Skip Navigation LinksHome > July 2002 - Volume 97 - Issue 1 > Volatile Anesthetics Mimic Cardiac Preconditioning by Primin...
Anesthesiology:
Special Section: Anesthetic Preconditioning

Volatile Anesthetics Mimic Cardiac Preconditioning by Priming the Activation of Mitochondrial KATP Channels via Multiple Signaling Pathways

Zaugg, Michael M.D., D.E.A.A.*; Lucchinetti, Eliana M.S.†; Spahn, Donat R. M.D.‡; Pasch, Thomas M.D.§; Schaub, Marcus C. M.D., Ph.D.∥

Free Access
Article Outline
Collapse Box

Author Information

Collapse Box

Abstract

Background: Volatile anesthetics induce pharmacological preconditioning in cardiac tissue. The purpose of this study was to test whether volatile anesthetics mediate this effect by activation of the mitochondrial adenosine triphosphate–sensitive potassium (mitoKATP) or sarcolemmal KATP (sarcKATP) channel in rat ventricular myocytes and to evaluate the signaling pathways involved.
Methods: A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to determine the effects of 5-hydroxydecanoate, a selective mitoKATP channel blocker, HMR-1098, a selective sarcKATP channel blocker, diazoxide, a preconditioning mimicking agent, and various modulators of putative signaling pathways on cardioprotection elicited by sevoflurane and isoflurane. Microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct index of mitoKATP channel activity.
Results: Volatile anesthetics significantly enhanced diazoxide-mediated activation of mitoKATP channels as assessed by autofluorescence of myocytes. Conversely, volatile anesthetics alone did not alter mitoKATP channel activity, implying a priming effect of volatile anesthetics on mitoKATP channels. Administration of the protein kinase C inhibitor chelerythrine completely blocked this effect. Also, pretreatment with volatile anesthetics potentiated diazoxide-mediated protection against ischemia, as indicated by a reduction in trypan blue–positive myocytes. Importantly, cardioprotection afforded by volatile anesthetics was unaffected by the sarcKATP channel blocker HMR-1098 but sensitive to modulations of nitric oxide and adenosine–Gi signaling pathways.
Conclusions: Using autofluorescence in live cell imaging microscopy and a simulated model of ischemia, the authors present evidence that volatile anesthetics mediate their protection in cardiomyocytes by selectively priming mitoKATP channels through multiple triggering protein kinase C–coupled signaling pathways. These observations provide important new insight into the mechanisms of anesthetic-induced preconditioning.
PRECONDITIONING is a most powerful mode of reducing myocardial infarction size after ischemia and has been established in every species and experimental model in which it was evaluated. 1 It represents an adaptive endogenous response to brief sublethal episodes of ischemia or to pharmacological interventions leading to paradoxical pronounced protection against subsequent lethal ischemia. Pharmacological induction of preconditioning, in contrast to classic ischemic preconditioning, would therefore be greatly desirable, specifically in high-risk patients in whom an ischemic-type of preconditioning may further jeopardize diseased myocardium.
Volatile anesthetics, which are known to improve postischemic recovery 2 and to decrease myocardial infarction size, 3 effectively activate protective cellular mechanisms. Notably, the protective effect of volatile anesthetics even occurs in the presence of already established cardioplegic protection. 4,5 To date, a substantial body of evidence implicates adenosine triphosphate–sensitive potassium (KATP) channels as playing a pivotal role in the acquisition of the preconditioned state in the heart and proposes opening of this channel as the final common step underlying all preconditioned-like states, including those elicited by volatile anesthetics. 6,7 Although a preponderance of studies point to mitochondrial rather than sarcolemmal channels as likely players in preconditioning, 8 so far it is not clear whether opening of the sarcolemmal KATP (sarcKATP) channel or the mitochondrial KATP (mitoKATP) channel is more important in mediating anesthetic-induced preconditioning. 9 Furthermore, while results from patch clamp experiments demonstrate increased open probability of the sarcKATP channel for a given ATP concentration in response to isoflurane, 10 no such data are available regarding the effects of volatile anesthetics on the activity of the mitoKATP channel, the proposed final effector of preconditioning. Therefore, the purpose of this study was to determine the protective effects of sarcKATP channels and mitoKATP channels in mediating cardioprotection by volatile anesthetics as well as the signaling pathways involved, and to test whether volatile anesthetics directly open mitoKATP channels.
Back to Top | Article Outline

Materials and Methods

This study was performed in accordance with the guidelines of the Animal Care and Use Committee of the University of Zurich.
Back to Top | Article Outline
Preparation of Isolated Rat Ventricular Myocytes
Ca2+-tolerant adult rat ventricular myocytes were isolated from hearts of male Sprague-Dawley rats (300 g) as previously described. 11 Thirty minutes prior to decapitation, animals were heparinized (500 units administered intraperitoneally). To avoid any putative effects on KATP channel activity, 12,13 no anesthetics were used. The hearts were quickly removed into a 4°C HEPES-buffered solution (117 mm NaCl, 5.7 mm KCl, 1.5 mm NaH2PO4, 4.4 mm NaHCO3, 20 mm HEPES, 10 mm glucose, 10 mm creatine, at pH 7.4) containing 1.8 mm Ca2+ and then perfused on a Langendorff apparatus for 5 min at 37°C gassed with oxygen. The perfusion solution was switched to a nominally Ca2+-free solution containing 0.1 mm EGTA for 7 min and then to a nominally Ca2+-free solution containing 0.15% collagenase A (Roche, Mannheim, Germany). After 30 min of digestion, the enzymatic solution was washed out, and the tissue from the left ventricle was cut into small pieces and gently swirled in the HEPES-buffered solution containing 0.125 mm Ca2+. Dissociated cells were filtered through a 200-μm mesh and allowed to settle for 20 min. The cells were then resuspended in the buffered solution containing 5 mg/ml BSA and exposed to a graded series of increasing Ca2+ concentrations up to 1.8 mm. Each step was followed by a gentle centrifugation with less than 20 g for 2 min to separate the ventricular myocytes from nonmyocytes. The isolated myocytes were resuspended in serum-free defined culture medium consisting of DMEM with 2 mg/ml BSA, 2 mm l-carnitine, 5 mm creatine, and 5 mm taurine. Notably, to avoid any putative effect on KATP channels, no antibiotics were added to culture medium. Cells were incubated for 3 h before experiments to allow reestablishment of normal electrolyte gradients. Purity of cardiomyocyte cultures was assessed by determining the percentage of myosin positive–staining cells using immunofluorescence with a myosin heavy chain specific antibody, MF-20, as previously described. Ninety-nine percent of cells stained positive. 11
Back to Top | Article Outline
Measurement of Flavoprotein Fluorescence
The fluorescence of FAD-linked enzymes, called flavoproteins, was used to monitor mitochondrial redox state, which is a direct indicator of mitoKATP channel activity. 14,15 Isolated myocytes were cultured at a density of 100–150 cells/mm2 on 20 mm round glass coverslips precoated with laminin (1 μg/cm2; Sigma, St. Louis, MO) placed in 35-mm plastic culture dishes. After 2 h, the dishes were washed with phosphate-buffered saline to remove cells that were not attached. Experiments were performed over the next 12 h. The treatment protocols and the concentrations of the reagents used were established previously. 16,17 Myocytes on glass coverslips were placed in a customized airtight perfusion chamber with a volume of 0.5 ml, covered with a 25-mm glass coverslip, which was tightly sealed with vacuum grease (Fisher, Pittsburgh, PA) and perfused at room temperature (25°C) with a buffer solution at a flow rate of 0.5 ml/min containing (pH 7.4) 140 mm NaCl, 5 mm KCl, 1 mm MgCl2, 1.8 mm CaCl2, and 10 mm HEPES. Myocytes were exposed in series to the following solutions: plain buffer solution (baseline), buffer with 100 μm diazoxide (Biomol, Plymouth Meeting, PA) followed by a washout with plain buffer, buffer saturated with sevoflurane or isoflurane (Abbott AG, Baar, Switzerland) in the presence or absence of 2 μm chelerythrine (Biomol) for 10 min followed by a washout with plain buffer, and finally buffer with 100 μm 2,4-dinitrophenol (Sigma, St. Louis, MO). Buffer solution was equilibrated with 2.8% (vol/vol) sevoflurane or 1.2% (vol/vol) isoflurane using a Sevotec 5 vaporizer (Datex-Ohmeda, Tewksbury, MA) or an Isotec 3 vaporizer (Datex-Ohmeda), respectively, with an air bubbler. Delivered vapor concentrations of the volatile anesthetics were continuously controlled by the infrared gas analyzer Capnomac Ultima (Datex-Ohmeda). Applied concentrations of sevoflurane and isoflurane were also measured in the buffer solution of the perfusion chamber using a gas chromatograph (Perkin-Elmer, Norwalk, CT): sevoflurane 2.8% (vol/vol) (2 minimum alveolar concentration [MAC] in rats at 25°C) 0.92 ± 0.01 mm, isoflurane 1.2% (vol/vol) (2 MAC in rats at 25°C) 0.63 ± 0.01 mm. Chelerythrine was dissolved in buffer at a concentration of 2 μm. Diazoxide was dissolved at 100 μm in buffer solution containing dimethyl sulfoxide (DMSO) 0.1%. Because DMSO was used as a solvent for diazoxide, a series of experiments was studied in which DMSO alone was administered to myocytes. Importantly, DMSO alone at the concentration used in the experiments had no effect on autofluorescence of myocytes (data not shown). Also, separate experiments showed that chelerythrine (2 μm) alone or followed by diazoxide did not affect autofluorescence of flavoproteins (see Results section). For each experimental group, myocytes of 8 different rat hearts were used (n = 8), and all experiments were performed in duplicate. Data from one heart were averaged. An upright microscope (Axioplan2; Zeiss, Jena, Germany) equipped with a xenon arc lamp and the appropriate filter set (excitation at 480 nm, emission at 530 nm) was used to monitor the autofluorescence of myocytes. Images were captured using a cooled CCD camera (ORCA-100, 12 bit digital output; Hamamatsu Photonics, Herrsching, Germany) controlled by an image acquisition software (Openlab; Improvision, Lexington, MA). Fluorescence intensity was recorded every 15 s by exposing myocytes for 125 ms using a computer-controlled high-speed shutter (Openlab; Improvision). Calibration of flavoprotein fluorescence was achieved by setting fluorescence obtained after 2,4-dinitrophenol exposure to 100%. 2,4-Dinitrophenol uncouples oxidative phosphorylation and subsequently leads to fully oxidized flavoproteins. All measurements of flavoprotein oxidation were then expressed as percentage of 2,4-dinitrophenol–induced maximal autofluorescence. In each experiment, the fluorescence of 5–10 myocytes was monitored with a 20× objective lens (LD Achroplane, NA = 0.4; Zeiss). Processing of the flavoprotein signals was achieved using a binary mask, which was separately drawn for each myocyte using Openlab software (Improvision). This allowed exclusion of artifacts from other myocytes and background, and the time course of flavoprotein fluorescence of multiple individual myocytes could be selectively and simultaneously traced. A pseudocolor palette was finally used to visualize the relative intensity of mitochondrial flavoprotein oxidation states. Myocytes with an increased initial autofluorescence greater than 30% of the peak 2,4-dinitrophenol–induced autofluorescence were excluded from analysis and considered as damaged cells.
Back to Top | Article Outline
Simulated Ischemia in Cardiomyocytes
Myocytes were suspended in the incubation buffer containing 119 mm NaCl, 25 mm NaHCO3, 1.2 mm KH2PO4, 4.8 mm KCl, 1.2 mm MgSO4, 1.8 mm CaCl2, 10 mm HEPES, 11 mm glucose, 24.9 mm creatine, and 58.5 mm taurine and supplemented with 1% basal medium Eagle amino acids (GIBCO, Paisley, Scotland, UK) and 1% minimum essential medium nonessential amino acids (Sigma) at pH 7.4. Volatile anesthetics at 0.5, 1.0, 1.5, and 2.0 MAC were administered to myocytes for 15 min before simulated ischemia by gently bubbling a 10-ml tube in a standard incubator at 37°C, at the bottom of which 1.5 ml of a myocyte suspension was placed. Control samples were only gassed with air. Applied concentrations were continuously monitored and in addition measured by gas chromatography: sevoflurane: 0.5 MAC 0.22 ± 0.02 mm, 1.0 MAC (2.5% [vol/vol]) 0.50 ± 0.03 mm, 1.5 MAC 0.71 ± 0.01 mm, 2.0 MAC 0.96 ± 0.01 mm; isoflurane: 0.5 MAC 0.16 ± 0.02 mm, 1 MAC (1.4% [vol/vol]) 0.34 ± 0.02 mm, 1.5 MAC 0.50 ± 0.02 mm, 2 MAC 0.72 ± 0.01 mm. In separate experiments, for each of the drugs listed below, dose–response curves with respect to myocyte death were established in the presence and absence of volatile anesthetics to determine the optimum concentration, which guaranteed the maximum inhibitory or stimulatory effect on the specific signal transduction component under investigation. Accordingly, depending on the treatment group, myocytes were exposed to 100 μm 8-sulfophenyl theophylline, 100 μm 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), 100 μm adenosine, 0.1 μm prazosin, 5 μm propranolol, 2 μm chelerythrine, 100 μm 5-hydroxydecanoate (all drugs purchased from Sigma), 50 μm HMR-1098 (a gift from Aventis AG, Frankfurt am Main, Germany), 100 μm 2-(4-carboxyphenyl)-4,4′,5,5′-tetramethylimidazole-1-oxyl-3-oxide (PTIO), 1 μg/ml pertussis toxin (PTX), 50 μm NG-nitro-l-arginine methyl ester (l-NAME), 50 μm l-N6-(1-iminoethyl)lysine (l-NIL), 1 mm 8-bromo-cGMP, and 100 μm S-nitroso-N-acetyl-dl-penicillamine (SNAP) (all drugs purchased from Biomol). Drugs were administered 20 min prior to simulated ischemia and 5 min prior to administration of volatile anesthetics, respectively, except for PTX, which was added to myocytes 2 h before ischemia. Diazoxide, adenosine, SPT, SNAP, and PTIO were dissolved in DMSO containing buffer solution (final concentration of DMSO 0.1%). Because DMSO was used as a solvent for these drugs, a series of experiments was performed in which DMSO alone was administered to myocytes. DMSO alone, at the concentration used in the experiments, had no effect on survival of myocytes. In separate experiments diazoxide was administered at 1 μm, 10 μm, and 100 μm in the presence and absence of 1 MAC sevoflurane or isoflurane 15 min before 120 min of ischemia. After the various treatment modalities, 1 ml of the myocyte suspension was pipetted from the bottom of the 10-ml tube into a 1.5-ml microcentrifuge tube and centrifuged for 20 s at 15 g. The supernatant was discarded, and 0.25 ml of mineral oil (Sigma) was layered onto the myocyte pellet to inhibit gaseous diffusion of oxygen, as previously described. 17,18 Following 60 and 120 min of incubation in a standard incubator at 37°C, 15 μl of myocytes was sampled through the mineral oil layer and mixed with 150 μl of a hypotonic trypan blue staining solution containing 11.9 mm NaHCO3, 0.4 mm KH2PO4, 2.7 mm KCl, 0.8 mm MgSO4, 1.8 mm CaCl2, 0.5% glutaraldehyde, and 0.5% trypan blue. 19,20 In the various protocols, for each experimental group, cells of 8 different rat hearts (n = 8) were used, and experiments were performed in duplicate. Myocyte viability was assessed by counting the number of myocytes staining clearly after 3 min of exposure to the hypoosmolar trypan blue staining solution. Myocytes, which stained dark blue, were considered irreversibly damaged. Five randomly chosen fields (1 mm2) were counted at 10 × 10 magnification with a phase-contrast microscope in duplicate and expressed as the percentage of total viable myocytes before ischemia. The percentage of myocytes viable at the beginning of the experiments was 90 ± 3% (n = 30). The small percentage of nonviable myocytes was due to the enzymatic isolation procedure. Importantly, the number of viable cells remained unchanged in untreated myocytes over the 1- or 2-h period of the experiments, and administration of volatile anesthetics did not affect myocyte viability over this period. Also, in the preparation used, the myocytes excluded trypan blue and retained their rod-shaped configurations over a 6-h period following isolation (89 ± 4%, n = 30).
Back to Top | Article Outline
Statistical Analysis
Data are expressed as mean ± SD. Analysis of variance with post hoc Scheffé test for multiple comparisons was performed to determine statistical significance of multiple treatments. P < 0.05 was considered to be significant (StatView Version 4.5; Abacus Concepts, Berkeley, CA).
Back to Top | Article Outline

Results

Volatile Anesthetics Preserve Myocyte Viability Dose-Dependently in a Cellular Model of Simulated Ischemia
Fig. 1
Fig. 1
Image Tools
To evaluate the potency of sevoflurane and isoflurane to protect myocytes from undergoing irreversible ischemic damage, isolated myocytes were exposed to increasing concentrations of sevoflurane and isoflurane (0.5 MAC, 1 MAC, 1.5 MAC, 2.0 MAC) 15 min before 60 or 120 min of ischemia. Cellular injury was determined by counting myocytes, which were not capable of excluding trypan blue staining under hypotonic conditions. Both volatile anesthetics dose-dependently reduced the percentage of trypan blue–positive myocytes, with isoflurane slightly more effective than sevoflurane at equipotent MAC values (fig. 1). After 120 min of ischemia, pretreatment of myocytes with 2 MAC sevoflurane and isoflurane decreased the percentage of trypan blue–positive myocytes markedly, from 67 ± 5% to 30 ± 3% and 26 ± 3%, respectively (P < 0.0001, n = 8). Importantly, no substantial further protection was achieved by sevoflurane and isoflurane with MAC values greater than 1.5.
Back to Top | Article Outline
Myocyte Protection by Volatile Anesthetics is Selectively Mediated by Mitochondrial KATP Channels
Fig. 2
Fig. 2
Image Tools
To test whether isoflurane- and sevoflurane-induced protection in myocytes is mediated by the sarcKATP channel or the mitoKATP channel, myocytes were exposed to 50 μm HMR-1098, a selective sarcKATP channel blocker, or 100 μm 5-hydroxydecanoate, a selective mitoKATP channel blocker, 5 min before exposure to volatile anesthetics (1 MAC sevoflurane or isoflurane for 15 min). Subsequent ischemia was maintained for 60 or 120 min. HMR-1098 did not diminish protection elicited by volatile anesthetics (after 120 min of ischemia, sevoflurane: 45 ± 4%vs. sevoflurane + HMR-1098: 44 ± 3%; isoflurane: 39 ± 3%vs. isoflurane + HMR-1098: 41 ± 4%; not significant, n = 8). In contrast, 5-hydroxydecanoate completely abolished this protection, as assessed by hypoosmolar trypan blue staining (after 120 min of ischemia, sevoflurane: 45 ± 4%vs. sevoflurane + 5-hydroxydecanoate: 63 ± 4%; isoflurane: 39 ± 3%vs. isoflurane + 5-hydroxydecanoate: 61 ± 3%;P < 0.0001, n = 8, sevoflurane + 5-hydroxydecanoate and isoflurane + 5-hydroxydecanoate vs. control (ischemia alone); not significant, n = 8) (fig. 2). These experiments clearly indicate at a cellular level that mitoKATP channels play a pivotal role in ischemic protection elicited by volatile anesthetics.
Back to Top | Article Outline
Volatile Anesthetics Potentiate Diazoxide-mediated Myocyte Protection
Fig. 3
Fig. 3
Image Tools
Diazoxide is known as a highly selective potent opener of the mitoKATP channels (2,000-fold more potent at the mitochondrial channel than at the surface channel). To test whether volatile anesthetics further potentiate the opening effect of diazoxide on mitoKATP channels, myocytes where exposed to increasing concentrations of diazoxide (1 μm, 10 μm, 100 μm) in the presence of sevoflurane or isoflurane (1 MAC for 15 min) before 60 or 120 min of ischemia. Volatile anesthetics markedly potentiated the protective effect of diazoxide and significantly reduced the percentage of trypan blue–positive myocytes (100 μm diazoxide: 22 ± 3%vs. 100 μm diazoxide + 1 MAC sevoflurane: 11 ± 2% and 100 μm diazoxide + 1 MAC isoflurane: 10 ± 2%, P < 0.0001, n = 8), with isoflurane slightly more potent than sevoflurane at the diazoxide concentrations of 1 μm and 10 μm (fig. 3). The results of these experiments suggest that volatile anesthetics enhance opening of mitoKATP channels.
Back to Top | Article Outline
Volatile Anesthetics Prime Activation of MitoKATP Channels as assessed by Flavoprotein Oxidation–Enhanced Autofluorescence in Myocytes
Fig. 4
Fig. 4
Image Tools
The redox state of flavoproteins directly reflects mitoKATP channel activity. To test whether volatile anesthetics directly open mitoKATP channels, the effect of sevoflurane and isoflurane on flavoprotein oxidation was visualized using fluorescence microscopy. Notably, exposure of sevoflurane and isoflurane as long as 30 min did not alter flavoprotein oxidation as compared with baseline values. Conversely, diazoxide administration to myocytes pretreated with sevoflurane (2.8% [vol/vol]) and isoflurane (1.2% [vol/vol]) clearly accelerated as well as markedly enhanced diazoxide-induced increases in flavoprotein-mediated autofluorescence, which indicates that volatile anesthetics prime activation of mitoKATP but do not open the channel directly (fig. 4). Importantly, coadministration of chelerythrine (2 μm), a specific protein kinase C (PKC) inhibitor, to sevoflurane abolished the priming effect of sevoflurane on diazoxide. Similar results were obtained for isoflurane.
Chelerythrine was previously reported to enhance fluorescence unspecifically. 17 However, at the low concentration of 2 μm used in the present work, chelerythrine did not affect baseline fluorescence of the flavoproteins (flavoprotein oxidation at emission wavelength of 530 nm of chelerythrine alone was 18 ± 3% as compared to control [16 ± 2%] in the absence of chelerythrine). We also tested whether chelerythrine alone would modify the subsequent diazoxide-induced fluorescence peak. Pretreatment with chelerythrine did not alter the diazoxide-induced fluorescence peak (41 ± 3%) compared to diazoxide without chelerythrine pretreatment (40 ± 4%).
Conversely, l-NAME, l-NIL, and PTIO could only be used in the experiments using the model of simulated ischemia on isolated myocytes. The latter three substances were found to significantly suppress baseline flavoprotein fluorescence: flavoprotein oxidation was 4 ± 2% for 100 μm PTIO, 7 ± 2% for 50 μm l-NAME, and 7 ± 3% for 50 μm l-NIL compared to baseline (16 ± 2%).
Back to Top | Article Outline
Myocyte Protection by Volatile Anesthetics is Mediated by Adenosine-Gi– and Nitric Oxide–sensitive Signaling Pathways and Involves Activation of Protein Kinase C
Table 1
Table 1
Image Tools
Fig. 5
Fig. 5
Image Tools
A number of modulators known to be involved in ischemic preconditioning were used to test their effects on volatile anesthetic–induced cellular protection. At the same time, this allowed us to define the main signaling pathways, which are known to contribute to the preconditioned state. Isolated myocytes were exposed to 2 MAC sevoflurane since the dose–response with regard to cellular protection leveled off between 1.5 and 2 MAC (fig. 1). The concentrations of the modulators used in these experiments were established in separate experiments and represent the concentrations required to obtain the maximum inhibitory or stimulatory effects on the signaling components under investigation. The percentage of trypan blue–positive myocytes as a measure for cell viability was evaluated after 120 min of ischemia. Concentration dependence of individual modulators and controls are summarized in table 1. The data concerning the specific effects of individual modulators at maximum inhibitory or stimulatory effects from table 1 is visualized for comparison in figure 5.
The unselective adenosine receptor blocker SPT and the selective adenosine 1 receptor blocker DPCPX significantly attenuated the sevoflurane-induced protection but did not completely block its protective effect (fig. 5). Furthermore, the Gi-inhibiting PTX significantly decreased protection by sevoflurane, and adenosine at 100 μm elicited significant protection, which was, however, less pronounced than administration of 2 MAC sevoflurane (2 MAC sevoflurane: 30 ± 3%vs. adenosine 42 ± 4%, P < 0.001, n = 8). Notably, SPT, DPCPX, and PTX alone did not affect the percentage of trypan blue–positive myocytes exposed to 120 min of ischemia. Taken together, these results indicate that mechanisms other than pure stimulation of adenosine receptors contribute to the protection elicited by volatile anesthetics in rat ventricular myocytes.
To determine the role of nitric oxide (NO) in mediating sevoflurane-induced ischemic protection, myocytes were treated with the NO-scavenger PTIO (100 μm) and the NO synthase (NOS) inhibitors l-NAME (50 μm) and l-NIL (50 μm) (relatively specific for inducible NOS). PTIO and both NOS inhibitors significantly diminished but did not abolish the protective effect of sevoflurane. PTIO, l-NAME, and l-NIL alone did not affect the percentage of trypan blue–positive myocytes exposed to 120 min of ischemia. In accordance with this observation, SNAP at 100 μm, a NO donor, and 8-bromo-cGMP at 1 mm, a membrane-permeable analog of cGMP, which is an important mediator of many NO effects, prevented myocytes from undergoing irreversible ischemic damage. Notably, prazosin at 0.1 μm and propranolol at 5 μm did not affect sevoflurane-induced protection. The PKC inhibitor chelerythrine at 2 μm alone and the coadministration of 100 μm SPT and 100 μm PTIO completely abolished the cytoprotection by sevoflurane. Chelerythrine, prazosin, and propranolol alone did not affect the percentage of trypan blue–positive myocytes exposed to 120 min of ischemia.
Fig. 6
Fig. 6
Image Tools
The results of these experiments suggest that, in rat ventricular myocytes, multiple signaling pathways may contribute to sevoflurane-induced protection against ischemia, which presumably culminate in activation of PKC and thereby prime mitoKATP channels. Figure 6 depicts a simplified scheme of the signaling circuits hypothetically involved in the priming of the mitoKATP channel in response to volatile anesthetics.
Back to Top | Article Outline

Discussion

The principal new findings of this investigation are as follows. Volatile anesthetics do not directly open mitoKATP channels but prime mitoKATP channel activity. First, volatile anesthetics did not affect basal flavoprotein fluorescence in myocytes but potentiated the oxidative effect of the highly specific mitoKATP channel opener diazoxide. Their coadministration to diazoxide also abbreviated the latency to peak mitoKATP channel activity. Second, diazoxide-induced myocyte protection was potentiated by volatile anesthetics in a cellular model of simulated ischemia. Opening of the mitoKATP channels, but not sarcKATP channels, elicited this protection. The specific PKC inhibitor chelerythrine completely abrogated both the enhanced flavoprotein oxidation and the cellular protection induced by volatile anesthetics. This suggests that PKC represents a key signaling component upstream of the mitoKATP channel and that these two events are closely associated. Lastly, our experiments indicate that the cardioprotective potency of volatile anesthetics parallels MAC values, but that different volatile anesthetics may confer varying degrees of protection at equipotent MAC values.
Recent studies focused on the elucidation of the molecular mechanisms that are involved in anesthetic-induced preconditioning. Since simultaneous administration of ischemic preconditioning and volatile anesthetics does not induce additional protection over that provided by each intervention alone, cardioprotection by volatile anesthetics is thought to be mediated by the same end effector as classic preconditioning. 21 Using blockers of the KATP channel, many studies identified this channel in a multitude of animal models and experimental conditions as a key element in mediating the anesthetic-induced preconditioned state. 2,3,9,22,23 Most recently, effective preconditioning of human atrial trabeculae by isoflurane, but not halothane, was reported, and this effect was clearly abolished by glibenclamide, a nonspecific KATP channel blocker. 24 Furthermore, desflurane reduced myocardial infarction size through mitoKATP channels as well as sarcKATP channels, 9 and sevoflurane was found to protect stunned myocardium, 25 which was blocked by the specific mitoKATP channel blocker 5-hydroxydecanoate. Although recent data suggest that the mitoKATP channel is even more important in mediating preconditioning-like effects, so far, no data were available with respect to interactions between volatile anesthetics and mitoKATP channel activity. Only one study investigated the effects of isoflurane on sarcKATP channel activity in rabbit ventricular myocytes and revealed that isoflurane inhibits channel activity without a change in single channel conductance. 10 However, isoflurane decreased the ATP sensitivity of the channel, leading to increased probability of channel opening for a given concentration of ATP. The results of our study are in line with these observations in sarcKATP channels in so much as no direct opening of the mitoKATP channel is recorded in response to volatile anesthetics.
The use of autofluorescence emerged as a new tool with great impact in the endeavor to understand cellular mechanisms. 26 In mammalian cells, autofluorescence is caused largely by the reduced pyridine nucleotides [NAD(P)/H] and by the oxidized flavoproteins (FAD/H2). These endogenous fluorophores transfer electrons to oxygen in the inner mitochondrial membrane, ultimately leading to formation of H2O and synthesis of ATP. The excitation of flavoproteins (excitation maximum at 480 nm) is maximal under full oxidation and minimal under full reduction, whereas the opposite is true for NAD(P)H (excitation maxima at 290, 336, 351 nm). The ratio of the concentration of oxidized and reduced electron carriers or of their fluorescence, respectively, therefore gives a measure of the cellular metabolic state. On the other hand, selective monitoring of flavoprotein-induced autofluorescence directly reflects mitoKATP channel activity, as previously shown. 27 This noninvasive technique has been successfully used by Marbán et al. to uncover important molecular mechanisms underlying the phenomenon of preconditioning. 14,16,17 A previous study investigated the effect of halothane (0.27 mm) on pyridine nucleotide [NAD(P)H]-induced autofluorescence in nonbeating rat ventricular myocytes. 28 Due to the opposite behavior of flavoprotein and pyridine nucleotides with respect to the redox state-dependent generation of autofluorescence, the results of this study could give some indications on how flavoproteins and thereby mitoKATP channel activity could be affected by volatile anesthetics. Interestingly, no change in NAD(P)H-mediated autofluorescence was recorded in response to halothane in the absence of electrical stimulation, which indirectly implies that halothane, at the indicated concentration, did not affect basal flavoprotein-induced fluorescence or the mitoKATP channel activity, respectively. This is in clear accordance with the results of our study.
How does activation of KATP channels mediate cardioprotection? A cardioplegic-like effect with action potential shortening, decreased energy consumption, and reduced cytosolic Ca2+ overload has been proposed as the protective mechanism caused by increased sarcKATP channel activity. 6 Conversely, dissipation of the inner mitochondrial membrane potential in response to opening of the mitoKATP channels blunts Ca2+ overload of mitochondria 29 and leads to restoration of the mitochondrial intermembrane space, 30 which reestablishes functional coupling between adenine nucleotide translocase and creatine kinase as well as energy processes from mitochondria to ATP-utilizing cytosolic sites. 31 Interestingly, considerable cross-talk was documented between sarcKATP and mitoKATP channels, whereby increased ATP consumption through uncoupled mitochondria leads, in turn, to activation of sarcKATP channels. 32 The results of the current study emphasize the importance of the protective effects of mitoKATP channel in mediating volatile anesthetic–induced protection, but the role of the sarcKATP channel should not be totally dismissed.
Recently, Sato et al. proposed a 3-state model, including resting, primed, and open state of the mitoKATP channel. 17 This was motivated by the observation that adenosine did not affect basal mitoKATP channel activity but significantly enhanced opening by diazoxide, a direct mitoKATP channel opener. The primed receptor state allows easy and rapid opening at the initiation of ischemia, and most probably represents a specifically phosphorylated state of the receptor. In our study, isoflurane and sevoflurane similarly potentiated diazoxide-mediated effects, which were blocked by chelerythrine, a specific PKC inhibitor. The important role of adenosine receptors and PKC in the cardioprotection elicited by volatile anesthetics was repeatedly reported in previous studies. 24,33,34 Of note, volatile anesthetics may even directly activate PKC, although their reported actions on PKC are contradictory. The so-far hypothetical model of a primed receptor state could explain the recently observed decrease in time threshold by sevoflurane for ischemic preconditioning. 35 In this context, an antiprimed state of the mitoKATP channel may also underlie the observed phenomenon of “antipreconditioning,” where the inability of the channel to open at initiation of ischemia may lead to the reported potentiated ischemic damage. 36 Taken together, priming of the mitoKATP channel may reflect a general characteristic of this channel.
Using a cellular model of simulated ischemia, we evaluated the effects of specific blockers on various putative signaling pathways involved in the preconditioning-like state induced by volatile anesthetics. This in vitro model mimics tissue ischemia by restriction of oxygen and extracellular fluid as well as accumulation of metabolites. 18,19 Subsequent superposition of an artificially high hypotonic stress upon cardiomyocytes allows sensitive detection of even latent ultrastructural ischemic lesions in sarcolemmal membrane integrity by trypan blue permeability exclusion. 20 The results of these experiments allowed us to delineate the signaling pathways involved in the preconditioned state in response to volatile anesthetics (fig. 6). Specifically, the involvement of G-protein–linked signaling, as previously shown in a canine model, 37 could be confirmed in our experiments. Two observations, however, need further consideration. First, although initially it was felt that adenosine receptors were not involved in preconditioning in rat, more recent evidence reveals that adenosine antagonists can at least blunt the preconditioning-induced protection. This is consistent with the results of our study, where two adenosine receptor antagonists, SPT and DPCPX, diminished the protective effects of volatile anesthetics. Also, a recent study in rat ventricular myocytes demonstrated that activation of adenosine 1 receptors reduces reactive oxygen species and significantly attenuates myocardial stunning. 38 Second, the presented results also suggest NO–cGMP as elements in volatile anesthetic–induced protection (fig. 6). Administration of the NO scavenger PTIO or the NOS inhibitors l-NAME and l-NIL clearly inhibited protection afforded by volatile anesthetics. Notably, NO and its metabolite peroxinitrite are known to activate PKC and the KATP channels. 16 NO–cGMP signaling and basal NOS activity were previously reported to play an important role in pacing-associated preconditioning in the isolated rat heart. 39,40 Moreover, a recent study in chicken myocytes demonstrated the abrogation of preconditioning protection using 5-hydroxydecanoate or l-NAME. 41 It may well be that volatile anesthetics differentially modulate the activity of the various isoenzymes of NOS (nNOS, eNOS, iNOS), which are ubiquitous but heterogeneously distributed in myocytes. 42 Although the role of NO in late preconditioning (second window of protection) is well established, its role in early preconditioning, specifically in anesthetic-induced preconditioning, needs further investigations.
Apoptosis, the programmed cell death, plays a key role in myocardial infarction and the various forms of cardiomyopathies. Volatile anesthetics were recently reported to inhibit catecholamine-induced apoptosis in rat ventricular myocytes by modulation of cellular Ca2+ homeostasis and inhibition of the apoptosis initiator caspase-9, which is closely related to mitochondrial integrity. 11 A recent study now links opening of the mitoKATP channel to significant antiapoptotic effects in myocytes, 43 thereby raising the interesting possibility that cardioprotection by volatile anesthetics during ischemia may be caused by their priming effect on mitoKATP channels. Taken together, the preconditioning effects of volatile anesthetics are sensitive to adenosine receptor– and NO-coupled signaling.
The results of the present study should be interpreted with caution. Specifically, we recognize that mechanistic information on preconditioning in rat myocytes may not be transferable to other species, in particular to humans. Also, isolated myocyte models have limitations with respect to the choice of external solutions, substrate selection, and unphysiologically low workload. In addition, the effects of only a limited number of putative signaling pathways involved in anesthetic-induced preconditioning were assessed in the present study. Importantly, the use of basal anesthesia, in particular the use of barbiturates 12 and ketamine, 13 has a great potential to affect experimental results and was therefore carefully avoided in our experiments. Even α-chloralose, which is appreciated for its neglectable effects on experimental results, can potentially affect KATP channel activity by its main metabolite trichloroethanol, since ethanol is known to induce preconditioning. 44 Finally, although the question of whether sarcKATP or mitoKATP channels would be the more important contributors to anesthetic-induced preconditioning in vivo could not be clarified by our experimental model, the results of these studies pinpoint the mitoKATP channel as a potential therapeutic target for cardioprotection.
In summary, volatile anesthetics prime mitoKATP channels through multiple PKC-coupled signaling pathways in a model of isolated rat ventricular myocytes. Since anesthetic-induced preconditioning not only affects the heart but also may protect a variety of other tissues, 45 appropriate clinical studies are now needed to ascertain the utility and efficacy of this promising therapeutic strategy in perioperative medicine, specifically in patients at high risk for perioperative ischemic injury.
Back to Top | Article Outline

References

1. Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74: 1124–36

2. Warltier D, Al-Wathiqui M, Kampine J, Schmeling W: Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane. A nesthesiology 1989; 69: 552–65

3. Davis R, Sidi A: Effect of isoflurane on the extent of myocardial necrosis and on systemic hemodynamics, regional myocardial blood flow, and regional myocardial metabolism in dogs after coronary artery occlusion. Anesth Analg 1989; 69: 575–86

4. Preckel B, Schlack W, Thämer V: Enflurane and isoflurane, but not halothane, protect against myocardial reperfusion injury after cardioplegic arrest with HTK solution in the isolated rat heart. Anesth Analg 1998; 87: 1221–7

5. Belhomme D, Peynet J, Louzy M, Launay JM, Kitakaze M, Menasché P: Evidence for preconditioning by isoflurane in coronary artery bypass graft surgery. Circulation 1999; 100(suppl II): II-340–4

6. O'Rourke B: Myocardial KATP channels in preconditioning. Circ Res 2000; 87: 845–55

7. Kersten JR, Gross GJ, Pagel PS, Warltier DC: Activation of adenosine triphosphate-regulated potassium channels. A nesthesiology 1998; 88: 495–513

8. Gross GJ, Fryer RM: Sarcolemmal versus mitochondrial ATP-sensitive K+ channels and myocardial preconditioning. Circ Res 1999; 84: 973–79

9. Toller WG, Gross ER, Kersten JR, Pagel PS, Gross GJ, Warltier DC: Sarcolemmal and mitochondrial adenosine triphosphate-dependent potassium channels. A nesthesiology 2000; 92: 1731–9

10. Han J, Kim E, Ho WK, Earm YE: Effects of volatile anesthetic isoflurane on ATP-sensitive K+ channels in rabbit ventricular myocardium. Biochem Biophys Res Commun 1996; 229: 852–6

11. Zaugg M, Jamali NZ, Lucchinetti E, Shafiq SA, Siddiqui MAQ: Norepinephrine-induced apoptosis is inhibited in adult rat ventricular myocytes exposed to volatile anesthetics. A nesthesiology 2000; 93: 209–18

12. Tsutsumi Y, Oshita S, Kitahata H, Kuroda Y, Kawano T, Nakaya Y: Blockade of adenosine triphosphate-sensitive potassium channels by thiamylal in rat ventricular myocytes. A nesthesiology 2000; 92: 1154–9

13. Molojavyi A, Preckel B, Comfère T, Müllenheim J, Thämer V, Schlack W: Effects of ketamine and its isomers on ischemic preconditioning in the isolated rat heart. A nesthesiology 2001; 94: 623–9

14. Liu Y, Sato T, O'Rourke B, Marbán E: Mitochondrial ATP-dependent potassium channels: Novel effectors of cardioprotection? Circulation 1998; 97: 2463–9

15. Romashko DN, Marbán E, O'Rourke B: Subcellular metabolic transients and mitochondrial redox waves in heart cells. Proc Natl Acad Sci U S A 1998; 95: 1618–23

16. Sasaki N, Sato T, Ohler A, O'Rourke B, Marbán E: Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation 2000; 101: 439–45

17. Sato T, Sasaki N, O'Rourke B, Marbán E: Adenosine primes the opening of mitochondrial ATP-sensitive potassium channels: A key step in ischemic preconditioning? Circulation 2000; 102: 800–5

18. Vander Heide RS, Rim D, Hohl CM, Ganote CE: An in vitro model of myocardial ischemia utilizing isolated adult rat myocytes. J Mol Cell Cardiol 1990; 22: 165–81

19. Armstrong SC, Hoover DB, Shivell LC, Ganote CE: Preconditioning of isolated rabbit cardiomyocytes: No evident separation of induction, memory and protection. J Mol Cell Cardiol 1997; 29: 2285–98

20. Armstrong SC, Shivell LC, Ganote CE: Sarcolemmal blebs and osmotic fragility as correlates of irreversible ischemic injury in preconditioned isolated rabbit cardiomyocytes. J Mol Cell Cardiol 2001; 33: 149–60

21. Boutros A, Wang J, Capuano C: Isoflurane and halothane increase adenosine triphosphate preservation, but do not provide additive recovery of function after ischemia, in preconditioned rat hearts. A nesthesiology 1997; 86: 1009–17

22. Kersten JR, Schmeling TJ, Hettrick DA, Pagel PS, Gross GJ, Warltier DC: Mechanism of myocardial protection by isoflurane. A nesthesiology 1996; 85: 794–807

23. Cason BA, Gamperl AK, Slocum RE, Hickey RF: Anesthetic-induced preconditioning: Previous administration of isoflurane decreases myocardial infarct size in rabbits. A nesthesiology 1997; 87: 1182–90

24. Roscoe AK, Christensen JD, Lynch C: Isoflurane, but not halothane, induces protection of human myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels. A nesthesiology 2001; 92: 1692–1701

25. Hara T, Tomiyasu S, Sungsam C, Fukusaki M, Sumikawa K: Sevoflurane protects stunned myocardium through activation of mitochondrial ATP-sensitive potassium channels. Anesth Analg 2001; 92: 1139–45

26. Harms GS, Cognet L, Lommerse PHM, Blab GA, Schmidt T: Autofluorescent proteins in single-molecule research: Applications to live cell imaging microscopy. Biophys J 2001; 80: 2396–408

27. Hajnoczky G, Robb-Gaspers LD, Seitz MB, Thomas AP: Decoding of cytosolic calcium oscillations in the mitochondria. Cell 1995; 82: 415–24

28. Jiang Y, Julian FJ: Pacing rate, halothane, and BDM affect fura 2 reporting of [Ca2+]i in intact rat trabeculae. Am J Physiol 1997; 273: C2046–56

29. Liu Y, Sato T, Seharaseyon J, Szewczyk A, O'Rourke B, Marbán E: Mitochondrial ATP-dependent potassium channels: Viable candidate effectors of ischemic preconditioning. Ann NY Acad Sci 1999; 874: 27–37

30. Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD: Bioenergetic consequences of opening the ATP-sensitive K+ channel of heart mitochondria. Am J Physiol 2001; 280: H649–57

31. Laclau MN, Boudina S, Thambo JB, Tariosse L, Gouverneur G, Bonoron-Adèle S, Saks VA, Garlid KD, Santos PD: Cardioprotection by ischemic preconditioning preserves mitochondrial function and functional coupling between adenine nucleotide translocase and creatine kinase. J Mol Cell Cardiol 2001; 33: 947–56

32. Sasaki N, Sato T, Marbán E, O'Rourke B: ATP consumption by uncoupled mitochondria activates sarcolemmal KATP channels in cardiac myocytes. Am J Physiol 2001; 280: H1882–8

33. Toller WG, Montgomery MW, Pagel PS, Hettrick DA, Warltier DC, Kersten JR: Isoflurane-enhanced recovery of canine stunned myocardium. A nesthesiology 1999; 91: 713–22

34. Ismaeli M, Tkachenko I, Hickey R, Cason BA: Colchicine inhibits isoflurane-induced myocardial preconditioning. A nesthesiology 1999; 90: 812–21

35. Toller WG, Kersten JR, Pagel PS, Hettrick DA, Warltier DC: Sevoflurane reduces myocardial infarction size and decreases the time threshold for ischemic preconditioning in dogs. A nesthesiology 1999; 91: 1437–46

36. Aitchison KA, Baxter GF, Awan MM, Smith RM, Yellon DM, Opie LH: Opposing effects on infarction of delta and kappa opioid receptor activation in the isolated rat heart: Implications for ischemic preconditioning. Basic Res Cardiol 2000; 95: 1–10

37. Toller WG, Kersten JJR, Gross ER, Pagel PS, Warltier DC: Isoflurane preconditions myocardium against infarction via activation of inhibitory guanine nucleotide binding proteins. A nesthesiology 2000; 92: 1400–7

38. Narayan P, Mentzer RM, Lasley RD Jr: Adenosine A1 receptor activation reduces reactive oxygen species and attenuates stunning in ventricular myocytes. J Mol Cell Biol 2001; 33: 121–9

39. Ferdinandy P, Szilvássy Z, Balogh N, Csonka C, Csont T, Koltai M, Dux L: Nitric oxide is involved in active preconditioning in isolated working rat hearts. Ann NY Acad Sci 1996; 793: 489–93

40. Csonka C, Szilvássy Z, Fülöp F, Pali T, Blasig IE, Tosaki A, Schullz R, Ferdinandy P: Classic preconditioning decreases the harmful accumulation of nitric oxide during ischemia and reperfusion in rat hearts. Circulation 1999; 100: 2260–6

41. Hoek TL, Becker LB, Shao Z, Schumacker PT: Preconditioning antioxidant protection by KATP channel opening requires nitric oxide synthase. Acad Emerg Med 2001; 8: 548–9

42. Brahmajothi MV, Campbell DL: Heterogeneous basal expression of nitric oxide synthase and superoxide dismutase isoforms in mammalian heart: Implications for mechanisms governing indirect and direct nitric-oxide-related effects. Circulation 1999; 85: 575–87

43. Akao M, Ohler A, O'Rourke B, Marbán E: Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells. Circ Res 2001; 88: 1267–75

44. Chen C, Gray MO, Mochly-Rosen D: Cardioprotection from ischemia by a brief exposure to physiological levels of ethanol: Role of epsilon protein kinase C. Proc Natl Acad Sci U S A 1999; 96: 12784–9

45. Lynch C: Anesthetic preconditioning: Not just for the heart? A nesthesiology 1999; 91: 606–8

Cited By:

This article has been cited 145 time(s).

Fundamental & Clinical Pharmacology
Volatile anaesthetics and cardioprotection - lessons from animal studies
Muntean, DM; Ordodi, V; Ferrera, R; Angoulvant, D
Fundamental & Clinical Pharmacology, 27(1): 21-34.
10.1111/j.1472-8206.2012.01055.x
CrossRef
Acta Anaesthesiologica Scandinavica
Isoflurane applied during ischemia enhances intracellular calcium accumulation in ventricular myocytes in part by reactive oxygen species
Dworschak, M; Breukelmann, D; Hannon, JD
Acta Anaesthesiologica Scandinavica, 48(6): 716-721.
10.1111/j.1399-6576.2004.00410.x
CrossRef
Clinical and Vaccine Immunology
General anesthesia delays the inflammatory response and increases survival for mice with endotoxic shock
Fuentes, JM; Talamini, MA; Fulton, WB; Hanly, EJ; Aurora, AR; De Maio, A
Clinical and Vaccine Immunology, 13(2): 281-288.
10.1128/CVI.13.2.281-288.2006
CrossRef
European Journal of Pharmacology
Upstream signaling of protein kinase C-epsilon in xenon-induced pharmacological preconditioning - Implication of mitochondrial adenosine triphosphate dependent potassium channels and phosphatidylinositol-dependent kinase-1
Weber, NC; Toma, O; Damla, H; Wolter, JI; Schlack, W; Preckel, B
European Journal of Pharmacology, 539(): 1-9.
10.1016/j.ejphar.2006.03.054
CrossRef
British Journal of Anaesthesia
Myocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: a meta-analysis
Symons, JA; Myles, PS
British Journal of Anaesthesia, 97(2): 127-136.
10.1093/bja/ae1149
CrossRef
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie
Is levosimendan an inoprotective drug in patients with acute coronary syndrome undergoing surgical revascularization?
Lehmann, A; Boldt, J; Lang, J; Isgro, F; Blome, M
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 38(9): 577-582.

British Journal of Anaesthesia
Off-pump coronary artery bypass surgery: physiology and anaesthetic management
Chassot, PG; van der Linden, P; Zaugg, M; Mueller, XM; Spahn, DR
British Journal of Anaesthesia, 92(3): 400-413.
10.1093/bja/aeh064
CrossRef
Anesthesia and Analgesia
Low-dose sevoflurane inhalation enhances late cardioprotection from the anti-ulcer drug geranylgeranylcacetone
Kitahata, H; Nozaki, J; Kawahito, S; Tomino, T; Oshita, S
Anesthesia and Analgesia, 107(3): 755-761.
10.1213/ane.0b013e31817f0e61
CrossRef
Anaesthesia
The effects of interrupted or continuous administration of sevoflurane on preconditioning before cardio-pulmonary bypass in coronary artery surgery: comparison with continuous propofol
Bein, B; Renner, J; Caliebe, D; Hanss, R; Bauer, M; Fraund, S; Scholz, J
Anaesthesia, 63(): 1046-1055.
10.1111/j.1365-2044.2008.05563.x
CrossRef
Anaesthesia and Intensive Care
Mechanism of cardiac preconditioning with volatile anaesthetics
Hu, ZY; Liu, J
Anaesthesia and Intensive Care, 37(4): 532-538.

Trends in Molecular Medicine
Mitochondria in cell death: novel targets for neuroprotection and cardioprotection
Mattson, MP; Kroemer, G
Trends in Molecular Medicine, 9(5): 196-205.

Journal of Muscle Research and Cell Motility
Signaling and cellular mechanisms in cardiac protection by ischemic and pharmacological preconditioning
Zaugg, M; Schaub, MC
Journal of Muscle Research and Cell Motility, 24(): 219-249.

Gastroenterology
Recent insights on the mechanisms of liver preconditioning
Carini, R; Albano, E
Gastroenterology, 125(5): 1480-1491.
10.1053/S0016-5085(03)01365-9
CrossRef
Anesthesia and Analgesia
Sevoflurane but not propofol preserves myocardial function during minimally invasive direct coronary artery bypass surgery
Bein, B; Renner, J; Caliebe, D; Scholz, J; Paris, A; Fraund, S; Zaehle, W; Tonner, PH
Anesthesia and Analgesia, 100(3): 610-616.
10.1213/01.ANE.0000145012.27484.A7
CrossRef
Journal of Molecular and Cellular Cardiology
K-ATP channels and preconditioning: A re-examination of the role of mitochondrial KATpchannels and an overview of alternative mechanisms
Hanley, PJ; Daut, J
Journal of Molecular and Cellular Cardiology, 39(1): 17-50.
10.1016/j.yjmcc.2005.04.002
CrossRef
American Journal of Physiology-Heart and Circulatory Physiology
Characterization of human cardiac mitochondrial ATP-sensitive potassium channel and its regulation by phorbol ester in vitro
Jiang, MT; Ljubkovic, M; Nakae, Y; Shi, Y; Kwok, WM; Stowe, DF; Bosnjak, ZJ
American Journal of Physiology-Heart and Circulatory Physiology, 290(5): H1770-H1776.
10.1152/ajpheart.01084.2005
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Cardioprotection by Noble Gases
Pagel, PS
Journal of Cardiothoracic and Vascular Anesthesia, 24(1): 143-163.
10.1053/j.jvca.2009.03.016
CrossRef
Anesthesia and Analgesia
Isoflurane activates human cardiac mitochondrial adenosine triphosphate-sensitive K+ channels reconstituted in lipid bilayers
Jiang, MT; Nakae, Y; Ljubkovic, M; Kwok, WM; Stowe, DF; Bosnjak, ZJ
Anesthesia and Analgesia, 105(4): 926-932.
10.1213/01.ane.0000278640.81206.92
CrossRef
Anesthesia and Analgesia
Preconditioning by isoflurane retains its protection against ischemia-reperfusion injury in postinfarct remodeled rat hearts
Lucchinetti, E; Jamnicki, M; Fischer, G; Zaugg, M
Anesthesia and Analgesia, 106(1): 17-23.
10.1213/01.ane.0000289527.70545.ed
CrossRef
Cardiovascular Research
Cardiac remodelling hinders activation of cyclooxygenase-2, diminishing protection by delayed pharmacological preconditioning: role of HIF1 alpha and CREB
Feng, J; Lucchinetti, E; Fischer, G; Zhu, M; Zaugg, K; Schaub, MC; Zaugg, M
Cardiovascular Research, 78(1): 98-107.
10.1093/cvr/cvn016
CrossRef
European Journal of Pharmacology
Dimethyl fumarate, a small molecule drug for psoriasis, inhibits Nuclear Factor-kappa B and reduces myocardial infarct size in rats
Meili-Butz, S; Niermann, T; Fasler-Kan, E; Barbosa, V; Butz, N; John, D; Brink, M; Buser, PT; Zaugg, CE
European Journal of Pharmacology, 586(): 251-258.
10.1016/j.ejphar.2008.02.038
CrossRef
British Journal of Pharmacology
Accelerated inactivation of cardiac L-type calcium channels triggered by anaesthetic-induced preconditioning
Tampo, A; Hogan, CS; Sedlic, F; Bosnjak, ZJ; Kwok, WM
British Journal of Pharmacology, 156(3): 432-443.
10.1111/j.1476-5381.2008.00026.x
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Postconditioning by volatile anesthetics: Salvaging ischemic myocardium at reperfusion by activation of prosurvival signaling
Pagel, PS
Journal of Cardiothoracic and Vascular Anesthesia, 22(5): 753-765.
10.1053/j.jvca.2008.03.005
CrossRef
Anesthesia and Analgesia
Helium Breathing Provides Modest Antiinflammatory, but No Endothelial Protection Against Ischemia-Reperfusion Injury in Humans In Vivo
Lucchinetti, E; Wacker, J; Maurer, C; Keel, M; Harter, L; Zaugg, K; Zaugg, M
Anesthesia and Analgesia, 109(1): 101-108.
10.1213/ane.0b013e3181a27e4b
CrossRef
British Journal of Anaesthesia
Sevoflurane pre- and post-conditioning protect the brain via the mitochondrial K-ATP channel
Adamczyk, S; Robin, E; Simerabet, M; Kipnis, E; Tavernier, B; Vallet, B; Bordet, R; Lebuffe, G
British Journal of Anaesthesia, 104(2): 191-200.
10.1093/bja/aep365
CrossRef
British Journal of Anaesthesia
Which anaesthetic agent for maintenance during normothermic cardiopulmonary bypass?
Marks, RRD
British Journal of Anaesthesia, 90(2): 118-121.
10.1093/bja/aeg027
CrossRef
Role of the Mitochondria in Human Aging and Disease: From Genes to Cell Signaling
Induction of thioredoxin and mitochondrial survival proteins mediates preconditioning-induced cardioprotection and neuroprotection
Chiueh, CC; Andoh, T; Chock, PB
Role of the Mitochondria in Human Aging and Disease: From Genes to Cell Signaling, 1042(): 403-418.
10.1196/annals.1338.034
CrossRef
Anesthesia and Analgesia
Sevoflurane enhances ethanol-induced cardiac preconditioning through modulation of protein kinase C, mitochondrial K-ATP channels, and nitric oxide synthase, in guinea pig hearts
Kaneda, K; Miyamae, M; Sugioka, S; Okusa, C; Inamura, Y; Domae, N; Kotani, J; Figueredo, VM
Anesthesia and Analgesia, 106(1): 9-16.
10.1213/01.ane.0000297298.93627.36
CrossRef
Journal of Molecular and Cellular Cardiology
Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury
Horikawa, YT; Patel, HH; Tsutsumi, YM; Jennings, MM; Kidd, MW; Hagiwara, Y; Ishikawa, Y; Insel, PA; Roth, DM
Journal of Molecular and Cellular Cardiology, 44(1): 123-130.
10.1016/j.yjmcc.2007.10.003
CrossRef
British Journal of Pharmacology
Activation of ATP-dependent potassium channels is a trigger but not a mediator of ischaemic preconditioning in pigs
Schulz, R; Gres, P; Heusch, G
British Journal of Pharmacology, 139(1): 65-72.

Vascular Pharmacology
Cardioprotection by volatile anesthetics
Bienengraeber, MW; Weihrauch, D; Kersten, JR; Pagel, PS; Warltier, DC
Vascular Pharmacology, 42(): 243-252.
10.1016/j.vph.2005.02.005
CrossRef
British Journal of Anaesthesia
Isoflurane does not mimic ischaemic preconditioning in decreasing hydroxyl radical production in the rabbit
Gozal, Y; Raphael, J; Rivo, J; Berenshtein, E; Chevion, M; Drenger, B
British Journal of Anaesthesia, 95(4): 442-447.
10.1093/bja/aei203
CrossRef
British Journal of Anaesthesia
Is protection by inhalation agents volatile? Controversies in cardioprotection
Zaugg, M
British Journal of Anaesthesia, 99(5): 603-606.
10.1093/bja/aem276
CrossRef
Pharmacological Research
Pre-conditioning and postconditioning to limit ischemia-reperfusion-induced myocardial injury: What could be the next footstep?
Balakumar, P; Rohilla, A; Singh, M
Pharmacological Research, 57(6): 403-412.
10.1016/j.phrs.2008.05.006
CrossRef
Anesthesia and Analgesia
The interaction of Isoflurane and protein kinase C-activators on sarcolemmal K-ATP channels
Turner, LA; Fujimoto, K; Suzuki, A; Stadnicka, A; Bosnjak, ZJ; Kwok, WM
Anesthesia and Analgesia, 100(6): 1680-1686.
10.1213/01.ANE.0000152187.17759.F6
CrossRef
British Journal of Anaesthesia
Myocardial injury and its prevention in the perioperative setting
Zaugg, M; Schaub, MC; Foex, P
British Journal of Anaesthesia, 93(1): 21-33.
10.1093/bja/aeh150
CrossRef
Anesthesia and Analgesia
Emulsified isoflurane produces cardiac protection after ischemia-reperfusion injury in rabbits
Rao, Y; Wang, YL; Zhang, WS; Liu, J
Anesthesia and Analgesia, 106(5): 1353-1359.
10.1213/ane.0b013e3181679347
CrossRef
Anasthesiologie & Intensivmedizin
Organ protection by volatile anaesthetics
Kehl, F; Smul, T; Lange, M; Redel, A; Roewer, N
Anasthesiologie & Intensivmedizin, 46(): 491-+.

Anesthesia and Analgesia
Anesthetic preconditioning with sevoflurane does not protect the spinal cord after an ischemic-reperfusion injury in the rat
Zvara, DA; Bryant, AJ; Deal, DD; DeMarco, MP; Campos, KM; Mansfield, CM; Tytell, M
Anesthesia and Analgesia, 102(5): 1341-1347.
10.1213/01.ane.0000204357.062198c
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Isoflurane, 0.5 minimum alveolar concentration administered through the precardiopulmonary bypass period, reduces postoperative dobutamine requirements of cardiac surgery patients: A randomized study
Ndoko, SK; Tual, L; Mamar, BA; Sauvat, S; Jabre, P; Zakhouri, M; Rosanval, O; Abdi, M; Kirsch, M; Pouzet, B; Loisance, D; Dhonneur, G
Journal of Cardiothoracic and Vascular Anesthesia, 21(5): 683-689.
10.1053/j.jvca.2006.12.015
CrossRef
Scandinavian Cardiovascular Journal
Isoflurane produces only minor preconditioning in coronary artery bypass grafting
Wang, X; Jarvinen, O; Kuukasjarvi, P; Laurikka, J; Wei, MX; Rinne, T; Honkonen, EL; Tarkka, M
Scandinavian Cardiovascular Journal, 38(5): 287-292.
10.1080/14017430410021471
CrossRef
British Journal of Anaesthesia
The mechanism of sevoflurane-induced cardioprotection is independent of the applied ischaemic stimulus in rat trabeculae
Bouwman, RA; van't Hof, FNG; de Ruijter, W; van Beek-Harmsen, BJ; Musters, RJP; de Lange, JJ; Boer, C
British Journal of Anaesthesia, 97(3): 307-314.
10.1093/bja/ael174
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Forty years on: The anesthetic for the world's first human-to-human heart transplant remembered
Gordon, PC; Brink, JG
Journal of Cardiothoracic and Vascular Anesthesia, 22(1): 133-138.
10.1053/j.jvca.2007.10.019
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Time Course of Desflurane-induced Preconditioning in Rabbits
Smul, TM; Redel, A; Stumpner, J; Lange, M; Lotz, C; Roewer, N; Kehl, F
Journal of Cardiothoracic and Vascular Anesthesia, 24(1): 91-98.
10.1053/j.jvca.2009.03.006
CrossRef
Anesthesia and Analgesia
Anesthetic preconditioning attenuates mitochondrial Ca2+ overload during ischemia in guinea pig intact hearts: Reversal by 5-hydroxydecanoic acid
Riess, ML; Camara, AKS; Novalija, E; Chen, Q; Rhodes, SS; Stowe, DF
Anesthesia and Analgesia, 95(6): 1540-1546.
10.1213/01.ANE.0000036621.59264.F0
CrossRef
British Journal of Anaesthesia
Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms
Zaugg, M; Lucchinetti, E; Uecker, M; Pasch, T; Schaub, MC
British Journal of Anaesthesia, 91(4): 551-565.
10.1093/bja/aeg205
CrossRef
Anaesthesia, Pain, Intensive Care and Emergency Medicine
Perioperative myocardial ischaemia
Foex, P
Anaesthesia, Pain, Intensive Care and Emergency Medicine, (): 595-601.

Annales Francaises D Anesthesie Et De Reanimation
Mitochondria in anaesthesia and intensive care
Nouette-Gaulain, K; Quinart, A; Letellier, T; Sztark, F
Annales Francaises D Anesthesie Et De Reanimation, 26(4): 319-333.
10.1016/j.annfar.2007.01.012
CrossRef
Anesthesia and Analgesia
Delayed inhibition of agonist-induced granulocyte-platelet aggregation after low-dose sevoflurane inhalation in humans
Wacker, J; Lucchinetti, E; Jamnicki, M; Aguirre, J; Harter, L; Keel, M; Zaugg, M
Anesthesia and Analgesia, 106(6): 1749-1758.
10.1213/ane.0b013e318172f9e9
CrossRef
Liver Transplantation
Effect of Ischemic Preconditioning on the Genomic Response to Reperfusion Injury in Deceased Donor Liver Transplantation
Jassem, W; Fuggle, S; Thompson, R; Arno, M; Taylor, J; Byrne, J; Heaton, N; Rela, M
Liver Transplantation, 15(): 1750-1765.
10.1002/lt.21936
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Cardioprotection Afforded by St Thomas Solution Is Enhanced by Emulsified Isoflurane in an Isolated Heart Ischemia Reperfusion Injury Model in Rats
Huang, H; Zhang, WS; Liu, SL; Chen, YF; Li, T; Liu, J
Journal of Cardiothoracic and Vascular Anesthesia, 24(1): 99-103.
10.1053/j.jvca.2009.10.016
CrossRef
Anasthesiologie & Intensivmedizin
Preconditioning - anaesthetic-induced organ protection?
Ebel, D; Mullenheim, J; Schlack, W
Anasthesiologie & Intensivmedizin, 45(9): 501-+.

Anaesthesist
Myocardial preconditioning with volatile anesthetics. General anesthesia as protective intervention?
Buchinger, H; Grundmann, U; Ziegeler, S
Anaesthesist, 54(9): 861-+.
10.1007/s00101-005-0902-6
CrossRef
Journal of Neurotrauma
Diazoxide, as a postconditioning and delayed preconditioning trigger, increases HSP25 and HSP70 in the central nervous system following combined cerebral stroke and hemorrhagic shock
O'Sullivan, JC; Yao, XL; Alam, H; McCabe, JT
Journal of Neurotrauma, 24(3): 532-546.
10.1089/neu.2006.0128
CrossRef
Anesthesia and Analgesia
Cardioprotection with volatile anesthetics: Mechanisms and clinical implications
De Hert, SG; Turani, F; Mathur, S; Stowe, DF
Anesthesia and Analgesia, 100(6): 1584-1593.
10.1213/01.ANE.0000153483.61170.OC
CrossRef
Anesthesia and Analgesia
The influence of mitochondrial K-ATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo
Obal, D; Dettwiler, S; Favoccia, C; Scharbatke, H; Preckel, B; Schlack, W
Anesthesia and Analgesia, 101(5): 1252-1260.
10.1213/01.ANE.0000181336.95611.32
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A(1) receptor antagonists
Liu, YH; Xiong, L; Chen, SY; Wang, Q
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 53(2): 194-201.

Anaesthesia, Pain, Intensive Care and Emergency Medicine
Perioperative neuroprotection: is it possible to prevent brain injury in high risk patients?
Schmidt, AP; Brudniewski, M; Auler, JOC
Anaesthesia, Pain, Intensive Care and Emergency Medicine, (): 573-583.

British Journal of Anaesthesia
Role of protein kinase C-epsilon (PKC epsilon) in isoflurane-induced cardioprotection
Obal, D; Weber, NC; Zacharowski, K; Toma, O; Dettwiler, S; Wolter, JI; Kratz, M; Mullenheim, J; Preckel, B; Schlack, W
British Journal of Anaesthesia, 94(2): 166-173.
10.1093/bja/aei022
CrossRef
Anesthesia and Analgesia
Emulsified intravenous versus evaporated inhaled isoflurane for heart protection: Old wine in a new bottle or true innovation?
Lucchinetti, E; Schaub, MC; Zaugg, M
Anesthesia and Analgesia, 106(5): 1346-1349.
10.1213/ane.0b01361816d1661
CrossRef
Anz Journal of Surgery
Anaesthesia and analgesia: Contribution to surgery, present and future
Shipton, E; Lin, A
Anz Journal of Surgery, 78(7): 540-547.
10.1111/j.1445-2197.2008.04568.x
CrossRef
Medical Science Monitor
Levosimendan in patients with cardiogenic shock undergoing surgical revascularization: a case series
Lehmann, A; Lang, J; Boldt, J; Isgro, F; Kiessling, AH
Medical Science Monitor, 10(8): MT89-MT93.

Physiological Genomics
Ischemic but not pharmacological preconditioning elicits a gene expression profile similar to unprotected myocardium
da Silva, R; Lucchinetti, E; Pasch, T; Schaub, MC; Zaugg, M
Physiological Genomics, 20(1): 117-130.
10.1152/physiolgenomics.00166.2004
CrossRef
Canadian Journal of Physiology and Pharmacology
Application of high-dose propofol during ischemia improves postischemic function of rat hearts: effects on tissue antioxidant capacity
Xia, ZY; Godin, DV; Ansley, DM
Canadian Journal of Physiology and Pharmacology, 82(): 919-926.
10.1139/Y04-097
CrossRef
Anesthesia and Analgesia
Myocardial protection by isoflurane preconditioning preserves Ca2+ cycling proteins independent of sarcolernmal and mitochondrial K-ATP channels
An, J; Bosnjak, ZJ; Jiang, MT
Anesthesia and Analgesia, 105(5): 1207-1213.
10.1213/01.ane.0000281053.13929.d0
CrossRef
Journal of Anesthesia
Volatile anesthetic-induced cardiac preconditioning
Stadnicka, A; Marinovic, J; Dubkovic, M; Bienengraeber, MW; Bosnjak, ZJ
Journal of Anesthesia, 21(2): 212-219.
10.1007/s00540-006-0486-6
CrossRef
Cardiovascular Research
Genomics in cardiac metabolism
Samuel, JL; Schaub, MC; Zaugg, M; Mamas, M; Dunn, WB; Swynghedauw, B
Cardiovascular Research, 79(2): 218-227.
10.1093/cvr/cvn061
CrossRef
Yonago Acta Medica
Cardiac Preconditioning by Anesthetic Agents: Roles of Volatile Anesthetics and Opioids in Cardioprotection
Inagaki, Y
Yonago Acta Medica, 50(3): 45-55.

Cardiovascular Research
Propofol enhances ischemic tolerance of middle-aged rat hearts: effects on 15-F-2t-isoprostane formation and tissue antioxidant capacity
Xia, ZY; Godin, DV; Ansley, DM
Cardiovascular Research, 59(1): 113-121.
10.1016/S0008-6363(03)00351-1
CrossRef
American Journal of Physiology-Heart and Circulatory Physiology
Cardiac pharmacological preconditioning with volatile anesthetics: from bench to bedside?
Riess, ML; Stowe, DF; Warltier, DC
American Journal of Physiology-Heart and Circulatory Physiology, 286(5): H1603-H1607.
10.1152/ajpheart.00963.2003
CrossRef
Anesthesia and Analgesia
Hepatic energy metabolism and the differential protective effects of sevoflurane and isoflurane anesthesia in a rat hepatic ischemia-reperfusion injury model
Bedirli, N; Ofluoglu, E; Kerem, M; Utebey, G; Alper, M; Yilmazer, D; Bedirli, A; Ozlu, O; Pasaoglu, H
Anesthesia and Analgesia, 106(3): 830-837.
10.1213/ane.0b013e3181616fc9
CrossRef
Anesthesia and Analgesia
Anesthetic preconditioning: The role of free radicals in sevoflurane-induced attenuation of mitochondrial electron transport in guinea pig isolated hearts
Riess, ML; Kevin, LG; McCormick, J; Jiang, MT; Rhodes, SS; Stowe, DF
Anesthesia and Analgesia, 100(1): 46-53.
10.1213/01.ANE.0000139346.76784.72
CrossRef
British Journal of Anaesthesia
Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning
Lucchinetti, E; da Silva, R; Pasch, T; Schaub, MC; Zaugg, M
British Journal of Anaesthesia, 95(2): 140-152.
10.1093/bja/aei155
CrossRef
Brain Research
Isoflurane preconditioning decreases glutamate receptor overactivation-induced Purkinje neuronal injury in rat cerebellar slices
Zheng, SQ; Zuo, ZY
Brain Research, 1054(2): 143-151.
10.1016/j.brainres.2005.06.064
CrossRef
Anesthesia and Analgesia
Inhibition of mitochondrial permeability transition enhances isoflurane-induced cardioprotection during early reperfusion: The role of mitochondrial K-ATP channels
Krolikowski, JG; Bienengraeber, M; Weihrauch, D; Warltier, DC; Kersten, JR; Pagel, PS
Anesthesia and Analgesia, 101(6): 1590-1596.
10.1213/01.ANE.0000181288.13549.28
CrossRef
British Journal of Pharmacology
A key role for the subunit SUR2B in the preferential activation of vascular K-ATP channels by isoflurane
Fujita, H; Ogura, T; Tamagawa, M; Uemura, H; Sato, T; Ishida, A; Imamaki, M; Kimura, F; Miyazaki, M; Nakaya, H
British Journal of Pharmacology, 149(5): 573-580.
10.1038/sj.bjp.0706891
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Effects of sevoflurane on biomechanical markers of hepatic and renal dysfunction after coronary artery surgery
Lorsomradee, S; Cromheecke, S; Lorsomradee, S; De Hert, SG
Journal of Cardiothoracic and Vascular Anesthesia, 20(5): 684-690.
10.1053/j.jvca.2006.02.035
CrossRef
Renal Failure
Glibenclamide effects on renal function and histology after acute hemorrhage in rats under sevoflurane anesthesia
Diego, LAD; Marques, CD; Vianna, PTG; Viero, RM; Braz, JRC; Castiglia, YMM
Renal Failure, 29(8): 1039-1045.
10.1080/08860220701641835
CrossRef
Anesthesia and Analgesia
The mechanism of helium-induced preconditioning: A direct role for nitric oxide in rabbits
Pagel, PS; Krolikowski, JG; Pratt, PF; Shim, YH; Amour, J; Warltier, DC; Weihrauch, D
Anesthesia and Analgesia, 107(3): 762-768.
10.1213/ane.0b013e3181815995
CrossRef
Cardiovascular Research
Phosphoproteome analysis of isoflurane-protected heart mitochondria: phosphorylation of adenine nucleotide translocator-1 on Tyr(194) regulates mitochondrial function
Feng, JH; Zhu, M; Schaub, MC; Gehrig, P; Roschitzki, B; Lucchinetti, E; Zaugg, M
Cardiovascular Research, 80(1): 20-29.
10.1093/cvr/cvn161
CrossRef
Acta Anaesthesiologica Scandinavica
Effects of volatile anesthetics on cardiac ion channels
Huneke, R; Fassl, J; Rossaint, R; Luckhoff, A
Acta Anaesthesiologica Scandinavica, 48(5): 547-561.
10.1111/j.1399-6576.2004.00391.x
CrossRef
Anesthesia and Analgesia
Molecular evidence of late preconditioning after sevoflurane inhalation in healthy volunteers
Lucchinetti, E; Aguirre, J; Feng, J; Zhu, M; Suter, M; Spahn, DR; Harter, L; Zaugg, M
Anesthesia and Analgesia, 105(3): 629-640.
10.1213/01.ane.0000278159.88636.aa
CrossRef
Anesthesia and Analgesia
Stem Cell-Like Human Endothelial Progenitors Show Enhanced Colony-Forming Capacity After Brief Sevoflurane Exposure: Preconditioning of Angiogenic Cells by Volatile Anesthetics
Lucchinetti, E; Zeisberger, SM; Baruscotti, I; Wacker, J; Feng, JH; Zaugg, K; Dubey, R; Zisch, AH; Zaugg, M
Anesthesia and Analgesia, 109(4): 1117-1126.
10.1213/ANE.0b013e3181b5a277
CrossRef
Anesthesia and Analgesia
Lidocaine attenuates cytokine-induced cell injury in endothelial and vascular smooth muscle cells
de Klaver, MJM; Buckingham, MG; Rich, GF
Anesthesia and Analgesia, 97(2): 465-470.
10.1213/01.ANE.0000073162.27208.E9
CrossRef
Anesthesia and Analgesia
Intracellular mechanism of mitochondrial adenosine triphosphate-sensitive potassium channel activation with isoflurane
Nakae, Y; Kohro, S; Hogan, QH; Bosnjak, ZJ
Anesthesia and Analgesia, 97(4): 1025-1032.
10.1213/01.ANE.0000077072.67502.CC
CrossRef
British Journal of Anaesthesia
Editorial II - Anaesthesia for off-pump coronary artery surgery
Kelleher, A; Gothard, J
British Journal of Anaesthesia, 92(3): 324-U1.
10.1093/bja/aeh058
CrossRef
Anesthesia and Analgesia
Protein kinase C inhibitors produce mitochondrial flavoprotein oxidation in cardiac myocytes
Kohro, S; Hogan, QH; Warltier, DC; Bosnjak, ZJ
Anesthesia and Analgesia, 99(5): 1316-1322.
10.1213/01.ANE.0000135636.45389.E6
CrossRef
Journal of Experimental Biology
Cardioprotective effects of K-ATP channel activation during hypoxia in goldfish Carassius auratus
Chen, J; Zhu, JX; Wilson, I; Cameron, JS
Journal of Experimental Biology, 208(): 2765-2772.
10.1242/jeb.01704
CrossRef
British Journal of Anaesthesia
Cardioprotective effects of desflurane: effect of timing and duration of administration in rat myocardium
Haelewyn, B; Zhu, L; Hanouz, JL; Persehaye, E; Roussel, S; Ducouret, P; Gerard, JL
British Journal of Anaesthesia, 92(4): 552-557.
10.1093/bja/aeh100
CrossRef
Anesthesia and Analgesia
Cardioprotective properties of sevoflurane in patients undergoing aortic valve replacement with cardiopulmonary bypass
Cromheecke, S; Pepermans, V; Hendrickx, E; Lorsomradee, S; ten Broecke, PW; Stockman, BA; Rodrigus, IE; De Hert, SG
Anesthesia and Analgesia, 103(2): 289-296.
10.1213/01.ane.0000226097.22384.f4
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
The effects of volatile anesthetics on cardiac ischemic complications and mortality in CABG: a meta-analysis
Yu, CH; Beattie, WS
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 53(9): 906-918.

Anesthesia and Analgesia
Anesthetic preconditioning combined with postconditioning offers no additional benefit over preconditioning or postconditioning alone
Deyhimy, DI; Fleming, NW; Brodkin, IG; Liu, H
Anesthesia and Analgesia, 105(2): 316-324.
10.1213/01.ane.0000267524.71445.e7
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
The influence of propofol versus sevoflurane anesthesia on outcome in 10,535 cardiac surgical procedures
Jakobsen, CJ; Berg, H; Hindsholm, KB; Faddy, N; Sloth, E
Journal of Cardiothoracic and Vascular Anesthesia, 21(5): 664-671.
10.1053/j.jvca.2007.03.002
CrossRef
Anesthesia and Analgesia
Differential increase of mitochondrial matrix volume by sevoflurane in isolated cardiac mitochondria
Riess, ML; Costa, AD; Carlson, R; Garlid, KD; Heinen, A; Stowe, DF
Anesthesia and Analgesia, 106(4): 1049-1055.
10.1213/ane.0b013e318167875e
CrossRef
Cardiovascular Research
Infarct-remodelled hearts with limited oxidative capacity boost fatty acid oxidation after conditioning against ischaemia/reperfusion injury
Lou, PH; Zhang, LY; Lucchinetti, E; Heck, M; Affolter, A; Gandhi, M; Kienesberger, PC; Hersberger, M; Clanachan, AS; Zaugg, M
Cardiovascular Research, 97(2): 251-261.
10.1093/cvr/cvs323
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Sevoflurane Confers Additive Cardioprotection to Ethanol Preconditioning Associated With Enhanced Phosphorylation of Glycogen Synthase Kinase-3 beta and Inhibition of Mitochondrial Permeability Transition Pore Opening
Onishi, A; Miyamae, M; Inoue, H; Kaneda, K; Okusa, C; Inamura, Y; Shiomi, M; Koshinuma, S; Momota, Y; Figueredo, VM
Journal of Cardiothoracic and Vascular Anesthesia, 27(5): 916-924.
10.1053/j.jvca.2012.10.002
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Myocardial Protection by Volatile Anesthetics in Patients Undergoing Cardiac Surgery: A Critical Review of the Laboratory and Clinical Evidence
Pagel, PS
Journal of Cardiothoracic and Vascular Anesthesia, 27(5): 972-982.
10.1053/j.jvca.2012.10.011
CrossRef
Journal of Physiological Sciences
Emulsified isoflurane postconditioning produces cardioprotection against myocardial ischemia-reperfusion injury in rats
Hu, ZY; Abbott, GW; Fang, YD; Huang, YS; Liu, J
Journal of Physiological Sciences, 63(4): 251-261.
10.1007/s12576-013-0261-z
CrossRef
Turk Gogus Kalp Damar Cerrahisi Dergisi-Turkish Journal of Thoracic and Cardiovascular Surgery
A comparison of preconditioning effects of propofol and desflurane on myocardial protection in cardiac surgery
Koksal, C; Kudsioglu, T; Yapici, N; Altuntas, Y; Tuncel, Z; Aykac, Z
Turk Gogus Kalp Damar Cerrahisi Dergisi-Turkish Journal of Thoracic and Cardiovascular Surgery, 21(2): 371-377.
10.5606/tgkdc.dergisi.2013.7744
CrossRef
Anesthesiology
Differential Activation of Mitogen-activated Protein Kinases in Ischemic and Anesthetic Preconditioning
da Silva, R; Grampp, T; Pasch, T; Schaub, MC; Zaugg, M
Anesthesiology, 100(1): 59-69.

PDF (1520)
Anesthesiology
Hypothermic Preconditioning Increases Survival of Purkinje Neurons in Rat Cerebellar Slices after an In Vitro Simulated Ischemia
Yuan, H; Huang, Y; Zheng, S; Zuo, Z
Anesthesiology, 100(2): 331-337.

PDF (387)
Anesthesiology
Sevoflurane Inhalation at Sedative Concentrations Provides Endothelial Protection against Ischemia–Reperfusion Injury in Humans
Lucchinetti, E; Ambrosio, S; Aguirre, J; Herrmann, P; Härter, L; Keel, M; Meier, T; Zaugg, M
Anesthesiology, 106(2): 262-268.

PDF (834)
Anesthesiology
Morphine Enhances Pharmacological Preconditioning by Isoflurane: Role of Mitochondrial KATP Channels and Opioid Receptors
Ludwig, LM; Patel, HH; Gross, GJ; Kersten, JR; Pagel, PS; Warltier, DC
Anesthesiology, 98(3): 705-711.

PDF (634)
Anesthesiology
Attenuation of Mitochondrial Respiration by Sevoflurane in Isolated Cardiac Mitochondria Is Mediated in Part by Reactive Oxygen Species
Riess, ML; Eells, JT; Kevin, LG; Camara, AK; Henry, MM; Stowe, DF
Anesthesiology, 100(3): 498-505.

PDF (1111)
Anesthesiology
Adenosine and a Nitric Oxide Donor Enhances Cardioprotection by Preconditioning with Isoflurane through Mitochondrial Adenosine Triphosphate-sensitive K+ Channel-dependent and -independent Mechanisms
Wakeno-Takahashi, M; Otani, H; Nakao, S; Uchiyama, Y; Imamura, H; Shingu, K
Anesthesiology, 100(3): 515-524.

PDF (696)
Anesthesiology
Protein Kinase C Translocation and Src Protein Tyrosine Kinase Activation Mediate Isoflurane-induced Preconditioning In Vivo: Potential Downstream Targets of Mitochondrial Adenosine Triphosphate–sensitive Potassium Channels and Reactive Oxygen Species
Ludwig, LM; Weihrauch, D; Kersten, JR; Pagel, PS; Warltier, DC
Anesthesiology, 100(3): 532-539.

PDF (547)
Anesthesiology
Role of Tyrosine Kinase in Desflurane-induced Preconditioning
Ebel, D; Müllenheim, J; Südkamp, H; Bohlen, T; Ferrari, J; Huhn, R; Preckel, B; Schlack, W
Anesthesiology, 100(3): 555-561.

PDF (762)
Anesthesiology
Contribution of Reactive Oxygen Species to Isoflurane-induced Sensitization of Cardiac Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channel to Pinacidil
An, J; Stadnicka, A; Kwok, W; Bosnjak, ZJ
Anesthesiology, 100(3): 575-580.

PDF (248)
Anesthesiology
Reduced Efficacy of Volatile Anesthetic Preconditioning with Advanced Age in Isolated Rat Myocardium
Sniecinski, R; Liu, H
Anesthesiology, 100(3): 589-597.

PDF (430)
Anesthesiology
Mechanisms of Cardioprotection by Volatile Anesthetics
Tanaka, K; Ludwig, LM; Kersten, JR; Pagel, PS; Warltier, DC
Anesthesiology, 100(3): 707-721.

PDF (709)
Anesthesiology
Isoflurane Produces Sustained Cardiac Protection after Ischemia–Reperfusion Injury in Mice
Tsutsumi, YM; Patel, HH; Lai, NC; Takahashi, T; Head, BP; Roth, DM
Anesthesiology, 104(3): 495-502.

PDF (622)
Anesthesiology
Impact of In Vivo Preconditioning by Isoflurane on Adenosine Triphosphate–sensitive Potassium Channels in the Rat Heart: Lasting Modulation of Nucleotide Sensitivity during Early Memory Period
Stadnicka, A; Marinovic, J; Bienengraeber, M; Bosnjak, ZJ
Anesthesiology, 104(3): 503-510.

PDF (751)
Anesthesiology
Gene Regulatory Control of Myocardial Energy Metabolism Predicts Postoperative Cardiac Function in Patients Undergoing Off-pump Coronary Artery Bypass Graft Surgery: Inhalational versus Intravenous Anesthetics
Feng, J; Zhu, M; Furrer, L; Schaub, MC; Tavakoli, R; Genoni, M; Zollinger, A; Zaugg, M; Lucchinetti, E; Hofer, C; Bestmann, L; Hersberger, M
Anesthesiology, 106(3): 444-457.

PDF (1782)
Anesthesiology
Age-related Attenuation of Isoflurane Preconditioning in Human Atrial Cardiomyocytes: Roles for Mitochondrial Respiration and Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channel Activity
Mio, Y; Bienengraeber, MW; Marinovic, J; Gutterman, DD; Rakic, M; Bosnjak, ZJ; Stadnicka, A
Anesthesiology, 108(4): 612-620.
10.1097/ALN.0b013e318167af2d
PDF (517) | CrossRef
Anesthesiology
Infarct-remodeled Myocardium Is Receptive to Protection by Isoflurane Postconditioning: Role of Protein Kinase B/Akt Signaling
Arras, M; Pasch, T; Perriard, J; Schaub, MC; Zaugg, M; Feng, J; Fischer, G; Lucchinetti, E; Zhu, M; Bestmann, L; Jegger, D
Anesthesiology, 104(5): 1004-1014.

PDF (1076)
Anesthesiology
Preconditioning by Sevoflurane Decreases Biochemical Markers for Myocardial and Renal Dysfunction in Coronary Artery Bypass Graft Surgery: A Double-blinded, Placebo-controlled, Multicenter Study
Chassot, P; Schmid, ER; Turina, MI; von Segesser, LK; Pasch, T; Spahn, DR; Zaugg, M; Julier, K; da Silva, R; Garcia, C; Bestmann, L; Frascarolo, P; Zollinger, A
Anesthesiology, 98(6): 1315-1327.

PDF (1710)
Anesthesiology
Anesthetic Preconditioning: Serendipity and Science
Warltier, DC; Kersten, JR; Pagel, PS; Gross, GJ; Todd, MM
Anesthesiology, 97(1): 1-3.

Anesthesiology
Differential Effects of Anesthetics on Mitochondrial KATP Channel Activity and Cardiomyocyte Protection
Zaugg, M; Lucchinetti, E; Spahn, DR; Pasch, T; Garcia, C; Schaub, MC
Anesthesiology, 97(1): 15-23.

PDF (1095)
Anesthesiology
Mechanisms of Sevoflurane-induced Myocardial Preconditioning in Isolated Human Right Atria In Vitro
Yvon, A; Hanouz, J; Haelewyn, B; Terrien, X; Massetti, M; Babatasi, G; Khayat, A; Ducouret, P; Bricard, H; Gérard, J
Anesthesiology, 99(1): 27-33.

PDF (889)
Anesthesiology
Translocation of Protein Kinase C Isoforms to Subcellular Targets in Ischemic and Anesthetic Preconditioning
Uecker, M; da Silva, R; Grampp, T; Pasch, T; Schaub, MC; Zaugg, M
Anesthesiology, 99(1): 138-147.

PDF (2833)
Anesthesiology
Role of Endothelial Nitric Oxide Synthase as a Trigger and Mediator of Isoflurane-induced Delayed Preconditioning in Rabbit Myocardium
Chiari, PC; Bienengraeber, MW; Weihrauch, D; Krolikowski, JG; Kersten, JR; Warltier, DC; Pagel, PS
Anesthesiology, 103(1): 74-83.

PDF (1362)
Anesthesiology
Distinct Roles for Sarcolemmal and Mitochondrial Adenosine Triphosphate-sensitive Potassium Channels in Isoflurane-induced Protection against Oxidative Stress
Marinovic, J; Bosnjak, ZJ; Stadnicka, A
Anesthesiology, 105(1): 98-104.

PDF (593)
Anesthesiology
Effects of Propofol, Desflurane, and Sevoflurane on Recovery of Myocardial Function after Coronary Surgery in Elderly High-risk Patients
De Hert, SG; Cromheecke, S; ten Broecke, PW; Mertens, E; De Blier, IG; Stockman, BA; Rodrigus, IE; Van der Linden, PJ
Anesthesiology, 99(2): 314-323.

PDF (409)
Anesthesiology
Anesthetic Preconditioning: Effects on Latency to Ischemic Injury in Isolated Hearts
Kevin, LG; Katz, P; Camara, AK; Novalija, E; Riess, ML; Stowe, DF
Anesthesiology, 99(2): 385-391.

PDF (383)
Anesthesiology
Reactive Oxygen Species Precede the ε Isoform of Protein Kinase C in the Anesthetic Preconditioning Signaling Cascade
Novalija, E; Kevin, LG; Camara, AK; Bosnjak, ZJ; Kampine, JP; Stowe, DF
Anesthesiology, 99(2): 421-428.

PDF (320)
Anesthesiology
Cardioprotective Properties of Sevoflurane in Patients Undergoing Coronary Surgery with Cardiopulmonary Bypass Are Related to the Modalities of Its Administration
De Hert, SG; Van der Linden, PJ; Cromheecke, S; Meeus, R; Nelis, A; Van Reeth, V; ten Broecke, PW; De Blier, IG; Stockman, BA; Rodrigus, IE
Anesthesiology, 101(2): 299-310.

PDF (610)
Anesthesiology
Protein Kinase C-ε Primes the Cardiac Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channel to Modulation by Isoflurane
Kwok, W; Aizawa, K; Turner, LA; Weihrauch, D; Bosnjak, ZJ
Anesthesiology, 101(2): 381-389.

PDF (1144)
Anesthesiology
Anesthetic-induced Preconditioning Delays Opening of Mitochondrial Permeability Transition Pore via Protein Kinase C-&epsiv;–mediated Pathway
Pravdic, D; Sedlic, F; Mio, Y; Vladic, N; Bienengraeber, M; Bosnjak, ZJ
Anesthesiology, 111(2): 267-274.
10.1097/ALN.0b013e3181a91957
PDF (1145) | CrossRef
Anesthesiology
Sevoflurane Confers Additional Cardioprotection after Ischemic Late Preconditioning in Rabbits
Müllenheim, J; Ebel, D; Bauer, M; Otto, F; Heinen, A; Frässdorf, J; Preckel, B; Schlack, W
Anesthesiology, 99(3): 624-631.

PDF (780)
Anesthesiology
Role of the β1-Adrenergic Pathway in Anesthetic and Ischemic Preconditioning against Myocardial Infarction in the Rabbit Heart In Vivo
Lange, M; Smul, TM; Blomeyer, CA; Redel, A; Klotz, K; Roewer, N; Kehl, F
Anesthesiology, 105(3): 503-510.

PDF (577)
Anesthesiology
Sevoflurane Provides Greater Protection of the Myocardium than Propofol in Patients Undergoing Off-pump Coronary Artery Bypass Surgery
Conzen, PF; Fischer, S; Detter, C; Peter, K
Anesthesiology, 99(4): 826-833.

PDF (285)
Anesthesiology
Intravenous Emulsified Halogenated Anesthetics Produce Acute and Delayed Preconditioning against Myocardial Infarction in Rabbits
Warltier, DC; Chiari, PC; Pagel, PS; Tanaka, K; Krolikowski, JG; Ludwig, LM; Trillo, RA; Puri, N; Kersten, JR
Anesthesiology, 101(5): 1160-1166.

PDF (372)
Anesthesiology
Isoflurane Postconditioning Prevents Opening of the Mitochondrial Permeability Transition Pore through Inhibition of Glycogen Synthase Kinase 3β
Feng, J; Lucchinetti, E; Ahuja, P; Pasch, T; Perriard, J; Zaugg, M
Anesthesiology, 103(5): 987-995.

PDF (13498)
Anesthesiology
Xenon and Sevoflurane Protect against Brain Injury in a Neonatal Asphyxia Model
Luo, Y; Ma, D; Ieong, E; Sanders, RD; Yu, B; Hossain, M; Maze, M
Anesthesiology, 109(5): 782-789.
10.1097/ALN.0b013e3181895f88
PDF (818) | CrossRef
Anesthesiology
Differential Protective Effects of Volatile Anesthetics against Renal Ischemia–Reperfusion Injury In Vivo
Lee, HT; Ota-Setlik, A; Fu, Y; Nasr, SH; Emala, CW
Anesthesiology, 101(6): 1313-1324.

PDF (1641)
Anesthesiology
Desflurane Preconditioning Induces Time-dependent Activation of Protein Kinase C Epsilon and Extracellular Signal-regulated Kinase 1 and 2 in the Rat Heart In Vivo
Toma, O; Weber, NC; Wolter, JI; Obal, D; Preckel, B; Schlack, W
Anesthesiology, 101(6): 1372-1380.

PDF (1280)
Journal of Cardiovascular Pharmacology
KATP Channel Openers Have Opposite Effects on Mitochondrial Respiration Under Different Energetic Conditions
Riess, ML; Camara, AK; Heinen, A; Eells, JT; Henry, MM; Stowe, DF
Journal of Cardiovascular Pharmacology, 51(5): 483-491.
10.1097/FJC.0b013e31816bf4a4
PDF (231) | CrossRef
Current Opinion in Anesthesiology
Molecular biology in cardiovascular anaesthesia
Weber, NC; Schlack, W; Preckel, B
Current Opinion in Anesthesiology, 21(1): 71-77.
10.1097/ACO.0b013e3282f3578f
PDF (180) | CrossRef
European Journal of Anaesthesiology (EJA)
The rationale for perioperative brain protection
Hans, P; Bonhomme, V
European Journal of Anaesthesiology (EJA), 21(1): 1-5.

PDF (702)
European Journal of Anaesthesiology (EJA)
Cardiac risk reduction in non‐cardiac surgery: the role of anaesthesia and monitoring techniques
Gal, J; Bogar, L; Acsady, G; Kertai, MD
European Journal of Anaesthesiology (EJA), 23(8): 641&hyhen;648.
10.1017/S0265021506000640
PDF (89) | CrossRef
European Journal of Anaesthesiology (EJA)
The effect of anaesthetics on the myocardium ‐ new insights into myocardial protection
Weber, NC; Preckel, B; Schlack, W
European Journal of Anaesthesiology (EJA), 22(9): 647-657.
10.1017/S0265021505001080
PDF (207) | CrossRef
European Journal of Anaesthesiology (EJA)
Sevoflurane preconditioning reverses impairment of hippocampal long-term potentiation induced by myocardial ischaemia–reperfusion injury
Zhu, J; Jiang, X; Shi, E; Ma, H; Wang, J
European Journal of Anaesthesiology (EJA), 26(11): 961-968.
10.1097/EJA.0b013e328330e968
PDF (447) | CrossRef
Journal of Neurosurgical Anesthesiology
The Effect of Isoflurane and Sevoflurane on Cerebrocortical Presynaptic Ca2+ and Protein Kinase C Activity
Moe, MC; Berg-Johnsen, J; Larsen, GA; Kampenhaug, EB; Vinje, ML
Journal of Neurosurgical Anesthesiology, 15(3): 209-214.

PDF (407)
Shock
Isoflurane Improves Survival and Protects Against Renal and Hepatic Injury in Murine Septic Peritonitis
Lee, HT; Emala, CW; Joo, JD; Kim, M
Shock, 27(4): 373-379.
10.1097/01.shk.0000248595.17130.24
PDF (244) | CrossRef
Transplantation
Sildenafil Citrate Augments Myocardial Protection in Heart Transplantation
Botha, P; MacGowan, GA; Dark, JH
Transplantation, 89(2): 169-177.
10.1097/TP.0b013e3181c42b22
PDF (1448) | CrossRef
Back to Top | Article Outline

© 2002 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Images

Share