BJA Advance Access originally published online on July 18, 2006
British Journal of Anaesthesia 2006 97(3):307-314; doi:10.1093/bja/ael174
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The mechanism of sevoflurane-induced cardioprotection is independent of the applied ischaemic stimulus in rat trabeculae
1 Department of Anesthesiology, VU University Medical Center (VUmc)-Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU) De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
2 Laboratory for Physiology, VU University Medical Center (VUmc)-Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU) van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
3 Abbott B.V. Siriusdreef 51, NL-2131 WT Hoofddorp The Netherlands
*Corresponding author: Department of Anesthesiology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail: a.bouwman{at}vumc.nl
Accepted for publication April 25, 2006.
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResultsDiscussionREFERENCES |
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Background. Sevoflurane protects the myocardium against ischaemic injury through protein kinase C (PKC) activation, mitochondrial
-channel (
) opening and production of reactive oxygen species (ROS). However, it is unclear whether the type of ischaemia determines the involvement of these signalling molecules. We therefore investigated whether hypoxia (HYP) or metabolic inhibition (MI), which differentially inhibit the mitochondrial electron transport chain (ETC), are comparable concerning the relative contribution of PKC, and ROS in sevoflurane-induced cardioprotection.
Methods. Rat right ventricular trabeculae were isolated and isometric contractile force (Fdev) was measured. Trabeculae were subjected to HYP (hypoxic glucose-free buffer; 40 min) or MI (glucose-free buffer, 2 mM cyanide; 30 min), followed by 60 min recovery (60 min). Contractile recovery (Fdev,rec) was determined at the end of the recovery period and expressed as a percentage of Fdev before hypoxia or MI, respectively. Chelerythrine (CHEL; 6 µM), 5-hydroxydecanoic acid sodium (100 µM) and n-(2-mercaptopropionyl)-glycine (MGP; 300 µM) were used to inhibit PKC, and ROS, respectively.
Results. Fdev,rec after HYP was reduced to 47 (3)% (P<0.001 vs control; n=5) whereas MI reduced Fdev,rec to 28 (5)% (P<0.001 vs control; n=5). A 15 min period of preconditioning with sevoflurane (3.8%) equally increased contractile recovery after HYP [76 (9)%; P<0.05 vs HYP] and MI [67 (8)%; P<0.01 vs MI]. Chelerythrine, 5-hydroxydecanoate and n-(2-mercaptopropionyl)-glycine abolished the protective effect of sevoflurane in both ischaemic models. Trabeculae subjected to HYP or MI did not demonstrate any increased apoptotic or necrotic markers.
Conclusions. PKC, and ROS are involved in sevoflurane-induced cardioprotection after HYP or MI, suggesting that the means of mitochondrial ETC inhibition does not determine the signal transduction pathway for cardioprotection by anaesthetics.
Keywords: anaesthetics volatile, sevoflurane; complications, hypoxia; heart, myocardial preservation; metabolism, free radicals; metabolism, second messengers
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionREFERENCES |
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The volatile anaesthetic sevoflurane protects the heart against ischaemia-induced adenosine triphosphate (ATP) depletion, Ca2+ overload and oxidative stress through activation of protein kinase C (PKC), opening of mitochondrial
channels (mito) and the production of reactive oxygen species (ROS).1–6 We previously simulated ischaemia by cyanide-induced metabolic inhibition (MI).4,7 Cyanide inactivates cytochrome c oxidase in complex IV of the mitochondrial electron transport chain (ETC), resulting in ATP depletion and ROS formation (Fig. 1).8 9 In contrast, hypoxia is associated with a reduction in O2 concentration and thereby prevents complex IV from donating electrons, finally leading to ATP depletion. Furthermore, hypoxia coincides with more mitochondrial nitric oxide (NO), which also inhibits complex IV and reduces mitochondrial O2 consumption, the latter resulting in superoxide generation.10 11 Finally, hypoxia, but not MI, is followed by reoxygenation, which may cause additional cardiac injury.12
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(superoxide). During ischaemia, the availability of electron acceptor O2 is reduced. This prevents complex IV from donating electrons and therefore inhibits ATP production. Furthermore, the lower availability of O2 leads to more nitric oxide (NO), which also inhibits complex IV and reduces O2 consumption, resulting in the generation of superoxide and ONOO– (peroxynitrite).It has already been shown that the type of preconditioning stimulus determines the relative contribution of distinct signalling molecules in the cardioprotective process13 and thus it may be possible that the type of metabolic deprivation induces variation in the signal transduction pathways involved in sevoflurane-induced cardioprotection.
We therefore investigated whether two different causes of ischaemic injury, that is MI and hypoxia, alter the relative contribution of PKC, mito and ROS in the signal transduction pathways for sevoflurane-induced cardioprotection in isolated right ventricular trabeculae of the rat.4
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionREFERENCES |
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Animals
Male Wistar rats (250–400 g, Harlan, The Netherlands) were used according to the Institutional Animal Care and Use Committee of the VU University Medical Center. Rats were anaesthetized with sodium pentobarbital (80 mg kg–1, i.p., Nembutal®, Sanofi Sante BV) and i.v. heparinized with 1000 units (Leo Pharma, Breda, The Netherlands). Subsequently, the heart was quickly removed and perfused through the aorta with Tyrode buffer (120 mM NaCl, 1.22 mM MgSO4.7H20, 1.99 mM NaH2PO4, 27.0 mM NaHCO3, 5.0 mM KCl, 1 mM CaCl2 and 10 mM glucose; 95% O2/5% CO2, pH 7.4). The myocardium was protected during dissection by adding 30 mM 2,3-butanedione monoxime and 15 mM KCl to the buffer solution.14 A suitable right ventricular trabecula (length 2–5 mm, diameter <0.2 mm) was carefully dissected.15
Experimental set-up
The muscle was mounted between a force-transducer (AE801, SensoNor, Norway) and a micromanipulator in an airtight organ bath. After mounting, superfusion was started with normal Tyrode buffer at 27°C (2 ml min–1), and trabeculae were stimulated (5 ms duration, stimulation frequency 0.5 Hz). Subsequently, trabeculae were stretched until passive force (Fpas) was approximately 8% of developed force.16 After 40 min of stabilization, the stimulation frequency and temperature were decreased to 0.2 Hz and 24°C, respectively, followed by another 20 min of stabilization. After this period, initial developed force of contraction (Fdev,start) and maximal force (Fmax,start), as determined by a post-extrasystolic potentiation protocol (PESP), were recorded. PESP determines the contractile reserve of trabeculae by maximal Ca2+ filling of the sarcoplasmic reticulum.17 Trabeculae failing to stabilize, failing to show PESP or spontaneously contracting trabeculae were excluded.
Experimental protocol
Figure 2 shows the experimental groups to which trabeculae were assigned. Trabeculae (except for time controls; n=5) were either subjected to a period of hypoxia (HYP; n=5) or metabolic inhibition (MI; n=5). During hypoxia, trabeculae were superfused with hypoxic Tyrode (95% N2 and 5% CO2, PO2
4 mm Hg), whereas during MI muscles were superfused with buffer containing 2 mM sodium cyanide. During hypoxia or MI, glucose was omitted from the buffer and the stimulation frequency was increased to 1 Hz. Shortly after starting hypoxia or MI, contractile force decreased to zero followed by an increase in Fpas. When Fpas increased to 50% of Fmax,start, trabeculae were subjected to another 40 min of hypoxia or to 30 min of MI. Subsequently, muscles were perfused with normal oxygenated buffer for 60 min to allow contractile recovery. The recovery of Fdev (Fdev,rec), time to peak, time to half relaxation, and rate of contraction (+dFdt) and relaxation (–dFdt) were determined and expressed as a percentage of the initial values during the start of experiment. Except for time and inhibitor control experiments, trabeculae were preconditioned for 15 min with normal Tyrode saturated with 3.8 vol% vaporized sevoflurane (Sevorane®, Abbott) 30 min before hypoxia or MI. The volume percentage of sevoflurane in the gas phase above the Tyrode was continuously monitored by a calibrated infrared anaesthetic monitor (Capnomac Ultima, Datex, Helsinki, Finland). After washout of sevoflurane, trabeculae were superfused for 15 min with normal Tyrode until hypoxia or MI.
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In the inhibitor groups, trabeculae were additionally superfused with either the PKC-catalytic site inhibitor chelerythrine (CHEL; 6 µM; n=5; Sigma-Aldrich), the mito
channel blocker 5-hydroxydecanoate (5-HD; 100 µM; n=5; Sigma-Aldrich) or the ROS-scavenger n-(2-mercaptopropionyl)-glycine (MPG; 300 µM; n=5; Sigma-Aldrich) 10 min before preconditioning until the washout period before hypoxia or MI (see Fig. 2). The effects of inhibitors alone on Fdev,rec were studied in separate inhibitor control experiments for both conditions of metabolic deprivation.
Determination of necrosis and apoptosis
The extent of necrosis and apoptosis was evaluated by cell morphology studies using haematoxylin–eosin staining, histochemical staining of myoglobin and TdT-mediated dUTP nick-end labelling (TUNEL) staining for evaluation of DNA fragmentation. All trabeculae subjected to these measurements were immediately embedded in gelatin after 60 min of recovery after either hypoxia or MI, frozen in liquid nitrogen and stored at –80°C until use.
Cross-sections (5 µm) were histochemically stained for myoglobin as previously described by Lee-de Groot and colleagues.18 In a separate set, TUNEL staining was performed with the Dead End Fluorometric TUNEL labelling kit (Promega). These sections were counterstained with 10% (v/v) wheat germ agglutinin (W-7024, Molecular Probes) to provide sarcolemmal staining and mounted on glass cover slips using 4',6-diamidino-2-phenylindole (DAPI)-containing medium (H1200, Vectashield, Vector Laboratories, Burlingame, USA) to stain the nuclei.
Sections stained for haematoxylin–eosin and TUNEL were analysed by digital imaging fluorescence microscopy equipped on a ZEISS Axiovert 200 MarianasTM inverted digital imaging microscopy workstation. Images were recorded with a cooled CCD camera [Cooke Sensicam (Cooke Co., Tonawanda, NY), 1280x1024 pixels]. The digital imaging microscopy workstation was under full software control [SlideBookTM software version 3.11 (Intelligent Imaging Innovations, Denver, CO)].
Statistical analysis
The sample size of each experimental group was five, except the inhibitor control groups (n=4). Data were tested for normal distribution and one-way ANOVA followed by a Tukey post hoc analysis or a Student's t-test, when appropriate, was performed to determine differences between the experimental groups. A P-value 0.05 was considered to reflect a significant difference. All values are given as mean (SEM).
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionREFERENCES |
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General characteristics
Time to rigor development was similar in both the HYP and MI group and was only minimally (not significantly) affected by sevoflurane pretreatment or the inhibitors (Table 1). In the time control group, Fdev was reduced after 3 h to 80 (9)%. Figure 3 shows the injury induced by hypoxia or MI. Fdev,rec was reduced to 47 (3)% [P=0.02 vs (Time Control)] and to 27 (6)% [P=0.0006 (MI) vs (Time Control)] in hypoxia and MI groups, respectively.
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indicates P<0.05 compared with HYP, # indicates P<0.05 compared with HYP+SEVO+MPG.Preconditioning with sevoflurane
Preconditioning with sevoflurane equally reversed hypoxia-induced and MI-induced decrease in Fdev,rec to 76 (9)% for hypoxia [P=0.02; (HYP+SEVO) vs (HYP)] and 72 (7)% for MI [P=0.0006; (MI+SEVO) vs (MI)] (see Fig. 3). PKC inhibition by chelerythrine completely abolished the protective response of sevoflurane during hypoxia [37 (5)%; P=0.003; (HYP+SEVO+CHEL) vs (HYP+SEVO)] and MI [31 (5)%; P=0.0005; (MI+ SEVO+CHEL) vs (MI+SEVO)] (Fig. 3). In addition, inhibition of mito
channels by 5-HD and scavenging ROS by MPG completely abolished sevoflurane-induced cardioprotection during hypoxia and MI. The inhibitors established no intrinsic cardioprotective effects and did not affect Fdev (data not shown). Figure 4 shows additional contractile parameters in the hypoxia group including time to peak, time to half relaxation and the rate of contraction (+dFdt) and relaxation (–dFdt). Values are expressed as a percentage of the initial value at the start of the experiment. Hypoxia did not reduce the time to peak [79 (4)% (HYP) vs 85 (1)% (Time Control); P>0.05] and the time to half relaxation [76 (2)% (HYP) vs 83 (1)% (Time Control); P>0.05]. However, preconditioning increased the time to half relaxation slightly, but significantly [85 (3)% (HYP+SEVO) vs 76 (2)% (HYP); P=0.04]. Interestingly, hypoxia reduced the +dFdt [62 (3)% (HYP) vs 89 (8)% (Time Control); P=0.006] and the –dFdt [70 (6)% (HYP) vs 98 (8)% (Time Control); P=0.04]. The decrease in +dFdt was completely reversed by sevoflurane [94 (6)%; P=0.006 vs (HYP)]. Although the decrease in –dFdt tended to be higher in preconditioned trabeculae, this difference was not significant compared with the hypoxia group [94 (7)%; P>0.05 vs (HYP)].
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Determination of necrosis and apoptosis
Figure 5 shows markers of apoptosis and necrosis in embedded trabeculae. There was no difference between the experimental groups in cell morphology as shown by haematoxylin–eosin staining (Fig. 5, panels A through C). In all sections, cardiomyocytes showed intact sarcolemmal membranes, no cytosolic vacuoles and no pyknosis of nuclei. Panels D through F show myoglobin histochemical staining, in which myoglobin is indicated by shades of grey. There was no difference in the amount of myoglobin between the different experimental groups of trabeculae. This suggests that the sarcolemmal integrity of trabeculae is preserved after either hypoxia or MI.
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Panels G–I show TUNEL staining of trabeculae. Blue indicates nuclei stained by DAPI. Green fluorescence indicates the presence of DNA strand breaks. Panel G shows TUNEL staining of a time–control trabecula and only a faint cytosolic background green fluorescent signal is detected and the nuclei are stained blue by DAPI. Neither trabeculae subjected to MI (panel H) nor in trabeculae after hypoxia (panel I), displayed green fluorescence in the nuclei, indicating the absence of double stranded DNA breakage and thus the absence of apoptosis.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionREFERENCES |
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We have demonstrated that the relative contribution of three common signalling molecules in sevoflurane-induced cardioprotection is not dependent on the type of applied ischaemic stimulus. PKC activation, opening of mito
channels and ROS are essential in conferring sevoflurane-induced protection against metabolic deprivation as induced by hypoxia and metabolic inhibition (MI) through cyanide. Furthermore, trabeculae subjected to hypoxia or MI showed no markers for apoptosis and necrosis, indicating cardiac contractile dysfunction after recovery after hypoxia or MI as a result of altered Ca2+ handling and/or myofilament Ca2+ sensitivity rather than loss of cardiomyocytes. Cyanide has frequently been used to model hypoxia. Recent studies show that clear differences exist in physiological responses to chemical anoxia and hypoxia.19 20 In addition isolated cardiomyocytes subjected to cyanide became necrotic and had more LDH-release compared with cells subjected to hypoxia.21 Differences between hypoxia and MI may rely on (i) distinct sources of ROS formation such as xanthine dehydrogenase-oxidase, myoglobin or NADPH-oxidase, as cyanide predominantly inhibits complex IV; (ii) higher concentrations of ROS formation during MI as high concentration of O2 are present as a result of inhibition of complex IV; and (iii) a different modulation of the O2-dependent regulation of mitochondrial redox signalling by NO during hypoxia (see also Fig. 1).11 Thus, the contribution of ROS and NO signalling pathways is different in hypoxia and MI-induced ischaemic injury.
It has been demonstrated that the production of ROS during sevoflurane preconditioning involves inhibition of the mitochondrial ETC.22 Interestingly, Riess and colleagues23 recently showed that inhibition of sevoflurane-induced preconditioning with either ROS- or NO-scavengers was associated with reduced attenuation of the mitochondrial ETC. This suggests that sevoflurane-induced inhibition of the ETC is mediated via ROS and NO and therefore implies that differences in ROS and NO signalling between hypoxia and MI may account for variation in the cardioprotective signalling induced by volatile anaesthetics. However, we demonstrated that in both hypoxia and MI, preconditioning with sevoflurane equally preserves contractile function of myocardial tissue. Moreover, in both models PKC, mito and ROS are likewise involved. This shows indirectly that the mechanism of preconditioning with sevoflurane involves mainly the protection against adverse effects of mitochondrial ETC inhibition during ischaemia, that is the generation of ROS, ATP-depletion and Ca2+ overload. It is important to note that the recovery of preconditioned trabeculae treated with the ROS-scavenger MPG was different in the hypoxia and MI group (Fig. 3). The underlying mechanism cannot be explained from these data, but it may suggest differences in the actual mechanism of protection against oxidative stress as a result of hypoxia or metabolic inhibition exist despite equal involvement of the signal transduction molecules in sevoflurane-induced cardioprotective signalling. Nevertheless, this remains speculative at this time and should be addressed in future studies.
Recently, it has been demonstrated that preconditioning with sevoflurane improved mitochondrial function during hypoxia, as demonstrated by increased ATP synthesis and reduced ROS formation in addition to a reduced Ca2+ load.3 6 This protection depended on opening of the mito channels. Akao and colleagues24 showed that hypoxia-induced ROS production results in a loss of mitochondrial membrane potential (
m), which serves as an indicator of mitochondrial function. This loss of m was attenuated by specific mitochondrial K+ channel openers, confirming the importance of mitochondrial integrity for the prevention of cellular injury. Similarly, volatile anaesthetics augment the open probability of mito channels via a PKC-dependent pathway,25 suggesting that they might preserve mitochondrial function via PKC and mito channels.
In our study, trabeculae subjected to either hypoxia or MI did not show increases in markers for necrosis or apoptosis. However, after 60 min of recovery after MI or hypoxia, apoptotic and necrotic markers may not yet be visible. This was also found in other studies showing that 60 min of ischaemia or less is not sufficient to induce significant apoptotic or necrotic characteristics.26 Our data suggest that in both models of metabolic deprivation the reduction of active force development might be provoked by post-ischaemic cardiomyocyte contractile dysfunction because of altered Ca2+ handling and/or Ca2+ sensitivity, rather than by a loss of cardiomyocytes. Currently, several mechanisms have been proposed to be involved in ischaemic cardiomyocyte dysfunction, such as the generation of ROS and Ca2+ overload, both leading to damage of proteins involved in either contraction or Ca2+ homeostasis.27 Interestingly, our data suggest that sevoflurane might protect SR function as demonstrated by alterations in the rate of contraction (+dFdt) and relaxation (–dFdt). Sevoflurane preserves the +dFdt and –dFdt compared with hypoxia alone, indicating preserved Ca2+ handling and Ca2+ availability.28 These data correspond to Ca2+ measurements performed in isolated trabecula, showing that the Ca2+ re-uptake capacity of the SR was improved in pharmacologically preconditioned trabeculae subjected to MI.7
In this study we used isolated right ventricular trabeculae to elucidate mechanisms of sevoflurane-induced preconditioning. We extensively applied this well-defined model for intracellular signalling and for functional studies in several previous publications.4 7 16 However several limitations should be taken into account in the interpretation of the present results. Experiments were performed at 24°C to maintain a stable preparation over several hours and to prevent oxygen limitation. These relatively hypothermic conditions may affect (cardioprotective) signalling processes. With regard to the production of ROS, the effect of hypothermia is difficult to predict, as reduced and increased production of ROS have been reported.29 30 Additionally, activation of other signalling molecules, such as PKC and mito-channels, has been demonstrated to occur under hypothermic conditions.31 32 Furthermore, this study depends on the specificity of the pharmacological inhibitors used. Chelerythrine, MPG and 5-HD are commonly used inhibitors in preconditioning studies and the concentrations used are comparable with existing literature.
In conclusion, our study shows that hypoxia and MI, are both suitable to study the cardioprotective properties of sevoflurane. Although hypoxic injury may be more relevant to the clinical situation, the effects of cyanide on complex IV of the mitochondrial ETC closely resembles carbon monoxide poisoning.33 The activated intracellular signal transduction pathway involved in sevoflurane-induced cardioprotection is not dependent on the applied ischaemic stimulus. This suggests that a common trigger, such as ROS production, may be responsible for the onset of the protective process in cardiomyocytes.
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Acknowledgments |
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The Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU Amsterdam, The Netherlands) provided support for this study. R. A. Bouwman is MD-clinical research trainee supported by ZonMw, The Netherlands Organization for Scientific Research, The Hague, The Netherlands.
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Footnotes |
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Declaration of Interest. Christa Boer is currently working for Abbott B.V., Hoofddorp, The Netherlands; this laboratory study and paper were finalized at the Laboratory for Physiology (VU University Medical Center, Amsterdam, The Netherlands) before she accepted the job offer from Abbott. 
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  R. A. Bouwman, R. J. P. Musters, B. J. van Beek-Harmsen, J. J. de Lange, R. R. Lamberts, S. A. Loer, and C. Boer Sevoflurane-induced cardioprotection depends on PKC-{alpha} activation via production of reactive oxygen species Br. J. Anaesth., November 1, 2007; 99(5): 639 - 645. [Abstract] [Full Text] [PDF]
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