| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
Anesth Analg 2007; 105:1027-1033 © 2007 International Anesthesia Research Society doi: 10.1213/01.ane.0000281046.77228.91
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Abstract |
|---|
 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
BACKGROUND: Vascular endothelial cells play an important role in maintaining cardiovascular homeostasis. Oxidative stress is a critical pathogenic factor in endothelial cell damage and the development of cardiovascular diseases. In this study we evaluated the effects of propofol on oxidative stress-induced endothelial cell insults and the role of serine–threonine kinase Akt modulation of endothelial nitric oxide synthase (eNOS) as a mechanism of protection.
METHODS: Human umbilical vein endothelial cells were used as the experimental model. Hydrogen peroxide (H2O2, 100 µM) was used as the stimulus of oxidative stress. Study groups included 1) control; 2) cells incubated with H2O2 alone; 3) cells incubated with propofol (50 µM) alone; or 4) cells pretreated with propofol 50 µM for 30 min then co-incubated with H2O2. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Trypan blue dye exclusion test. Cell apoptosis was evaluated by Hoechst 33258 staining. Caspase-3 activity was determined by the colorimetric CaspACETM Assay System. Expressions of Akt, phospho-Akt, and eNOS were detected by Western blotting.
RESULTS: H2O2 decreased cell viability, induced apoptosis, and increased caspase-3 activity in human umbilical vein endothelial cells. Propofol significantly protected cells from H2O2-induced cell damage, apoptosis and decreased H2O2-induced increase in caspase-3 activity. Propofol treatment significantly increased eNOS expression compared to control and H2O2-stimulated cells. There was no significant difference in phospho-Akt (Ser 473 or Thr 308) expression among the groups.
CONCLUSIONS: Propofol 50 µM can reduce H2O2-induced damage and apoptosis in endothelial cells, by suppressing caspase-3 activity and by increasing eNOS expression via an Akt-independent mechanism.
|
Introduction |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
The vascular endothelium serves as a barrier between the bloodstream and the vascular wall, and plays an important role in maintaining cardiovascular homeostasis. Oxidative stress and reactive oxygen species (ROS) are regarded as critical pathogenic factors in endothelial cell injury and the development of cardiovascular diseases (1,2). Inhibition of ROS formation, scavenging ROS, or interfering with ROS pathogenic signaling pathways might be the potential ways to protect endothelial cells from injury and its sequelae.
Propofol has direct scavenging action against ROS and antiapoptotic effects in vitro (3–6), but the effect is not universal. The actions of propofol on cells are varied and different mechanisms may be involved (7). We previously demonstrated that propofol inhibits tumor necrosis factor-
induced human umbilical vein endothelial cells (HUVECs) apoptosis (8). This was associated with increased cellular nitric oxide (NO) release. NO synthesized by endothelial nitric oxide synthase (eNOS) is capable of inhibiting apoptosis and is regarded as an endothelial cell survival factor (9). We postulate that propofol confers protection against endothelial cell injury by modulating eNOS to produce the increase NO generation we observed.
There is increasing evidence that the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway regulates expression/activation of eNOS and prevents ROS-induced endothelial cell injury. Thus, the PI3K/Akt/ eNOS/NO pathway is identified as an important survival pathway in endothelial cells (10,11). The effect of propofol on the Akt signal pathway in endothelial cells has never been reported. The objectives of the present study were 1) to evaluate and confirm the protective effects of propofol on endothelial cells against oxidative stress-induced insult and apoptosis; and 2) to investigate its effect on Akt and eNOS as a potential mechanism of protection in a hydrogen peroxide (H2O2)-stimulated HUVECs model.
|
METHODS |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Reagents
Propofol injection containing 1% (w/v) propofol (Novopharm, Toronto, Canada) was used. The Colorimetric CaspACETM Assay System was purchased from Promega (Madison, WI). All culture reagents and Trypan Blue solution were from Invitrogen (New York, NY). All SDS-PAGE reagents and Bradford protein assay reagent were from Bio-Rad Laboratories (Hercules, CA). RIPA lysis buffer, rabbit antihuman eNOS, Akt 1/2, phospho-Akt (Ser 473 and Thr 308) antibodies and horseradish peroxidase-conjugated goat antirabbit IgG were obtained from Santa Cruz Biotechnology.(Santa Cruz, CA). Enhanced chemiluminescence Western Blotting Detection Reagents were from Amersham Biosciences (Piscataway, NJ). H2O2, Hoechst 33258, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were purchased from Sigma Chemical (St. Louis, MO).
Endothelial Cell Culture and Treatment Protocol
HUVEC line was purchased from the American Type Culture Collection (ATCC, CRL-1730; Passage 12) and was cultured in growth medium comprising Ham’s F12K medium (containing 2 mM l-glutamine and 1.5 g/L sodium bicarbonate) supplemented with 0.1 mg/mL heparin, 0.03 mg/mL endothelial cell growth supplement, 10% fetal bovine serum, 100 U/mL penicillin, and 100 µg/mL streptomycin. Cells were grown in a humidified incubator containing 95% air and 5% CO2 at 37°C with media replenishment every 3 days. All cells used in the study were derived from the same initial CRL-1730 cell culture. Experiments were subsequently conducted in Passage 14–17 cells.
Before experimental intervention, confluent cultured cells were preincubated for 24 h in starved medium comprising Ham’s F12K medium supplemented with 1% fetal bovine serum. The starved cells were then divided into four experimental groups characterized by culture medium prepared for different conditions 1) control; 2) cultured cells incubated with H2O2 alone; 3) cells incubated with propofol alone; or 4) cells pretreated with propofol for 30 min then co-incubated with H2O2. The concentrations of H2O2 (100 µM) and propofol (50 µM) applied were determined from pilot studies by our group and based on similar methods described in the literature (8,12,13).
Assessment of Cell Viability by MTT Assay and Trypan Blue Exclusion Test
The cell survival was measured by MTT assay. The assay is based on enzymic cleavage and conversion of the soluble yellow dye MTT to the water insoluble purple formazan in living cells. Therefore, the amount of formazan produced is proportional to the number of living cells. For MTT assay, cells were cultured in 96-well plate and treated as described above. After 24 h treatment by different medium condition, 50 µL MTT (2.5 mg/mL) was added to each well and cells were incubated with MTT at 37°C for 3 h. Then culture medium with dye was removed and 150 µL of dimethylsulfoxide per well was added for formazan solubilization. The absorbance of converted dye was measured at 570 nm using a plate reader (Beckman, Fullerton, CA). Four independent survival experiments, each comprising 8–12 repeats, were performed.
Cell death rate was also determined by Trypan blue dye exclusion test. It is based on the fact that the chromophore is negatively charged and does not interact with the cell unless the membrane is damaged. Therefore, all the cells which exclude the dye are viable. Briefly, after 24 h treatment by different medium condition, cells from each group were detached by trypsinizing the cell layer, and were collected by centrifugation. After resuspension in phosphate buffered saline, equal volumes of cell suspension and 0.4% Trypan blue were mixed and incubated for 5–10 min at room temperature. The number of nonviable cells (stained cells) was counted using a hemocytometer and expressed as a percentage of the total cells counted. Four independent experiments were conducted in triplicate.
Evaluation of Cell Apoptosis by Hoechst 33258
After 24 h treatment by different medium condition, cells from each group were washed with phosphate buffered saline and fixed with 4% formalin for 10 min. Fixed cells were then stained with 10 µg/mL Hoechst 33258 for 30 min in the dark to stain nuclei. Cells were observed and photographed under a fluorescence microscope (Olympus, Center Valley, PA). Apoptotic cells were identified as those with a nucleus exhibiting brightly stained condensed chromatin or nuclear fragments and normal nuclei are blue chromatin with organized structure. For each experimental condition, four separate cell populations were prepared. At least 100 cells from five randomly selected fields were counted in each cell population and quantified for each experimental condition (total: 500 cells per population). The apoptotic index (percentage of apoptotic cells) was calculated as number of apoptotic cells to total cells counted x 100. The investigator was blinded with respect to treatment group being evaluated.
Assay of Caspase-3 Activity
After 4 h treatment by different medium condition, cells of each group were lysed and caspase-3 activity was measured in the cell lysate by the colorimetric CaspACETM Assay System according to the manufacturer’s recommendations. The colorimetric, caspase-3 specific substrate N-acetyl-Asp-Glu-Val-Asp-p-nitroaniline (Ac-DEVD-pNA) provided in the Assay System is labeled with the chromophore p-nitroaniline (pNA). pNA is released from the substrate upon cleavage by caspase-3 (DEVDase). Free pNA produces a yellow color that is monitored by a spectrophotometer at 405 nm. The amount of yellow color produced upon cleavage is proportional to the amount of DEVDase (caspase-3) activity present in the sample. Assays were performed in triplicate and three independent experiments were performed in this study.
Western Blot Analysis of Akt, Phospho-Akt, and eNOS Expressions
After 24 h treatment by different medium condition, cells from each group were lysed by using RIPA lysis buffer containing 20 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1% Nonider P-40, 0.5% sodium deoxycholate, 0.1% SDS, 0.004% sodium azide, 1% PMSF, 1% sodium orthovanadate, and 1% protease inhibitor cocktail at 4°C. For each experimental condition, four separate cell populations were prepared. The lysate was centrifuged at 10,000g at 4°C for 30 min to remove the insoluble material. Supernatants were collected, and the protein concentration was then measured with the Bradford protein assay reagent using BSA as a standard. Then equal amounts of protein (60 µg) from each sample were separated by 10% SDS-PAGE and transferred to nitrocellulose membrane. The membranes were blocked for 1 h in 5% skim milk and then incubated overnight at 4°C with primary antibody against eNOS, or Akt, or phospho-Akt (Ser 473), or phospho-Akt (Thr 308). After a 30-min wash, the membranes were incubated with secondary antibody conjugated to horseradish peroxide for 1 h at room temperature. The membranes were then washed for 30 min and exposed to enhanced chemiluminescence reagents for 1 min and developed on film. Densitometric analysis was performed to quantify the signal intensity.
Statistical Analysis
All results were expressed as mean and standard deviation (mean ± sd). Difference was analyzed for significance by one-way repeated-measures ANOVA followed by Tukey’s test. A value of P < 0.05 was considered statistically significant.
|
RESULTS |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Propofol Attenuated H2O2-Induced Decrease in the Viability of HUVECs
Figure 1 demonstrates cell survival as evidenced by MTT in our four experimental groups. Incubation with 100 µM H2O2 for 24 h resulted in a decrease in cell viability of 30%. Propofol had no obvious effect on cell viability compared to control. Propofol pretreatment, however, significantly inhibited the H2O2-induced decrease in cell viability, restoring it to control values.
|
Trypan blue exclusion test results were consistent with that of MTT assay (Fig. 2). Twenty-four-hour incubation with 100 µM H2O2 led to 26% death rate of HUVECs. Propofol itself had no obvious effect on cell death rate compared to control. Propofol pretreatment significantly inhibited H2O2-induced cell death in our experimental model.
|
Propofol Reduced HUVECs Apoptosis Induced by H2O2
Hoechst 33258 was used as an apoptosis marker, which detected apoptotic nuclei with condensed and/ or fragmented DNA. Figures 3A and B show representative fields from control and propofol-only groups. Most nuclei in control and propofol-only groups were uniform blue chromatin with organized structure. Very few significant intense Hoechst 33258-stained nuclei were seen in these two groups. H2O2-stimulated cells (Fig. 3C) showed an increased frequency of apoptotic nuclei compared to control. Propofol pretreatment reduced H2O2-induced apoptosis, demonstrating very few apoptotic nuclei (Fig. 3D), similar to control conditions. Apoptotic indices were determined by direct visualization and counting of a minimum of 500 cells per population. A graph in Figure 3 demonstrated the apoptotic indices of the HUVECs for each experimental condition. The data showed that the apoptotic index increased dramatically in cells stimulated by H2O2, a condition which was prevented by previous incubation with propofol (P < 0.05).
|
Propofol Decreased the Activation of Caspase-3 in HUVECs Induced by H2O2
As shown in Figure 4, H2O2 led to a significant increase in caspase-3 activity as compared to control. Propofol administration significantly decreased H2O2-induced caspase-3 activation as compared to H2O2 stimulated alone group.
|
Effects of Propofol on eNOS, Akt, and Phospho-Akt Expression
To determine propofol’s mechanisms of action, eNOS, Akt, and phospho-Akt (for serine 473 and threonine 308 isoforms) expressions were detected by Western blotting. As shown in Figure 5A, 24 h exposure of HUVECs to H2O2 led no obvious changes in eNOS expression. Propofol treatment, in the presence of H2O2, significantly increased eNOS expression compared to control and H2O2-stimulated cell groups. There was, however, no significant intergroup difference in total and phospho-Akt (Ser 473 and Thr 308) expression observed (Fig. 5B).
|
|
DISCUSSION |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Propofol has been shown to exhibit potent H2O2 scavenging action in vitro (14). Although the attenuation of the H2O2 toxicity by propofol is observed in several types of preparation (15–20), there has been limited information on the effects of propofol on endothelial cells, and the mechanisms of action of propofol have yet to be elucidated (21,22). Because cultured umbilical vein endothelial cells are particularly prone to oxidative damage, they are often used to study H2O2-induced apoptosis (12). In the present study, cultured HUVECs were used as a model to study the effects and mechanisms of propofol on H2O2-induced insults and apoptosis. Our results demonstrated that a clinically relevant concentration of propofol (50 µM) effectively protected HUVECs from damage and apoptosis induced by H2O2. Propofol treatment increased eNOS expression and decreased caspase-3 activity in H2O2-stimulated cells. This was associated with no change in Akt phosphorylation, suggesting that propofol may modulate eNOS in endothelial cells through an Akt independent pathway.
NO, derived from the action of eNOS, is one of the most important mediators in the regulation of endothelial cell functions. NO has a bifunctional role, demonstrating contradictory (antiapoptotic and proapoptotic) effects in different types of cells. The overall outcome depends, at least in part, on the NO concentration and oxidative status of the cell. Endothelial NO produced by eNOS inhibits apoptosis and is regarded as an endothelial cell survival factor (9). NO can avidly scavenge superoxide anion, preventing the formation of its dismutation product, H2O2, to protect cells from oxidative stress-induced apoptosis. However, the more important antiapoptotic effect of NO has been attributed to its reversible S-nitrosylation of key cysteine residues in various members of the proapoptotic caspase cascade. Alterations in NO production can affect signal transduction pathways that control apoptotic cell death (3,10,23). Thus, eNOS-synthesized NO can inhibit caspase-mediated apoptosis in endothelial cells. By contrast, susceptibility to atherosclerosis or age-related endothelial dysfunction is due, at least in part, to the diminished production or availability of NO and enhanced apoptosis (9,24).
In a previous study we observed that propofol enhanced the generation of NO in tumor necrosis factor--stimulated HUVECs, which was associated with a reduction in apoptosis (8). In the present study, we found that eNOS expression was significantly up-regulated by propofol treatment. We postulate that propofol increases NO availability to confer an antiapoptotic effect in endothelial cells. We found that propofol significantly decreased caspase-3 activation induced by H2O2. This suggests that one of the potential antiapoptotic mechanisms of propofol may include NO-derived inhibition of capsase-3 activation secondary to the modulation of eNOS in this model.
How does propofol regulate the eNOS signal? The serine–threonine kinase Akt activation has been reported to activate eNOS, which leads to NO production promoting cell survival. The PI3K/Akt pathway can regulate expression/activation of eNOS and prevent ROS-induced endothelial cell injury. Thus, PI3K/ Akt/eNOS/NO pathway has been identified as an important survival pathway in endothelial cells (10,11). Propofol’s effect on the Akt signal pathway has not been reported, and was an objective of our study. We studied the expression and phosphorylation of Akt in HUVECs. Of interest, whereas propofol increased eNOS expression in endothelial cells, we cannot detect a role for Akt in the regulation of eNOS in our model.
The regulation on eNOS in endothelial cells is complex, involving multiple signal pathways in addition to the PI3K/Akt pathway. For example, protein kinase C (PKC), protein kinase A, adenosine monophosphate kinase, and calmodulin kinase are all important and responsible for regulation on eNOS function and NO production (23). Based on our current findings, alternative Akt-independent signal pathways might be involved in propofol-induced eNOS activation in endothelial cells. Of interest, propofol has been reported to be able to stimulate activation of PKC in the presence of physiologically relevant lipid bilayer vesicles in vitro (25). Furthermore, Wickley et al. (26,27) recently reported the regulation of eNOS in cardiomyocytes by propofol via a PKC-dependent pathway. To further understand the regulation of eNOS activation in endothelial cells by propofol, future studies emphasizing the role of Akt-independent signaling, such as the PKC signal pathway, are required.
The antiapoptotic action of propofol may be of clinical relevance. Because endothelial apoptosis precedes cardiomyocyte apoptosis, free radical-mediated endothelial injury may explain poor outcomes after coronary bypass surgery (28–30). Propofol, in a large dose, has been shown to reduce biomarkers of cardiac injury and inotrope requirements in coronary surgery patients (31). Corroborating data from our laboratory demonstrate that propofol up-regulates eNOS and increases NO bioavailability in human atrial tissue biopsies and increases the phosphorylation of Akt to decrease apoptosis in cardiomyocyte cell culture (unpublished data). Based on our current findings, propofol may regulate eNOS expression in endothelial cells through an Akt-independent pathway. This would confer an alternative route of endothelial protection, especially under conditions of increased oxidant stress, such as occurs in diabetes or heart failure.
Study Limitations
HUVECs cell lines that are readily available and are an established in vitro model of endothelial cells may not fully represent the in vivo characteristics of cardiac endothelial cells. Second, factors other than ROS, such as inflammatory mediators, also contribute to the development of vascular endothelial injury and myocardial ischemia-reperfusion injury and were not explored in this model. Therefore, caution must be taken when extrapolating our findings to the clinical situation. Lastly, studies involving the use of specific and nonspecific NOS inhibitors are required to clarify the effects of propofol on eNOS activation in detail.
|
CONCLUSIONS |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Administration of H2O2 increases cellular oxidative stress and leads to endothelial cell death via an apoptotic mechanism. Propofol, in a therapeutic concentration, can protect endothelial cells against H2O2-induced apoptosis. H2O2 activates caspase-3. Propofol can significantly reduce H2O2-enhanced caspase-3 activity. In addition, propofol can increase eNOS expression (via an Akt-independent pathway), which is responsible for the endothelial-derived NO production and inhibition of caspase-3. In conclusion, this study, for the first time, demonstrates an Akt-independent eNOS/ NO/caspase-3 antiapoptotic mechanism of propofol in endothelial cells. This observation provides mechanistic support for the possible use of propofol in clinical conditions such as coronary bypass surgery.
|
ACKNOWLEDGMENTS |
|---|
The authors thank Dr. David Granville and Ms. Hongyan Zhao for facilitating our use of fluorescent microscopy in their laboratory, without which, completion of this project would not have been possible. We also acknowledge the previous contributions of our colleague, Dr. Zhengyuan Xia, to the study of propofol as a preemptive cardioprotectant.
|
Footnotes |
|---|
Accepted for publication June 28, 2007.
Supported by UBC Department of Anesthesiology, Pharmacology and Therapeutics and Vancouver Coastal Health Research Institute Interim Bridge Funding Program.
|
REFERENCES |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
- Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury. II. Animal and human studies. Circulation 2003; 108:2034–40
[Free Full Text] - Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury. I. Basic mechanisms and in vivo monitoring of ROS. Circulation 2003;108:1912–16
[Free Full Text] - Tesauro M, Thompson WC, Moss J. Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells. Cell Death Differ 2006;13:597–606[Web of Science][Medline]
- Acquaviva R, Campisi A, Murabito P, Raciti G, Avola R, Mangiameli S, Musumeci I, Barcellona ML, Vanella A, Li Volti G. Propofol attenuates peroxynitrite-mediated DNA damage and apoptosis in cultured astrocytes: an alternative protective mechanism. Anesthesiology 2004;101:1363–71[Web of Science][Medline]
- Song HK, Jeong DC. The effect of propofol on cytotoxicity and apoptosis of lipopolysaccharide-treated mononuclear cells and lymphocytes. Anesth Analg 2004;98:1724–8
[Abstract/Free Full Text] - Chang H, Tsai SY, Chang Y, Chen TL, Chen RM. Therapeutic concentrations of propofol protects mouse macrophages from nitric oxide-induced cell death and apoptosis. Can J Anaesth 2002;49:477–80[Web of Science][Medline]
- Chikutei K, Oyama TM, Ishida S, Okano Y, Kobayashi M, Matsui H, Horimoto K, Nishimura Y, Ueno SY, Oyama Y. Propofol, an anesthetic possessing neuroprotective action against oxidative stress, promotes the process of cell death induced by H2O2 in rat thymocytes. Eur J Pharmacol 2006;540:18–23[Web of Science][Medline]
- Luo T, Xia Z, Ansley DM, Ouyang J, Granville DJ, Li Y, Xia ZY, Zhou QS, Liu XY. Propofol dose-dependently reduces tumor necrosis factor-alpha-induced human umbilical vein endothelial cell apoptosis: effects on Bcl-2 and Bax expression and nitric oxide generation. Anesth Analg 2005;100:1653–9
[Abstract/Free Full Text] - Dimmeler S, Zeiher AM. Nitric oxide-an endothelial cell survival factor. Cell Death Differ 1999;6:964–8[Web of Science][Medline]
- Ho FM, Lin WW, Chen BC, Chao CM, Yang CR, Lin LY, Lai CC, Liu SH, Liau CS. High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-kappaB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/ Akt/eNOS pathway. Cell Signal 2006;18:391–9[Web of Science][Medline]
- Abdallah Y, Schafer C. Insulin: an overall cardiovascular protector? Cardiovasc Res 2006;69:4–6[Web of Science][Medline]
- Cai H. Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences. Cardiovasc Res 2005; 68:26–36
[Abstract/Free Full Text] - Luo T, Xia Z. A small dose of hydrogen peroxide enhances tumor necrosis factor-alpha toxicity in inducing human vascular endothelial cell apoptosis: reversal with propofol. Anesth Analg 2006;103:110–16
[Abstract/Free Full Text] - Gulcin I, Alici HA, Cesur M. Determination of in vitro antioxidant and radical scavenging activities of propofol. Chem Pharm Bull (Tokyo) 2005;53:281–5[Medline]
- Kokita N, Hara A. Propofol attenuates hydrogen peroxide-induced mechanical and metabolic derangements in the isolated rat heart. Anesthesiology 1996;84:117–27[Web of Science][Medline]
- Eriksson O, Pollesello P, Saris NE. Inhibition of lipid peroxidation in isolated rat liver mitochondria by the general anaesthetic propofol. Biochem Pharmacol 1992;44:391–3[Web of Science][Medline]
- Lee H, Jang YH, Lee SR. Protective effect of propofol against kainic acid-induced lipid peroxidation in mouse brain homogenates: comparison with trolox and melatonin. J Neurosurg Anesthesiol 2005;17:144–8[Web of Science][Medline]
- Tsuchiya M, Asada A, Kasahara E, Sato EF, Shindo M, Inoue M. Antioxidant protection of propofol and its recycling in erythrocyte membranes. Am J Respir Crit Care Med 2002;165:54–60
[Abstract/Free Full Text] - Ansley DM, Lee J, Godin DV, Garnett ME, Qayumi AK. Propofol enhances red cell antioxidant capacity in swine and humans. Can J Anaesth 1998;45:233–9[Web of Science][Medline]
- Navapurkar VU, Skepper JN, Jones JG, Menon DK. Propofol preserves the viability of isolated rat hepatocyte suspensions under an oxidant stress. Anesth Analg 1998;87:1152–7
[Abstract/Free Full Text] - Balyasnikova IV, Visintine DJ, Gunnerson HB, Paisansathan C, Baughman VL, Minshall RD, Danilov SM. Propofol attenuates lung endothelial injury induced by ischemia-reperfusion and oxidative stress. Anesth Analg 2005;100:929–36
[Abstract/Free Full Text] - Peng Z, Luo M, Ye S, Critchley LA, Joynt GM, Ho AM, Yao S. Antioxidative and anti-endotoxin effects of propofol on endothelial cells. Chin Med J (Engl) 2003;116:731–5[Medline]
- Sessa WC. eNOS at a glance. J Cell Sci 2004;117:2427–9
[Free Full Text] - Dimmeler S, Zeiher AM. Nitric oxide and apoptosis: another paradigm for the double-edged role of nitric oxide. Nitric Oxide 1997;1:275–81[Web of Science][Medline]
- Hemmings HC Jr, Adamo AI, Hoffman MM. Biochemical characterization of the stimulatory effects of halothane and propofol on purified brain protein kinase C. Anesth Analg 1995;81:1216–22[Abstract]
- Wickley PJ, Shiga T, Murray PA, Damron DS. Propofol decreases myofilament Ca2+ sensitivity via a protein kinase C-, nitric oxide synthase-dependent pathway in diabetic cardiomyocytes. Anesthesiology 2006;104:978–87[Web of Science][Medline]
- Wickley PJ, Ding X, Murray PA, Damron DS. Propofol-induced activation of protein kinase C isoforms in adult rat ventricular myocytes. Anesthesiology 2006;104:970–7[Web of Science][Medline]
- Sellke FW, Shafique T, Ely DL, Weintraub RM. Coronary endothelial injury after cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals. Circulation 1993;88:II395–400[Medline]
- He GW. Endothelial function related to vascular tone in cardiac surgery. Heart Lung Circ 2005;14:13–18[Medline]
- Molavi B, Mehta JL. Oxidative stress in cardiovascular disease: molecular basis of its deleterious effects, its detection, and therapeutic considerations. Curr Opin Cardiol 2004;19:488–93[Web of Science][Medline]
- Xia Z, Huang Z, Ansley DM. Large-dose propofol during cardiopulmonary bypass decreases biochemical markers of myocardial injury in coronary surgery patients: a comparison with isoflurane. Anesth Analg 2006;103:527–32
[Abstract/Free Full Text]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
