Anesth Analg 2003;97:442-448
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Propofol Displays No Protective Effect Against Hypoxia/Reoxygenation Injury in Rat Liver Slices
Hiroo Shimono, MD,
Teruko Goromaru, PhD,
Yoshitami Kadota, MD,
Takeshi Tsurumaru, MD, and
Yuichi Kanmura, MD
Department of Anesthesiology and Critical Care Medicine, Kagoshima University School of Medicine, Kagoshima, Japan
Address correspondence and reprint requests to Yoshitami Kadota, MD, Department of Anesthesiology and Critical Care Medicine, Kagoshima University School of Medicine, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. Address e-mail to kadotayo{at}med4.kufm.kagoshima-u.ac.jp
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Abstract
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Using precision-cut liver slices (20–25 mg wet weight) from male Wistar rats, we examined whether clinically relevant propofol concentrations have hepatoprotective or -toxic effects during hypoxia/reoxygenation. Slices were preincubated for 2 h in sealed roller vials (three slices per vial) containing Waymouth’s medium (37°C; 95% oxygen/5% CO2). Then, propofol or Intralipid was added to create four different groups (control, Intralipid, small-concentration propofol [0.5–1.5 µg/mL], and large-concentration propofol [2.0–6.0 µg/mL]). Thereafter, each group was incubated for 4 h under 95% oxygen/5% CO2 (no hypoxia) or for 2 h under 100% nitrogen plus 2 h under 95% oxygen/5% CO2 (hypoxia/reoxygenation). Slice viability and hypoxia/reoxygenation injury were assessed at 2, 3, and 4 h after incubation began by using the slice intracellular K+ concentration, energy status (adenosine triphosphate content, total adenine nucleotides content, and energy charge), and liver enzyme leakage (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase). Propofol and Intralipid caused a significant delay in energy charge recovery in comparison with the control. There were no significant differences between the propofol groups and the other two groups in intracellular K+ content or liver enzyme leakage. Propofol had no hepatotoxic effect under no-hypoxia conditions in rat liver slices, nor did it have a protective effect against hypoxia/reoxygenation-induced hepatic injury.
IMPLICATIONS: Propofol had no hepatotoxic effect under no-hypoxia conditions in rat liver slices, nor did it have a protective effect against hypoxia/reoxygenation-induced hepatic injury.
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Introduction
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Propofol has been reported to have a protective effect against ischemia/reperfusion injury in several organs: for example, heart (1,2) and brain (3,4), as well as in the lower limbs (5). The mechanism underlying this protective effect reportedly involves either radical scavenging (6,7) or inhibitory effects on calcium channels (8). In addition, the reported propofol-induced nitric oxide (NO) and vasodilatory prostanoid production (9) might be beneficial during ischemia/reperfusion injury (10). Surprisingly, there are only limited experimental and clinical data that are relevant to a potential beneficial effect of propofol on liver ischemia/reperfusion injury.
Precision-cut tissue-slice technology has advanced sufficiently for such slices to be considered a reliable alternative to microsomes, freshly isolated hepatocytes, and whole animals (11,12). As a consequence, there has recently been a dramatic increase in the use of this technique for metabolism and toxicity studies involving various organs. The application of this technique to experiments on organ ischemia, reperfusion, or both has also been reported, and in several organs, attempts have been made to clarify the effects of these maneuvers on cellular metabolism and drug biotransformation, as well as to examine the effects of drugs on organ injury (3,13,14).
The main objective of this study was to examine whether propofol has a hepatoprotective or -toxic effect under hypoxia/reoxygenation conditions by using rat liver slices. To assess propofol’s effects, we used several markers, including the slice intracellular K+ concentration, liver enzyme leakage into the medium (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase [LDH]), and indicators of the energy level of the slice (the concentrations of adenosine triphosphate [ATP], total adenine nucleotides [TAN = ATP + adenosine diphosphate + adenosine monophosphate], and energy charge [EC = [ATP + 1/2 adenosine diphosphate]/TAN]). The intracellular K+ concentration and the level of liver enzyme leakage are reflections of generalized cellular and membrane integrity. The intracellular concentrations of ATP, TAN, and EC provide an insight into both the energy status and the metabolic capacity of the tissue slice.
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Methods
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The study was approved by the Institute Animal Use Committee of Kagoshima University. Propofol and Intralipid were supplied by AstraZeneca-Japan Ltd. (Osaka, Japan) and Ootsuka Pharmaceutical Co. (Tokushima, Japan), respectively. Waymouth’s MB752/1 powdered medium was obtained from Sigma Chemical Co. (St. Louis, MO), and fetal bovine serum was obtained from Gibco Laboratories (Grand Island, NY). All other chemicals were obtained from Nacalai Tesque Inc. (Kyoto, Japan) or Wako Pure Chemical Industries Ltd. (Osaka, Japan).
The Brendel/Vitron tissue slicer, Teflon/Vitron/Titanium rollers, loading platform, cordless coring tool, and dynamic organ-culture incubator were obtained from Vitron Inc. (Tucson, AZ). Male Wistar rats purchased from Kyudo Inc. (Kumamoto, Japan) were maintained on a 12-h light cycle at 22°C ± 1°C room temperature until the start of the experiments at the Institute of Laboratory Animal Sciences, Faculty of Medicine, Kagoshima University.
Ten male Wistar rats weighing 350–440 g were used. A laparotomy was performed, and livers were excised under ether anesthesia. Then, the livers were placed in ice-cold, oxygenated Krebs-Henseleit buffer (pH 7.4). Cores (8-mm outer diameter) were taken from the various liver lobes by using a cordless coring tool, and slices (20–25 mg wet weight) were prepared with a Brendel/Vitron tissue slicer. Three slices chosen at random were placed onto Vitron/Titanium rollers and loaded into each glass scintillation vial (containing 1.6 mL of Waymouth’s culture medium oxygenated with 95% oxygen/5% CO2 gas), and then a 2-h preincubation of the sealed vials was performed in a dynamic organ-culture incubator (37°C). The Waymouth’s medium used in this study was supplemented with 10% fetal calf serum and 2.24 g/L of sodium bicarbonate.
We prepared 24 vials as described and allocated the vials randomly to a no-hypoxia (12 vials) or hypoxia/reoxygenation (12 vials) group (Fig. 1). Each of these groups was divided into four subgroups: 1) a control group (three vials containing only Waymouth’s medium), 2) an Intralipid group (three vials containing 0.02% Intralipid in Waymouth’s medium), 3) a small-concentration propofol group (three vials, each containing 0.5–1.5 µg/mL; pro-L group), and 4) a large-concentration propofol group (three vials, each containing 2.0–6.0 µg/mL; pro-H group). In the propofol groups, the vials contained propofol and 0.02% Intralipid in Waymouth’s medium.
Thus, the study was conducted with eight experimental groups. In the no-hypoxia condition, incubation vials were gassed with 95% oxygen/5% CO2 gas for 30 s every hour for 4 h. In the hypoxia/reoxygenation condition, the vials were gassed with 100% nitrogen for 60 s every hour for 2 h and then reoxygenated with 95% oxygen/5% CO2 gas for 30 s every hour for 2 h. Propofol was added to the vials every hour with the aim of keeping its concentration at 0.5–1.5 µg/mL or 2.0–6.0 µg/mL (small-concentration and large-concentration groups, respectively). These concentrations are similar to those found clinically when propofol is used for sedation or hypnosis (0.5–1.5 µg/mL or 2.0–6.0 µg/mL, respectively) (15). Before the experiment proper, we determined how much propofol had to be added to the vials every hour to maintain the desired concentration range in the media throughout the incubation period. In this preliminary experiment, we measured the propofol concentration just before adding the propofol at 2 and 3 h after the start of incubation and also at the end of the incubation (4 h after its start). In this way, we measured the smallest propofol concentration during each 1-h period.
After 2 h of preincubation, Vitron/Titanium rollers, each loaded with three slices, were transferred into the appropriate vials for each experimental group. After a 2-, 3-, or 4-h incubation period at 37°C in the dynamic organ-culture incubator, one vial from each group was taken out of the incubator, and the intracellular K+ concentration, the energy status of the slice (ATP, TAN, and EC), and enzyme leakage into the media (AST, ALT, and LDH) were measured to assess the slice viability and the degree of hypoxia/reoxygenation injury. The propofol concentration in the media was also measured, giving values for 2-, 3-, and 4-h incubation periods.
The intracellular K+ concentration was measured according to the method of Fisher et al. (16). Briefly, the liver slice was homogenized with an ultrasonic disrupter (Model UD-201; TOMY, Tokyo, Japan), and then, after deproteinization with perchloric acid and centrifugation, the supernatant was assayed with an atomic absorption spectrophotometer (Model 180-50; Hitachi, Tokyo, Japan). The adenine nucleotides concentration was determined by high-performance liquid chromatography (HPLC) on the anion-exchange column (4.6 x 250 mm) of a DEAE-2SW (TOSOH, Tokyo, Japan). HPLC was performed by using 360 mM sodium phosphate buffer, pH 6.0, at a 0.9 mL/min flow rate and by monitoring at a 254-nm wavelength via an ultraviolet/visible absorbance detector (17). For this purpose, the slice was immediately frozen in liquid nitrogen; then, after weighing, it was homogenized in ice-cold perchloric acid and centrifuged for 10 min at 4°C and 13,000 rpm. The supernatant was neutralized with KOH and allowed to stand for 30 min in an ice bath. After the KClO4 precipitate was removed, the filtrate obtained through a Millex®-LG (Millipore, Tokyo, Japan) was injected into the HPLC. The AST, ALT, and LDH activities in the medium were measured with an auto dry chemistry analyzer (SPOTCHEMTM; Model SP-4410; Kyotodaiiti-kagagu K.K., Kyoto, Japan). The propofol concentration in the medium was determined by HPLC with the method of Plummer (18). In this study, we used a Gilson HPLC system equipped with an ultraviolet/visible absorbance detector, fluorometer, and autoinjector (Models 118, 122, and 234, respectively; Gilson Inc., Middleton, WI).
Statistical analysis was performed with StatView 5.0 (SAS Institute, Inc., Cary, NC). The results are expressed as mean ± SE. To evaluate differences over time within each group, a repeated-measures analysis of variance (ANOVA) was used. To evaluate differences among the four groups under the no-hypoxia or hypoxia/reoxygenation condition, a one-way ANOVA was used. When significant differences were detected by ANOVA, a post hoc Tukey-Kramer test was used. The statistical differences between two corresponding groups (no-hypoxia versus hypoxia/reoxygenation conditions) in a given variable at the same time point were assessed with a paired Student’s t-test. P < 0.05 was considered significant.
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Results
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In the no-hypoxia condition, the smallest propofol concentrations in the media (i.e., the concentrations measured just before propofol was added at 2 and 3 h after the start of the incubation and at the end of the incubation) were 0.31–0.37 µg/mL and 1.97–2.21 µg/mL in the pro-L and pro-H groups, respectively (Table 1). The propofol concentrations at Time Point A in both the pro-L and pro-H groups were significantly larger in the hypoxia/reoxygenation condition than in the no-hypoxia condition. This was also true for Time Point B in the pro-H group. In the pro-L group in the hypoxia/reoxygenation condition, the propofol concentration at Time Point A was significantly larger than that at Time Point B.
In the no-hypoxia condition, the K+ content was well maintained within the range 60–70 nmol/mg in all groups, and no significant differences were found among the groups at any time point (Fig. 2). For the hypoxia/reoxygenation condition, immediately after the hypoxic period (i.e., Time Point A), the K+ content in each group was within the range 41–46 nmol/mg, and these levels were significantly less than the corresponding ones in the no-hypoxia condition. Although the K+ content had recovered to within the range 60–70 nmol/mg in each group at Time Points B and C, the K+ content in the pro-L group at Time Point C was still significantly smaller than the corresponding one in the no-hypoxia condition.
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Figure 2. Liver-slice K+ contents in the media in each group. Propofol-L = small-concentration propofol group; propofol-H = large-concentration propofol group; A, B, and C are time points 120, 180, and 240 min after the start of the incubation, respectively; n = 10; data are mean ± SE. *P < 0.05, **P < 0.01 versus the corresponding no-hypoxia value; #P < 0.05, ##P < 0.01 versus the corresponding value at Time Point A in the same condition (no hypoxia or hypoxia/reoxygenation).
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The leakage of all the liver enzymes examined (AST, ALT, and LDH) increased in a time-dependent manner in each group (Fig. 3) in the no-hypoxia condition. There were no significant differences among the groups in AST, ALT, or LDH levels at any time point. At every time point in the hypoxia/reoxygenation condition, each group showed a significantly larger leakage of all three liver enzymes than the corresponding values obtained for the no-hypoxia condition. In the hypoxia/reoxygenation condition, there were no significant differences among the groups at any time point after reoxygenation.
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Figure 3. Concentrations of liver enzymes in the media in each group. AST = aspartate aminotransferase; ALT = alanine aminotransferase; LDH = lactate dehydrogenase. A, B, and C are time points 120, 180, and 240 min after the start of the incubation, respectively; n = 10; data are mean ± SE. *P < 0.05, **P < 0.01 versus the corresponding no-hypoxia value; #P < 0.05, ##P < 0.01 versus the corresponding value at Time Point A in the same condition (no hypoxia or hypoxia/reoxygenation).
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In each group, ATP, TAN, and EC concentrations were well maintained at all time points (Table 2) in the no-hypoxia condition. There were no significant differences among the groups in ATP, TAN, or EC at any time point. For the hypoxia/reoxygenation condition, in each group, the ATP, TAN, and EC concentrations decreased significantly immediately after the period of hypoxia and were not fully restored to the levels seen in the no-hypoxia condition at any time points after reoxygenation (except for three EC values; see Table 2). In the Intralipid group and the two propofol groups, the recovery of the EC after hypoxia to the level shown by the corresponding group in the no-hypoxia condition was significantly delayed (in comparison with the control). In the hypoxia/reoxygenation condition, there were no significant differences among the groups at any time point after reoxygenation (except for the TAN concentration in the Intralipid group at Time Point A, which was significantly larger than in the pro-H group).
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Discussion
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In this study, we established an ischemia/reperfusion model by using the precision-cut liver-slice technique as follows. Glass scintillation vials containing liver slices and culture medium are usually gassed with an appropriate mixture (e.g., 95% oxygen/5% CO2); however, if the vials are instead gassed with low-oxygen-tension gas, we can create a state of hypoxia in the liver slices. Further, if the vials are gassed with high-oxygen-tension gas followed by low-oxygen-tension gas and then again with high-oxygen-tension gas, we can create a hypoxia/reoxygenation state, which is considered to be a condition similar to organ ischemia/reperfusion.
During the time for which the liver slices were incubated in the hypoxia condition, the slices in every group showed a decreased energy level and a disruption of cellular and membrane integrity. Propofol did not protect against these hypoxia-induced changes. As the liver slices were reoxygenated, the ATP and TAN contents in all groups were not fully restored to the levels seen at the corresponding time points in the no-hypoxia condition. Propofol (and Intralipid) caused a significant delay in EC recovery to the levels seen at the corresponding time points in the no-hypoxia condition (in comparison with the control). In addition, all indices of liver enzyme leakage increased after hypoxia/reoxygenation in every group, and propofol displayed no protective effect against this liver enzyme leakage. From these results, propofol, at least at the concentrations we tested, shows no evidence of having a beneficial effect against hepatic hypoxia/reoxygenation injury.
Although we found no evidence of propofol having a beneficial effect against liver hypoxia/reoxygenation injury in rat liver slices, propofol has been reported to have protective effects against ischemia/reperfusion injury in several organs: for example, heart (1,2) and brain (3,4), as well as in the lower limbs (5). Mechanisms that might underlie the reported beneficial effects of propofol against organ ischemia/reperfusion injury are a radical scavenging effect (6,7), inhibitory effects on calcium channels (8), or a propofol-induced NO and vasodilatory prostanoid production (9). Regarding the possible reasons why propofol displayed no protective effects against hepatic hypoxia/reoxygenation injury in our study despite showing an apparent protective effect in other organs, the important factor may be the metabolic capacity for both propofol and its lipid vehicle shown by the target organ. Both propofol and its lipid vehicle are mainly metabolized in the liver, even under hypoxic conditions (19,20). This may lead to a depletion of hepatic ATP, a decrease in the propofol concentration in the liver (resulting in a depletion of its protective ability against ischemia/reperfusion injury), and an increase in free fatty acids degraded from triglycerides (which are components of the vehicle used for propofol). The heart, brain, lung, and lower limbs have a limited capacity to metabolize propofol, and the propofol concentration in these organs is considered to be well preserved during ischemia (as compared with the situation in the liver). Therefore, both the energy level of the tissues and propofol’s protective abilities against ischemia/reperfusion may be well preserved in these organs.
According to a review on the protective effects of anesthetics against organ ischemia/reperfusion injury (21), the important factors for these effects of anesthetics are the preservation of ATP levels during ischemia, an inhibition of free-radical production, a reduction in calcium overloading, a reduced adhesion of polymorphonuclear neutrophils, and increased NO production. Our results, in the light of this review, suggest that propofol may exert a much less appreciable protective effect against liver ischemia/reperfusion injury than seen in other organs with ischemia/reperfusion injury. In addition, intracellular fatty acid overload has been suggested to induce membrane degradation and impaired energy metabolism in an experiment on cardiac muscle cells (22). Free fatty acids also reportedly have the potential to mediate cell injury via lipid peroxidation of the cellular membrane (23). Interestingly, Tanaka et al. (24) reported that Intralipid (soy-oil group) inflicted significant damage on the perfused, isolated murine liver in a condition that did not involve ischemic loading, although propofol caused no such damage.
To try to explain the absence of a beneficial effect of propofol against hepatic hypoxia/reoxygenation injury, we have to consider the concentrations of propofol used in this experiment, besides the different metabolic capacities for propofol and its lipid vehicle among various organs. The blood concentration of propofol is reportedly 5–30 µM (25) in the clinical setting. In our experiment, we used values within this concentration range to investigate the effect of propofol on hypoxia/reoxygenation injury in rat liver slices. However, propofol did not exhibit a protective effect against hypoxia/reoxygenation injury in this study. De La Cruz et al. (3) reported that 50, 150, and 300 µM, but not 10 µM, propofol had significant effects on all the oxidative-stress variables they studied (e.g., lipid peroxide concentration and tissue glutathione levels) in rat brain slices. Kokita et al. (1) reported that propofol (25 or 50 µM) both improved the recovery of mechanical function and energy state in ischemic/reperfused rat hearts and dose-dependently inhibited lipid peroxidation in the rat heart. Navapurkar et al. (6) reported that 28 µM propofol protected rat hepatocytes from an oxidant stress sufficient to cause cell death at one hour. Hepatocytes form a monolayer in cell culture, whereas liver slices are multi-cell-layer aggregates containing Kupffer cells, besides hepatocytes. Therefore, it is likely that propofol needs to be at a larger concentration in a slice experiment than in a hepatocyte experiment to produce the same results. In view of the above, it is conceivable that larger propofol concentrations than ours may exhibit a protective effect (e.g., inhibition of lipid peroxidation) against hypoxia/reoxygenation injury in rat liver slices. Further study will be needed to clarify whether larger concentrations of propofol than those used in our study might inhibit lipid peroxidation and have a beneficial effect against ischemia/reperfusion injury even in the liver, in which propofol and its lipid vehicle are more extensively metabolized than in other organs.
As for the clinical implications of these data, they suggest that propofol may not be the first-choice anesthetic for use in surgery during which there is a temporary interruption of liver blood flow (such as hepatic tumor resection or liver transplantation). This is because propofol and its lipid vehicle are metabolized in the liver and may decrease its energy level during hypoxia and because the lipid portion of the propofol emulsion may act as a hepatotoxicant during ischemia/reperfusion. Further study is needed to establish which anesthetics are suitable for use in hepatic surgery during which ischemia/reperfusion of the liver occurs. One further caveat should be added regarding the interpretation of the data presented here. It is generally accepted that both Kupffer cells and neutrophils—which produce reactive oxygen, proteases, and proinflammatory mediators—play an important role in liver ischemia/reperfusion injury (10). Although liver slices contain Kupffer cells with maintained cell-cell and cell-matrix interactions, there are no blood components, such as neutrophils, in the media in the vials. Hence, the changes occurring in liver slices after hypoxia/reoxygenation will be somewhat different from those observed under similar clinical conditions (when the influence of blood components, including neutrophils, may be exerted on the ischemia/reperfusion injury).
In conclusion, at the concentrations we tested, propofol showed no evidence of having either a hepatotoxic effect under no-hypoxia conditions or a protective effect against hypoxia/reoxygenation-induced injury in rat liver slices in our study with a dynamic organ-culture method.
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Acknowledgments
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The authors thank Jyunko Miyao and Masumi Inada for their assistance with these experiments and Dr. Robert Timms for his helpful advice on the manuscript.
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References
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Accepted for publication March 4, 2003.
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Abstract
Introduction
= 95% oxygen/5% CO2 gassing; 
= 100% nitrogen gassing.
