurotoxicity. In addition, the levels of proinflammatory factors interleukin (IL)-6 and tumor necrosis factor (TNF)-α were reduced by edaravone pretreatment. The use of the tropomyosin receptor kinase B (TrkB) antagonist ANA-12 and TrkB agonist 7,8DHF with propofol groups showed that edaravone mitigated excessive propofol-induced neurotoxicity through the mature brain-derived neurotrophic factor (mBDNF)/TrkB/phosphoinositide 3-kinase (PI3K) pathway. However, the current dose of propofol did not significantly affect long-term learning and memory in rats. CONCLUSION: Edaravone pretreatment ameliorated propofol-induced proliferation inhibition, neuroapoptosis, and neural inflammation by activating the mBDNF/TrkB/PI3K pathway.

Metformin Inhibits Propofol-Induced Apoptosis of Mouse Hippocampal Neurons HT-22 Through Downregulating Cav-1.

OBJECTIVE: To elucidate the neuroprotective function of metformin in suppressing propofol-induced apoptosis of HT-22 cells. METHODS: HT-22 cells were treated with 0, 10 or 100 µmol/L propofol, followed by determination of their proliferative ability. Subsequently, changes in proliferation and apoptosis of propofol-treated HT-22 cells induced with metformin were assessed. Apoptosis-associated genes in HT-22 cells were detected by Western blot. At last, regulatory effects of Cav-1 on propofol and metformin-treated HT-22 cells were examined. RESULTS: Propofol treatment dose-dependently decreased proliferative ability and increased apoptosis ability in HT-22 cells, which were partially blocked by metformin administration. Upregulated Bcl-2 and downregulated Bax were observed in propofol-treated HT-22 cells following metformin administration. In addition, Cav-1 level in HT-22 cells was regulated by metformin treatment. Notably, metformin reversed propofol-induced apoptosis stimulation and proliferation decline in HT-22 cells via downregulating Cav-1. CONCLUSION: In our study, we found that propofol could induce apoptosis of HT-22 cells and metformin could rescue the apoptosis effect regulated by propofol. Then, we found that metformin protects propofol-induced neuronal apoptosis via downregulating Cav-1.

RE-1 silencing transcription factor alleviates the growth-suppressive effects of propofol on mouse neuronal cells.

OBJECTIVE: Propofol is broadly utilized for maintaining anesthesia. Propofol affects neurodegeneration and neurogenesis by regulation of autophagy via effects on intracellular calcium homeostasis. The underlying molecular mechanism, however, is still unclear. METHODS: In the present research, we systematically analyzed the effect of propofol on mouse neuronal cells (cell line: HT-22). Cell Counting Kit-8 assays were utilized to examine cell proliferation. Flow cytometry was used to determine the levels of cell apoptosis. Quantitative real-time PCR and western blot were used to examine the relative mRNA and protein levels in mouse neuronal cells. RESULTS: Our results suggest that propofol inhibits proliferation and promotes apoptosis in neuronal cells. Moreover, overexpression of the transcriptional repressor RE-1 silencing transcription factor rescued the effect of propofol on neuronal cells. Additionally, the autophagy inhibitor 3-methyladenine also significantly reduced the effect of propofol on mouse neuronal cells. Finally, overexpression of RE-1 silencing transcription factor promoted the expression of brain-derived neurotrophic factor in mouse neuronal cells. CONCLUSION: Our research not only enhances our understanding of propofol on mouse neuronal cells but also uncovers a potential signaling pathway that may mediate the effects of propofol on neuronal cells.

Propofol Suppresses LPS-Induced Inflammation in Amnion Cells via Inhibition of NF-κB Activation.

Background: Preterm labor is a leading risk factor for neonatal death and long-term impairment and linked closely with inflammation. Non-obstetric surgery is occasionally needed during pregnancy and the anesthetic drugs or surgery itself can give rise to inflammation. Here, we examined the influence of propofol pretreatment on the expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) after lipopolysaccharide (LPS) stimulation. In addition, we evaluated the expression of pro-inflammatory cytokines and nuclear factor kappa B (NF-κB). Methods: Human amnion-derived WISH cells were used to investigate the effect of propofol on the LPS-induced expression of inflammatory substances involved in preterm labor. For the experiment, WISH cells were pretreated with various concentrations propofol (0.01-10 µg/ml) for 1 h and then treated with LPS (1 µg/ml) for 24 h. Cytotoxicity was evaluated using MTT assay. PGE2 concentration was assessed by ELISA. Protein expressions of COX-2, PGE2 and NF-κB were analyzed by western blotting analysis. RT-PCR was used for analysis of mRNA expression of COX-2, PGE2, interlukin (IL)-1ß and tumor necrosis factor (TNF)-α. Results: Propofol showed no cytotoxicity on the WISH cells. LPS-induced PGE2 production and COX-2 and PGE2 expression were decreased after propofol pretreatment. Propofol also attenuated the LPS-induced mRNA expression of IL-1ß and TNF-α. Moreover, the activation of NF-κB was inhibited by propofol pretreatment on LPS-stimulated WISH cells. Conclusion: We demonstrated that propofol suppresses the expression of inflammatory substances enhanced by LPS stimulation. Furthermore, this inhibitory effect of propofol on the inflammatory substance expression is mediated by suppression of NF-κB activation.

Dexmedetomidine attenuates the neurotoxicity of propofol toward primary hippocampal neurons in vitro via Erk1/2/CREB/BDNF signaling pathways.

BACKGROUND: Propofol is a commonly used general anesthetic for the induction and maintenance of anesthesia and critical care sedation in children, which may add risk to poor neurodevelopmental outcome. We aimed to evaluate the effect of propofol toward primary hippocampal neurons in vitro and the possibly neuroprotective effect of dexmedetomidine pretreatment, as well as the underlying mechanism. MATERIALS AND PROCEDURES: Primary hippocampal neurons were cultured for 8 days in vitro and pretreated with or without dexmedetomidine or phosphorylation inhibitors prior to propofol exposure. Cell viability was measured using cell counting kit-8 assays. Cell apoptosis was evaluated using a transmission electron microscope and flow cytometry analyses. Levels of mRNAs encoding signaling pathway intermediates were assessed using qRT-PCR. The expression of signaling pathway intermediates and apoptosis-related proteins was determined by Western blotting. RESULTS: Propofol significantly reduced cell viability, induced neuronal apoptosis, and downregulated the expression of the BDNF mRNA and the levels of the phospho-Erk1/2 (p-Erk1/2), phospho-CREB (p-CREB), and BDNF proteins. The dexmedetomidine pretreatment increased neuronal viability and alleviated propofol-induced neuronal apoptosis and rescued the propofol-induced downregulation of both the BDNF mRNA and the levels of the p-Erk1/2, p-CREB, and BDNF proteins. However, this neuroprotective effect was abolished by PD98059, H89, and KG501, further preventing the dexmedetomidine pretreatment from rescuing the propofol-induced downregulation of the BDNF mRNA and p-Erk1/2, p-CREB, and BDNF proteins. CONCLUSION: Dexmedetomidine alleviates propofol-induced cytotoxicity toward primary hippocampal neurons in vitro, which correlated with the activation of Erk1/2/CREB/BDNF signaling pathways.

Effects of propofol on conditioned place preference in male rats: Involvement of nitrergic system.

BACKGROUND: Drug-induced conditioned place preference (CPP) is linked to the addictive properties of the drug used. The number of studies that have investigated the effects of propofol on CPP is limited. Research findings suggest that nitric oxide (NO) might play an important role in substance use disorders. OBJECTIVES: The present study sought to investigate the role of the nitrergic system on the rewarding effects of propofol by using the CPP protocol in rats. METHODS: The experiment followed habituation, pre-conditioning, conditioning, and post conditioning sessions. Male Wistar albino rats weighing 240-290 g were divided into eight groups: control (saline), propofol (10, 20, and 40 mg/kg), the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) alone (30 and 60 mg/kg), and in combination with propofol (30 and 60 mg/kg L-NAME plus 40 mg/kg propofol) (n = 8 for each group). The CPP effects of propofol, L-NAME, saline, and their combinations were evaluated. All the drug and saline administrations were performed by intraperitoneal (ip) injections. RESULTS: Propofol (10-40 mg/kg) produced CPP that was statistically significant relative to saline. Propofol-induced CPP was significantly reversed by pretreatment with L-NAME. When administered alone, L-NAME did not produce CPP and also did not produce any significant change on locomotor activity of naïve rats. CONCLUSION: Our results suggest that propofol produces CPP effects in rats and that NO-related mechanisms may be responsible for propofol-induced CPP. Thus, propofol might have the potential to be addictive, and this possibility should be considered during clinical applications of this drug.

Serum albumin attenuates the open-channel blocking effects of propofol on the human Kv1.5 channel.

The intravenous anesthetic propofol modulates various ion channel functions. It is generally accepted that approximately 98% of propofol binds to blood constituents and that the free (unbound) drug preferentially affects target proteins including ion channels. However, modulatory effects of propofol on ion channels have not been previously explored in the presence of serum albumin. This study was designed to investigate the effects of serum albumin on the blocking action of propofol on the human Kv1.5 (hKv1.5) current. Whole-cell patch-clamp method was used to record the hKv1.5 channel current, heterologously expressed in Chinese hamster ovary cells, in the absence and presence of bovine serum albumin (BSA). Propofol induced a time-dependent decline of the hKv1.5 current during depolarizing steps and slowed the time course of tail current decay upon repolarization, supporting that propofol acts as an open-channel blocker. This blocking effect was reversible and concentration-dependent with an IC50 of 62.9±3.1µM (n = 6). Bath application of 1% BSA markedly reduced the blocking potency of propofol on hKv1.5 current (IC50 of 1116.0±491.4µM; n = 6). However, in the presence of BSA, the propofol-induced inhibition of hKv1.5 current was also accompanied by a gradual decline of activated current during depolarization and deceleration of deactivating tail current upon repolarization. The presence of BSA greatly attenuated the blocking potency of propofol on hKv1.5 channel without affecting the mode of action of propofol on the channel. Serum albumin thus appears to bind to propofol and thereby reducing effective concentrations of the drug for inhibition of hKv1.5 channel.

Locomotor stimulation by acute propofol administration in rats: Role of the nitrergic system.

BACKGROUND: The addictive potential of propofol has been scientifically discussed. Drugs' psychostimulant properties that can be assessed via measurements of locomotor activity are linked to their addictive properties. No studies that have investigated the effects of propofol on locomotor activity have been reported to date. The present study sought to investigate the effects and possible mechanisms of action of propofol on locomotor activity in rats. METHODS: Adult male albino Wistar rats (250-330g) were used as subjects. The locomotor activities of the rats were recorded for 30min immediately following intraperitoneal administration of propofol (20 and 40mg/kg), saline or vehicle (n=8 for each group). NG-nitro arginine methyl ester (l-NAME, 15-60mg/kg), a nitric oxide (NO) synthase inhibitor, and haloperidol (0.125-5mg/kg), a non-specific dopamine receptor antagonist, were also administered to other groups of rats 30min prior to the propofol (40mg/kg) injections, and locomotor activity was recorded for 30min immediately after propofol administration (n=8 for each group). RESULTS: Propofol produced significant increases in the locomotor activities of the rats in the first 5min of the observation period [F(2,21)=9.052; p<0.001]. l-NAME [F(4,35)=3.112; p=0.02] but not haloperidol [F(4,35)=2.440; p=0.067] pretreatment blocked the propofol-induced locomotor hyperactivity. l-NAME did not cause any significant change in locomotor activity in naïve rats [F(2,21)=0.569; p=0.57]. CONCLUSIONS: Our results suggest that propofol might cause a short-term induction of locomotor activity in rats and that this effect might be related to nitrergic but not dopaminergic mechanisms.

Partial antagonism of propofol anaesthesia by physostigmine in rats is associated with potentiation of fast (80-200 Hz) oscillations in the thalamus.

BACKGROUND: Positron emission tomography studies in human subjects show that propofol-induced unconsciousness in humans is associated with a reduction in thalamic blood flow, suggesting that anaesthesia is associated with impairment of thalamic function. A recent study showed that antagonism of propofol-induced unconsciousness by the anticholinesterase physostigmine is associated with a marked increase in thalamic blood flow, supporting the implication of the thalamus. The aim of the present study was to assess the role of the thalamus in the antagonistic effects of physostigmine during propofol anaesthesia using electrophysiological recordings in a rat model. METHODS: Local field potentials were recorded from the barrel cortex and ventroposteromedial thalamic nucleus in 10 chronically instrumented rats to measure spectral power in the gamma/high-gamma range (50-200 Hz). Propofol was given i.v. by target-controlled infusion at the lowest concentration required to abolish righting attempts. Physostigmine was given during anaesthesia to produce behavioural arousal without changing anaesthetic concentration. RESULTS: Compared with baseline, gamma/high-gamma power during anaesthesia was reduced by 31% in the cortex (P=0.006) and by 65% in the thalamus (P=0.006). Physostigmine given during anaesthesia increased gamma/high-gamma power in the thalamus by 60% (P=0.048) and caused behavioural arousal that correlated (P=0.0087) with the increase in power. Physostigmine caused no significant power change in the cortex. CONCLUSIONS: We conclude that partial antagonism of propofol anaesthesia by physostigmine is associated with an increase in thalamic activity reflected in gamma/high-gamma (50-200 Hz) power. These findings are consistent with the view that anaesthetic-induced unconsciousness is associated with impairment of thalamic function.

Critical involvement of the thalamus and precuneus during restoration of consciousness with physostigmine in humans during propofol anaesthesia: a positron emission tomography study.

BACKGROUND: Functional brain imaging offers a way to investigate how general anaesthetics impair consciousness. However, functional imaging changes may result from drug effects unrelated to hypnosis. Establishing a causal link with loss of consciousness is thus difficult. METHODS: To identify changes of neuronal activity functionally linked to the level of consciousness, physostigmine was used to restore consciousness without changing the anaesthetic concentration in 11 subjects anaesthetized with propofol. Eight subjects (responders) regained consciousness after physostigmine and three did not (non-responders). Positron emission tomography was used to measure regional cerebral blood flow (rCBF); during baseline (awake), after anaesthesia-induced loss of consciousness, after physostigmine administration, and recovery. In addition to subtraction analyses, we used conjunction analysis in the responders to identify changes common to the baseline-anaesthesia and physostigmine-anaesthesia contrasts. RESULTS: Complete data were available for seven subjects (four responders and three non-responders). The analyses revealed that unconsciousness was associated with rCBF decreases in the thalamus and precuneus. Restoration of consciousness by physostigmine was associated with rCBF increases in these same structures, with the strongest effect in the thalamus. CONCLUSIONS: The results provide strong evidence that reductions in rCBF in the thalamus and precuneus are functionally related to propofol-induced unconsciousness independently of any non-specific effects of propofol. These observations confirm that the thalamus and precuneus are key elements to understand how general anaesthetics cause unconsciousness and how patients wake up from anaesthesia. Furthermore, they are consistent with the notion that anaesthetic-induced unconsciousness is associated with reduced cholinergic activation.

Propofol and aminophylline antagonize each other during the mobilization of intracellular calcium in human umbilical vein endothelial cells.

This study examined whether propofol and aminophylline affect the mobilization of intracellular calcium in human umbilical vein endothelial cells. Intracellular calcium was measured using laser scanning confocal microscopy. Cultured and serum-starved cells on round coverslips were incubated with propofol or aminophylline for 30 min, and then stimulated with lysophosphatidic acid, propofol and aminophylline. The results were expressed as relative fluorescence intensity and fold stimulation. Propofol decreased the concentration of intracellular calcium, whereas aminophylline caused increased mobilization of intracellular calcium in a concentration-dependent manner. Propofol suppressed the lysophosphatidic acid-induced mobilization of intracellular calcium in a concentration-dependent manner. Propofol further prevented the aminophylline-induced increase of intracellular calcium at clinically relevant concentrations. However, aminophylline reversed the inhibitory effect of propofol on the elevation of intracellular calcium by lysophosphatidic acid. Our results suggest that propofol and aminophylline antagonize each other on the mobilization of intracellular calcium in human umbilical vein endothelial cells at clinically relevant concentrations. Serious consideration should be given to how this interaction affects mobilization of intracellular calcium when these two drugs are used together.

Dose-dependent effects of erythropoietin in propofol anesthetized neonatal rats.

Exposure to Gamma-aminobutyric-acid (GABA)(A)-receptor agonists and N-Methyl-D-Aspartate (NMDA)-antagonists has been demonstrated to induce neurodegeneration in newborn rats. Exogenous erythropoietin (EPO) protects against NMDA antagonist-mediated neuronal death. In this study we evaluated whether EPO is also effective in limiting neurodegeneration of the GABA(A)-mimetic agent propofol in newborn rats. 6 day old rats were randomized to one of four groups and treated with intraperitoneal applications of 3 x 30 mg/kg propofol at 0, 90 and 180 min, propofol in combination with 5000 IU/kg rEPO, propofol in combination with 20,000 IU/kg rEPO or sham injections of PAD II solution as controls. After 24h, brains of the animals were histopathologically examined and a summation score of degenerated cells was calculated for every brain. Propofol increased neuronal degeneration scores from 16,090+/-4336 to 28,860+/-6569 (p<0.01). This effect was completely abolished by low-dose rEPO (14,270+/-4542, p<0.001 versus propofol only; p>0.05 versus controls). In contrast, high-dose rEPO was not protective (23 930+/-8896, p>0.05 versus propofol only). Propofol may cause neuronal death in newborn rat brains, which is prevented by low-dose rEPO but not high-dose rEPO.

Convulsions with propofol: a rare adverse event.

We present a rare but potentially harmful adverse reaction of propofol. A 50-year-old patient was posted for laparoscopic cholecystectomy, developed generalized convulsions after few seconds of propofol administration at anesthesia induction. Convulsions subsided with intravenous administrations of thiopentone and midazolam. Patient remained hemodynamically stable and surgery was uneventful. Blood sugar, serum electrolytes and arterial blood gas analysis were normal. Postoperatively, there was no evidence of postictal phase, serum electrolytes and postoperative computerized tomographic scanning of the head were normal. Patient had uneventful recovery. The administration of propofol has been associated with abnormal movements collectively termed as seizure-like phenomenon. Despite the claims that propofol may have proconvalsant activity, there is significant amount of evidence to the contrary also. The pathophysiological mechanisms behind the neuroexcitatory symptoms with propofol are unknown. Propofol alters the conscious state, the transition from the conscious state to anesthesia or vice versa may be a particularly vulnerable period and may be prolonged after the end of propofol administration.

Propofol sedation is reduced by delta9-tetrahydrocannabinol in mice.

BACKGROUND: Delta9-tetrahydrocannabinol (Delta9-THC) induces analgesic effects and alterations of alertness. It has been reported that propofol increases endocannabinoid levels in the brain, but the effects of Delta9-THC on propofol sedation remain unclear. Our aim was to characterize the interaction between Delta9-THC and propofol in terms of sedation and analgesia. METHODS: Sedation was monitored by a rota-rod and analgesia by tail-flick latencies. Twenty mice received intraperitoneal injections of 50 mg/kg Delta9-THC with 50, 75 and 100 mg/kg propofol after baseline values were established for each drug. Control experiments were performed with Delta9-THC and thiopental or Intralipid. RESULTS: Injection of 50 mg/kg propofol caused a rapid onset of sedation with a minimum of 24 s on the rota-rod. Fifty mg/kg Delta9-THC alone had no sedative effects. Administration of Delta9-THC significantly reduced the sedative effect of propofol to at least 60 s on the rota-rod (P < 0.001). After increasing the propofol dose to 100 mg/kg in the presence of Delta9-THC, sedation was re-established with 27 s on the rota-rod. Thiopental sedation was significantly reduced (P < 0.01) in the presence of Delta9-THC. CONCLUSION: The results indicate a dose-dependent antagonistic interaction between Delta9-THC and propofol, and also between Delta9-THC and thiopental.

Propofol causes neurite retraction in neurones.

BACKGROUND: The mechanism by which anaesthetic agents produce general anaesthesia is not yet fully understood. Retraction of neurites is an important function of individual neurones and neural plexuses during normal and pathological conditions, and it has been shown that such a retraction pathway exists in developing and mature neurones. We hypothesized that propofol decreases neuronal activity by causing retraction of neuronal neurites. METHODS: Primary cultures of rat cortical neurones were exposed in concentration- and time-response experiments to 0.02, 0.2, 2, and 20 microM propofol or lipid vehicle. Neurones were pretreated with the GABA(A) receptor (GABA(A)R) antagonist, bicuculline, the myosin II ATPase activity inhibitor, blebbistatin, and the F-actin stabilizing agent, phalloidin, followed by administration of propofol (20 microM). Changes in neurite retraction were evaluated using time-lapse light microscopy. RESULTS: Propofol caused a concentration- and time-dependent reversible retraction of cultured cortical neurone neurites. Bicuculline, blebbistatin, and phalloidin completely inhibited propofol-induced neurite retraction. Images of retracted neurites were characterized by a retraction bulb and a thin trailing membrane remnant. CONCLUSIONS: Cultured cortical rat neurones retract their neurites after exposure to propofol in a concentration- and time-dependent manner. This retraction is GABA(A)R mediated, reversible, and dependent on actin and myosin II. Furthermore, the concentrations and times to full retraction and recovery correspond to those observed during propofol anaesthesia.

Clinical assessment of propofol-induced yawning with heart rate variability: a pilot study.

STUDY OBJECTIVES: To investigate the proportion of propofol-induced yawning and sympathovagal balance during propofol-induced yawning. DESIGN: Prospective, observational, clinical study. SETTING: University hospital and 2400-bed tertiary medical center. PATIENTS: 546 ASA physical status I and II patients undergoing elective surgery with general anesthesia. INTERVENTIONS: Standard induction of anesthesia was performed with intravenous (IV) propofol two to four mg/kg (group P), or pretreatment with atropine 0.1 mg/kg (group AP) or with fentanyl 1 to 3 microg/kg (group FP) before propofol. Continuous standard electrocardiogram for heart rate variability (HRV) was performed in another 20 patients to investigate sympathovagal balance during propofol-induced yawning. MEASUREMENTS AND MAIN RESULTS: The proportions of yawning were 53.5% (207/386), 61.1% (55/90), and 0% (0/50) in the P, AP, and FP groups, respectively. Propofol-induced yawning could be dramatically decreased by pretreatment with IV fentanyl (P < 0.001, chi2 test). Significant increased ratio of low-frequency/high-frequency power was detected during HRV monitoring in 9 patients with yawning in comparison with 11 patients without yawning (P < 0.05, Wilcoxon signed-rank test). CONCLUSIONS: Pretreatment with fentanyl may inhibit propofol-induced yawning. Fluctuations in autonomic function have been noted during propofol-induced yawning.

Aminophylline reversal of prolonged postoperative sedation induced by propofol.

Propofol is frequently used for intravenous sedation or anesthesia in ambulatory and office-based anesthesia. Although awakening is usually rapid, there are instances of delayed recovery from propofol anesthesia. It has been reported that aminophylline antagonizes the sedative effects of several anesthetic and analgesic drugs. The case reports presented here demonstrate that intravenous aminophylline effectively reversed prolonged propofol-induced sedation/anesthesia in the postoperative period. There were no side effects or delayed re-sedation after the administration of aminophylline. Our study suggests that aminophylline could be a clinically useful propofol antagonist.

Ketamine, but not propofol, anaesthesia is regulated by metabotropic glutamate 5 receptors.

BACKGROUND: Group I metabotropic glutamate receptors (mGluRs) have been reported to regulate N-methyl-d-aspartate (NMDA) receptor function in various brain regions. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) can potentiate NMDA antagonists such as PCP and MK-801-induced behavioural responses. In the present study, the role of group I mGluRs on ketamine- and propofol-induced general anaesthesia was examined. METHODS: Mice were pretreated with various doses of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG), selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) and mGluR5 antagonist MPEP followed by administration of ketamine (120 mg kg(-1)) or propofol (140 mg kg(-1)) to induce anaesthesia. The duration of loss of righting reflex was recorded. RESULTS: DHPG and CHPG antagonized and MPEP potentiated ketamine-induced anaesthesia in a dose-dependent manner. CPCCOEt was ineffective. However, propofol-induced anaesthesia was not affected after manipulating mGluR1 and mGluR5 receptors. CONCLUSIONS: mGluR5 receptors play an important role in modulation of anaesthesia induced by ketamine, but not propofol.

Characteristics of propofol-evoked vascular pain in anaesthetized rats.

BACKGROUND: In this study we have assessed vascular pain caused by the i.v. anaesthetic agent, propofol, using the flexor reflex response and compared this with that of capsaicin in anaesthetized intact rats. METHODS: Experiments were performed on 133 male Sprague-Dawley rats weighing 280-340 g. The animals were anaesthetized with urethane (1.3 g kg(-1), i.p.), and an arterial cannula was inserted to the level of the bifurcation of the femoral artery. The magnitude of the flexor reflex was examined by recording the electromyogram from the posterior biceps femoris/semitendinosus muscles. RESULTS: Our data show that the flexor reflexes evoked by intra-arterial (i.a.) injection of propofol (1%, 25-100 microl) and capsaicin (0.05-0.2 microg) were dose dependent. An initial i.a. injection of procaine (2%, 200 microl) blocked both responses. Furthermore, the flexor reflex induced by these chemical stimuli were inhibited by morphine (5 mg kg(-1), s.c.) and restored with naloxone (1.5 mg kg(-1), s.c.). Pre-treatment with capsazepine (20 microg, i.a.), a selective VR1 antagonist, inhibited the capsaicin-evoked response, but not that of propofol. Indomethacin (10 mg kg(-1), i.p.), a non-selective cyclo-oxygenase inhibitor, inhibited only the propofol-evoked response and this recovered with arterial PGE2 (5 microg). CONCLUSIONS: Collectively our data suggest that propofol-evoked vascular pain is mainly initiated by prostanoids.