Isoflurane does not mimic ischaemic preconditioning in decreasing hydroxyl radical production in the rabbit

Y. Gozal1,*, J. Raphael1, J. Rivo1, E. Berenshtein2, M. Chevion2 and B. Drenger1

1 Departments of Anesthesiology and Critical Care Medicine and 2 Cellular Biochemistry and Human Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

* Corresponding author: Department of Anesthesiology and CCM, Hadassah University Hospital, Jerusalem 91120, Israel. E-mail: gozaly{at}md.huji.ac.il

Accepted for publication May 15, 2005.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Reactive oxygen species are an important mediator in isoflurane-induced myocardial preconditioning. However, hydroxyl radicals are also released during reperfusion after regional ischaemia. The purpose of the present study was to test whether ischaemic preconditioning and isoflurane would influence the production of hydroxyl radicals during reperfusion.

Methods. After i.v. administration of salicylate 100 mg kg–1 and a 30 min stabilization period, New Zealand White rabbits were subjected to 40 min of regional myocardial ischaemia and 2 h of reperfusion. Ischaemic preconditioning was elicited by 5 min ischaemia followed by 10 min reperfusion (before the 40 min ischaemia). In another group, isoflurane (2.1%) was administered for 30 min, followed by 15 min washout, before the long ischaemia. Area at risk and infarct size were assessed by blue dye injection and tetrazolium chloride staining. We quantified the level of OH-mediated conversion of salicylate to its dihydrobenzoate derivatives (2,3- and 2,5-DHBAs). Normalized values of the DHBAs (ng DHBA per mg salicylate) were calculated.

Results. Mean (SE) infarct size was 57 (6)% of the risk area in the untreated controls. This was significantly smaller in the ischaemic preconditioning and isoflurane groups: 22 (5) and 23 (6)% respectively. At 10 min of reperfusion, ischaemic preconditioning limited the mean increase in 2,3-DHBA to 24% from baseline, compared with 81% in control and 74% in the isoflurane group. Normalized 2,5-DHBA was maximally increased by 75% in the untreated group, 4 min after reperfusion. Ischaemic preconditioning significantly inhibited this increase (24% increase from baseline, P<0.01). However, the increase observed in the isoflurane group was not different from control (71%).

Conclusions. As already known, ischaemic preconditioning and isoflurane markedly reduced infarct size. However, only ischaemic preconditioning decreased postischaemic production of hydroxyl radicals. These different effects suggest different protective mechanisms at the cellular level.

Keywords: anaesthetics volatile, isoflurane ; heart, ischaemia ; metabolism, free radicals ; model, rabbit


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Recent studies have shown that isoflurane protects the ischaemic myocardium by triggering pharmacological preconditioning.13 This protection requires activation of mitochondrial adenosine triphosphate-regulated potassium channels (KATP) and then the release of a minute amount of reactive oxygen species.4 It is presumed that isoflurane interacts with the electron transport chain in the mitochondria, which is the source of oxygen-derived products.4 The preconditioning effect of isoflurane in the heart in vivo and in vitro is also associated with attenuation of superoxide production and coronary vascular adherence of activated neutrophils.5 Formation of superoxide is the first of several steps in forming other oxygen-derived products, such as hydroxyl radicals.6

In contrast to their beneficial effect of starting the preconditioning cascade, a large number of studies have demonstrated that oxygen free radicals play a detrimental role in the pathogenesis of reperfusion injury, both directly by damaging membranes and enzymes and indirectly by initiating the inflammatory process.

We have reported that halothane administered before and during ischaemia in a canine model of ischaemia/reperfusion decreased hydroxyl radical (•OH) formation significantly.7 When given during a sustained ischaemic period,8 or during 30 min followed by 15 min washout before prolonged ischaemia,9 halothane significantly decreased infarct size, thus inducing pharmacological preconditioning.

In the present study, performed in the in vivo rabbit model, we tested the hypothesis that ischaemic preconditioning and/or isoflurane would block postischaemic production of hydroxyl radicals in a similar manner to halothane. We used an experimental model in which hydroxyl radicals react with salicylate to generate 2,3- and 2,5-dihydroxybenzoic acids (DHBAs), which can be measured by a high-performance liquid chromatography with electrochemical detection. The formation of DHBAs after systemic administration of salicylate is used as an index of hydroxyl radical generation in the heart.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
All experiments were conducted with the approval of the institutional Committee for Animal Care and Laboratory Use, and in compliance with the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIH publication No. 85-23, revised 1996).

General preparation
New Zealand White rabbits weighing between 2.5 and 3.5 kg were anaesthetized with i.v. pentobarbital 30 mg kg–1 administered via a 20-G i.v. cannula in a marginal ear vein. Hetastarch 5 ml kg–1 h–1 was infused continuously via the i.v. cannula. Anaesthesia was maintained during the experiment by pentobarbital supplements as needed (according to pedal and palpebral reflexes). Isoflurane was used according to the study protocol. Neuromuscular blocking drugs were not administered in order to assess anaesthetic depth. The neck was opened with a ventral midline incision and a tracheostomy was performed. The rabbits' lungs were mechanically ventilated with positive pressure ventilation and an inspiratory fraction of oxygen of 1.0. The ventilation rate was 30–35 b.p.m. and tidal volume was approximately 15 ml kg–1. The respiratory rate was adjusted to keep the arterial pH in the physiological range of 7.35–7.45. End-expiratory carbon dioxide tension was monitored continuously. A 22-G catheter filled with heparinized saline was placed in a carotid artery for arterial blood pressure monitoring and blood sampling. Core body temperature was measured via a rectal temperature probe and maintained at 38.5 (0.3)°C (normothermic for rabbits) with radiant heat and a warming blanket. Needle electrodes were inserted subcutaneously in a lead II configuration to enable recording of an electrocardiogram (ECG) to determine heart rate and help confirm the occurrence of ischaemia (ST segment elevation) and reperfusion of the myocardium distal to the coronary occlusion. A left thoracotomy was performed in the fourth intercostal space and a 4–0 silk suture was passed around a prominent branch of the left coronary artery (approximately halfway between the apex and the base) and threaded through a small vinyl tube to form a snare. Coronary artery occlusion was achieved by tightening the snare around the coronary artery. Regional epicardial cyanosis and ST segment elevation in the ECG confirmed myocardial ischaemia. Reperfusion was achieved by releasing the snare and was confirmed by visual observation of reactive hyperaemia. Ventricular fibrillation, if it occurred, was reversed using direct mechanical stimulation: an index finger was flicked directly against the right ventricle side of the fibrillating heart one to three times to achieve defibrillation. Failure to convert to an organized rhythm after three attempts was defined as intractable fibrillation.

Experimental protocol
Before a 30-min stabilization period, all animals were given salicylate (100 mg kg–1) i.v. Salicylate is a highly effective hydroxyl free radical scavenger, which, upon scavenging •OH, forms 2,3- and 2,5-DHBA by hydroxylation. All animals underwent 40 min of regional ischaemia followed by 2 h of reperfusion. Preconditioning was elicited by 5 min of coronary occlusion followed by 10 min of reperfusion,10 beginning 15 min before the period of prolonged coronary occlusion. Rabbits were assigned randomly to the following groups according to a computer-generated random number schedule: control group (ischaemia and reperfusion without further intervention) (n=10); ischaemic preconditioning group (n=10) and isoflurane group (I, n=10). A 1.0 minimal alveolar concentration of isoflurane (2.1%)11 was started at the end of the stabilization period and administered for 30 min, followed by a 15 min washout period before coronary occlusion. End-tidal concentrations of isoflurane were measured continuously at the tip of the tracheostomy tube with a gas analyser (Drager Iris, Lübeck, Germany) that was calibrated with known standards before and during the experiments. Arterial pressure, heart rate and temperature were recorded continuously. Blood samples for hydroxyl free radical measurements were obtained as follows: at the beginning of the experiment (baseline), at 20 and 40 min of occlusion, every 2 min in the first 10 min of reperfusion, and thereafter at 20, 30, 60, 90 and 120 min of reperfusion.

We quantified the level of •OH-mediated conversion of salicylate to its dihydroxybenzoate derivatives by high-performance liquid chromatography coupled with electrochemical detection. The results are expressed as the ratio of DHBA to salicylate concentration (ng DHBA per µg salicylate) to normalize DHBA levels to different concentrations of salicylate.7

Determination of infarct size and area at risk
At the end of the experimental protocol, hearts were excised, mounted on a Langendorff apparatus, and perfused with phosphate-buffered saline (PBS) at 100 cm H2O for 1 min to wash out intravascular blood. The coronary artery was re-occluded and methylene blue 0.2% was infused into the aortic root to label the normally perfused zone with deep blue colour, thereby delineating the risk zone as a non-stained area. The hearts were then removed from the Langendorff apparatus, trimmed of atria and great vessels, weighed and frozen (in a cold chamber at –18°C). Hearts were then cut into 2 mm transverse slices. The slices were incubated in 2,3,5-triphenyl tetrazolium chloride (TTC) 1% in pH 7.4 buffer for 20 min at 37°C. The slices were then placed in 10% neutral buffered formalin for 10 min to increase the contrast between stained and non-stained tissue. Since TTC stains viable tissue a deep red colour, non-stained tissue was presumed to be infarcted. Slices were then photographed, and risk and infarct areas in each slice were measured by computed planimetry. The mass-weighted average of the ratio of infarct area to the area at risk of the ventricle from each slice was determined (percentage infarction).

Quantification of hydroxyl radicals by interaction with salicylate
DHBA levels were identified and measured by high-performance liquid chromatography coupled with electrochemical detection using a Varian 5000 liquid chromatograph (Varian Medical Systems, Palo Alto, CA, USA), equipped with a Rheodyne 7125 sample injector (20 µl loop) (Rheodyne LLC, Rohnert Park, CA, USA). The column used for separation of salicylate and DHBA was a 25 cmx4 mm Li Chrospher 100 RP-18, 5 µm (E-Merck, Darmstadt, Germany). The mobile phase contained 0.03 M citric acid, 0.03 M acetic acid, sodium azide 0.2 g litre–1 and 2x methanol. The mobile phase was titrated with solid NaOH to pH 3, followed by titration with CH3COONa to a final pH of 3.6. The flow rate was 1 ml min–1. The system was equipped with two detectors in series. Salicylate was identified and measured fluorimetrically using a FD-300 model fluorescence detector (Spectrovision, Chelmsford, MA, USA) using excitation and emission wavelengths of 300 and 412 nm respectively. DHBA derivatives were quantified using an electrochemical amperometric detector (Model 4A; Bioanalytical Systems, West Lafayette, IN, USA), with a plastic cell equipped with a glass carbon electrode operated at +0.80 V, using an Ag–AgCl reference electrode. The signals from the detector were acquired on an EZChrom data acquisition and handling system (EZChrom EliteTM, Scientific Software Inc., San Ramon, CA, USA) and subsequently processed.

Statistical analysis
Haemodynamic data over time within each group were analysed by analysis of variance (ANOVA) with repeated measures on one factor. Differences in haemodynamics between groups were analysed by ANOVA with the Tukey post hoc test. Incidence of ventricular fibrillation was analysed with the Kruskal–Wallis test. Intergroup comparisons for infarct sizes were made with one-way ANOVA, and group differences were detected with Tukey's post hoc test. Differences between the study groups in DHBA levels were assessed by ANOVA with the Tukey post hoc test. Statistical calculations were performed using SPSS 10.0 for Windows software (SPSS, Chicago, IL, USA). Data are expressed as mean (SEM) and significance was assumed for P<0.05.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Thirty rabbits were studied. The results from 26 animals contributed to the final data set: eight controls, nine in the ischaemic preconditioning group and nine isoflurane-treated rabbits. The remaining four animals were excluded because of technical failures: accidental release of the snare during the ischaemia period (n=1) or intractable ventricular fibrillation (n=3). The incidence of refractory ventricular fibrillation was not significantly different among groups.

Mean arterial pressure was lower in the isoflurane group when the volatile anaesthetic was administered. This returned to normal after the washout period, before ischaemia. Afterwards, there was a trend for mean arterial pressure to decrease over time within all groups. Heart rate was higher (not significantly different) in the isoflurane group. There were no significant differences in rate–pressure product within the three groups (Table 1).


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Table 1 Systemic haemodynamics. Mean (SEM). C, control; IP, ischaemic preconditioning; I, isoflurane; HR, heart rate; MAP, mean arterial pressure; RPP, rate pressure product

 
The ratio of area at risk to left ventricular mass did not differ significantly among the groups [51 (2)% in the control group, 51 (1)% in the ischaemic preconditioning group and 53 (2)% in the isoflurane group]. These data suggest that changes in the infarct sizes observed in the different experimental groups cannot be related to the percentage of the left ventricular myocardium that was occluded. In the control group, the measured infarct size was 57 (6)% of the area at risk. Ischaemic preconditioning and isoflurane resulted in much smaller infarcts, averaging 22 (5) and 23 (6)%, respectively, of the risk zone (P<0.01) (Fig. 1).



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Fig 1 Myocardial infarct size expressed as a percentage of the left ventricular area at risk. **Significantly (P<0.01) different from control. C, control; IP, ischaemic preconditioning; I, isoflurane.

 
An acute increase of 50% compared with baseline values (P<0.05) in normalized 2,3-DHBA in the control group was already observed after 2 min of reperfusion. After 10 min of reperfusion, the peak value was measured (81% increase compared with baseline levels; P<0.01) (Fig. 2). After 10 min of reperfusion there was only a 24.3% increase in the concentration of 2,3-DHBA in the ischaemic preconditioning group (P<0.01 compared with control group). However, administration of isoflurane did not produce this effect. Hydroxyl radical production increased to a degree similar to that seen in the control group (increase of 74.5%, P=not significant compared with control group). Maximal production of 2,5-DHBA occurred in the control group after 4 min of reperfusion: a 75% increase compared with baseline values (P<0.01) (Fig. 3). Ischaemic preconditioning, however, significantly attenuated this increase to only 24% above baseline values (P<0.05 compared with control group). The increase in 2,5-DHBA in the isoflurane group (71%) was comparable to that in the control group (P=not significant).



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Fig 2 Mean normalized concentrations of 2,3-dihydroxybenzoic acid (2,3 DHBA) (ng DHBA/µg salicylate) in the blood of rabbits exposed to 40 min of regional ischaemia (occlusion of a prominent branch of the left coronary artery). The asterisks denote a significant difference between control (n=8) or isoflurane (n=9), and ischaemic preconditioning (n=9) experiments. *P<0.05; **P<0.01. OCC, occlusion; REP, reperfusion.

 


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Fig 3 Mean normalized concentrations of 2,5-dihydroxybenzoic acid (2,5 DHBA) (ng DHBA/µg salicylate) in the blood of rabbits exposed to 40 min of regional ischaemia (occlusion of a prominent branch of the left coronary artery). The asterisks denote a significant difference between control (n=8) or isoflurane (n=9), and ischaemic preconditioning (n=9) experiments. *P<0.05; **P<0.01. OCC, occlusion; REP, reperfusion.

 
At all time points during reperfusion (up to 30 min), there was a significant difference between the control and isoflurane groups on the one hand and the preconditioning group on the other hand (Figs 2 and 3). At 60 min of reperfusion and afterwards, there was a return to baseline values in all groups.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The main finding of this investigation is that, despite their similar effects in reducing infarct size, ischaemic preconditioning and isoflurane did not affect hydroxyl radical production during reperfusion after regional ischaemia in a rabbit heart model in vivo in the same manner.

This study confirms that isoflurane mimics ischaemic preconditioning when infarct size is the end-point. Kersten and colleagues2 showed that isoflurane reduced infarct size in dogs, and this beneficial action was found to persist despite its discontinuation before coronary artery occlusion. This favourable action of isoflurane was also demonstrated in a rabbit model similar to ours.3 The timing of isoflurane administration seems to play an important role. In the study of Preckel and colleagues,12 isoflurane did not affect infarct size in the rabbit in vivo, when it was introduced to the inspired gas a few minutes before reperfusion and was continued for the first 15 min of reperfusion. However, when it was administered and washed out for 15–30 min before ischaemia, its effect was comparable to that of ischaemic preconditioning.2 3 9 13 14

The protecting effect of isoflurane on the heart is thought to be mediated by the same end effector as classic preconditioning since there is no additional effect of isoflurane and ischaemic preconditioning when they are administered alone or simultaneously.15 Zaugg and colleagues15 showed in a simulated cellular model of ischaemia that isoflurane mediated its protection in cardiomyocytes by selectively priming mitochondrial KATP channels through multiple triggered protein kinase C-coupled signalling pathways.

The release of reactive oxygen species (ROS) plays a major role in tissue damage and infarction during reperfusion.16 However, release of minute quantities of ROS has been reported to be an important feature of isoflurane-induced preconditioning. Tanaka and colleagues17 and Müllenheim and colleagues18 reported attenuation of isoflurane-induced reduction in myocardial infarct size by the use of ROS scavengers in rabbits.

The oxygen free radicals, including superoxide, are released when neutrophils adhere to the vascular endothelium.5 This production results from activation and assembly of NADH oxidase, which is a transmembrane electron transport chain enzyme that reduces oxygen to superoxide.19 Hanley and colleagues20 have investigated the effects of volatile anaesthetics (halothane, isoflurane and sevoflurane) on electron transport chain activity in intact ventricular myocytes of the guinea-pig. All three volatile anaesthetics inhibited NADH oxidation in submitochondrial particles. However, only halothane was found to inhibit succinate oxidation, suggesting that only halothane blocked complexes II, III and IV of the electron transport chain. In addition, in experiments performed on neutrophil suspensions and coronary rings from mongrel dogs, Hu and colleagues19 found that isoflurane inhibited superoxide production by neutrophils, neutrophil adherence to the endothelial surface of coronary artery segments, and neutrophil-induced coronary endothelial dysfunction, and that these effects could be caused by a direct inhibitory effect on NADH oxidase. The mechanism of isoflurane-decreased superoxide production is not yet known. There are KATP channels that modulate neutrophil activity.20 However, the administration of glibenclamide, a KATP channel blocker, did not alter the ability of isoflurane to inhibit neutrophil superoxide production, suggesting that another mechanism is implicated in this effect. Superoxide is at the origin of other ROS, such as hydroxyl radicals. In the present study, classical ischaemic preconditioning but not isoflurane decreased hydroxyl production during reperfusion. This is in contrast to the work of Nakamura and colleagues,21 who showed that isoflurane and halothane, but not sevoflurane, reduced hydroxyl radical production in the reperfused working rat heart. We have also demonstrated that halothane prevents hydroxyl radical production in an in vivo canine model of ischaemia–reperfusion.7 These discrepancies may be attributed to the different models (different species and different protocols) used, implying that different mechanisms of cardioprotection are involved. Hydroxyl radicals are associated with intracellular Ca2+ overload during ischaemia and reperfusion.22 Reduced cytosolic Ca2+ overload caused by increased sarcolemmal KATP channel activity23 (which is one of the pathways of ischaemic preconditioning) has been proposed as a protective mechanism for volatile anaesthetics. Isoflurane decreases this activity in rabbit ventricular myocytes; however, it also decreases the ATP sensitivity of the channel, thus increasing the possibility of opening for a certain ATP concentration.15

In our previous work, we hypothesized that attenuation of free radical production by halothane might be mediated via inhibition of intracellular Ca2+ influx.7 The present findings concerning isoflurane may be explained by the different modes of action of these two volatile anaesthetics on the voltage-sensitive calcium channel. It has already been demonstrated that halothane and enflurane, but not isoflurane, act on a calcium release channel of the sarcoplasmic reticulum.24 Isoflurane only decreases trans-sarcolemmal calcium entry.25

Iron and copper play major roles in biological systems, catalysing free radical production. Hydroxyl radicals are formed from superoxide by Fe-catalysed reactions (the Haber–Weiss and Fenton reactions).26 We have shown in isolated rat hearts that ischaemia-induced myocardial iron mobilization was attenuated by ischaemic preconditioning, and that the signalling for ferritin accumulation, a protective step which prepares the heart for accommodating the high load of free iron, was also promoted by ischaemic preconditioning.27 Isoflurane does not seem to have any effect on this mechanism.

The difference in the effects of ischaemic preconditioning and isoflurane on hydroxyl free radical production may indicate that different mechanisms are involved. These mechanisms have yet to be described.


    Acknowledgments
 
This work was supported in part by grant 2322 from the Chief Scientist Fund, Ministry of Health, the State of Israel (Y.G.). M.C. is the incumbent of the Dr William Ganz Chair of Heart Studies at the Hebrew University of Jerusalem. This study was also supported by grants from the Israel Science Foundation (585/2002) and the `Pepka and Dr Moshe Bergman Memorial Fund' at the Hebrew University of Jerusalem.


    References
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 Abstract
 Introduction
 Methods
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 Discussion
 References
 
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9 Piriou V, Chiari P, Lhuillier F, et al. Pharmacological preconditioning: comparison of desflurane, sevoflurane, isoflurane and halothane in rabbit myocardium. Br J Anaesth 2002; 89: 486–91[Abstract/Free Full Text]

10 Ueda Y, Kitakaze M, Komamura K, et al. Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction. J Am Coll Cardiol 1999; 34: 2120–5[Abstract/Free Full Text]

11 Drummond JC. MAC for halothane, enflurane, and isoflurane in the New Zealand white rabbit: And a test for the validity of MAC determination. Anesthesiology 1985; 62: 336–8[ISI][Medline]

12 Preckel B, Schlack W, Comfère T, Obal D, Barthel H, Thämer V. Effects of enflurane, isoflurane, sevoflurane and desflurane on reperfusion injury after regional myocardial ischaemia in the rabbit heart in vivo. Br J Anaesth 1998; 81: 905–12[Abstract/Free Full Text]

13 Ismaeil MS, Tkachenko I, Gamperl AK, Hickey RF, Cason BA. Mechanisms of isoflurane-induced myocardial preconditioning in rabbits. Anesthesiology 1999; 90: 812–21[CrossRef][ISI][Medline]

14 Ludwig LM, Patel HH, Gross GJ, Kersten JR, Pagel PS, Warltier DC. Morphine enhances pharmacological preconditioning by isoflurane. Role of mitochondrial KATP channels and opioid receptors. Anesthesiology 2003; 98: 705–11[CrossRef][ISI][Medline]

15 Zaugg M, Lucchinetti E, Spahn DR, Pasch T, Schaub MC. Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial KATP channels via multiple signaling pathways. Anesthesiology 2002; 97: 4–14[CrossRef][ISI][Medline]

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17 Tanaka K, Weihrauch D, Kehl F, et al. Mechanism of preconditioning by isoflurane in rabbits: a direct role for reactive oxygen species. Anesthesiology 2002; 97: 1485–90[CrossRef][ISI][Medline]

18 Müllenheim J, Ebel D, Frässdorf J, Preckel B, Thämer V, Schlack W. Isoflurane preconditions myocardium against infarction via release of free radicals. Anesthesiology 2002; 96: 934–40[CrossRef][ISI][Medline]

19 Hu G, Vinten-Johansen J, Ramez Salem M, Zhao Z-Q, Crystal GJ. Isoflurane inhibits neutrophil-endothelium interactions in the coronary circulation: lack of a role for adenosine triphosphate-sensitive potassium channels. Anesth Analg 2002; 94: 849–56[Abstract/Free Full Text]

20 Hanley PJ, Ray J, Brandt U, Daut J. Halothane, isoflurane and sevoflurane inhibit NADH: ubiquinone oxidoreductase (complex I) of cardiac mitochondria. J Physiol 2002; 544.3: 687–93[Abstract/Free Full Text]

21 Nakamura T, Kashimoto S, Oguchi T, Kumazawa T. Hydroxyl radical formation during inhalation anesthesia in the reperfused working rat heart. Can J Anaesth 1999; 46: 470–5[Abstract]

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