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Anesth Analg 2008; 106:384-391
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318160650f
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CARDIOVASCULAR ANESTHESIOLOGY

Activation of Mitochondrial Large-Conductance Calcium-Activated K+ Channels via Protein Kinase A Mediates Desflurane-Induced Preconditioning

Andreas Redel, MD, Markus Lange, MD, Virginija Jazbutyte, MSc, Christopher Lotz, MD, Thorsten M. Smul, MD, Norbert Roewer, MD, PhD, and Franz Kehl, MD, PhD, DEAA

From the Department of Anesthesiology, University of Würzburg, Bayerische Julius-Maximilians-Universität, Würzburg, Germany.

Address correspondence and reprint requests to Franz Kehl, MD, PhD, DEAA, Universität Würzburg, Klinik und Poliklinik für Anästhesiologie, Zentrum Operative Medizin, Oberdürrbacher Str. 6, 97080 Würzburg, Germany. Address e-mail to franz.kehl{at}mail.uni-wuerzburg.de.

Abstract

BACKGROUND: ATP-regulated K+ channels are involved in anesthetic-induced preconditioning (APC). The role of other K+ channels in APC is unclear. We tested the hypothesis that APC is mediated by large-conductance calcium-activated K+ channels (KCa).

METHODS: Pentobarbital-anesthetized male C57BL/6 mice were subjected to 45 min of coronary artery occlusion and 3 h reperfusion. Thirty minutes before coronary artery occlusion, 1.0 MAC desflurane was administered for 15 min alone or in combination with the large-conductance KCa channel activator NS1619 (1 µg/g i.p.), its respective vehicle dimethylsulfoxide (10 µL/g i.p.), the large-conductance KCa channel blocker iberiotoxin (0.05 µg/g i.p.), or the protein kinase A (PKA) inhibitor H-89 (0.5 µg/g intraventricular). Infarct size was determined with triphenyltetrazolium chloride and area at risk with Evans blue. Mitochondrial and sarcolemmal localization of large-conductance KCa channels in cardiac myocytes was investigated with immunocytochemical staining of isolated cardiac myocytes.

RESULTS: Desflurane significantly reduced infarct size compared with control animals (7.4% ± 0.8% vs 51.3% ± 6.1%; P < 0.05). Activation of large-conductance KCa channels by NS1619 (7.5% ± 1.8%; P < 0.05) mimicked and blockade of large-conductance KCa channels by iberiotoxin (49.1% ± 7.5%) abrogated desflurane-induced preconditioning. PKA blockade by H-89 abolished desflurane-induced (45.1% ± 4.0%) but not NS1619-induced (9.0% ± 2.4%, P < 0.05) preconditioning. Immunocytochemical staining revealed that large-conductance KCa channels were localized in the mitochondria but not in the sarcolemma of cardiac myocytes.

CONCLUSION: These data suggest that desflurane-induced APC is mediated in part by activation of mitochondrial large-conductance KCa channels, and that activation of these channels by desflurane is mediated by PKA.

Volatile anesthetics possess remarkable cardioprotective properties and confer anesthetic-induced preconditioning (APC) against myocardial infarction.1,2 Various triggers and mediators of APC have been identified including, but not limited to, phosphatdylinositol 3-kinase/protein kinase B,3 extracellular signal regulated kinase 1/2,4 protein kinase A (PKA),5 protein kinase C,6,7 reactive oxygen species (ROS),8 nitric oxide,9 and β-adrenergic receptors.5

Several studies suggest a crucial role of ATP sensitive potassium (KATP) channels for both ischemic preconditioning (IPC)10,11 and APC.12 Apart from KATP channels, other K+ channels might contribute as mediators of preconditioning against ischemia/reperfusion injury. One candidate channel is the large-conductance calcium-activated K+ channel (KCa).13 This channel has been reported to mediate angiotensin converting enzyme-inhibitor-,14 and tumor necrosis factor {alpha}-15 induced cardioprotection as well as IPC.16–18

In smooth muscle cells (SMC), large-conductance KCa channels are located in the sarcolemma and are activated by volatile anesthetics.19,20 PKA activates large-conductance KCa channels21–23 and is itself activated by volatile anesthetics in platelets24 and in endothelial SMC.25 It is unknown whether large-conductance KCa channels are expressed in sarcolemmal or mitochondrial membranes or both in cardiac myocytes.

We tested the hypothesis that activation of mitochondrial large-conductance KCa channels via PKA is necessary for desflurane-induced myocardial preconditioning.

METHODS

Animals
Male C57BL/6 mice (8–12 wk) were used for all experiments (Charles River Laboratories, Sulzfeld, Germany). Animals were housed under controlled conditions (22°C, 55%–65% humidity and 12-h light– dark cycle) and were allowed free access to tap water and a standard laboratory chow.

All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Government of Lower Franconia, Bavaria, Germany. All experiments conformed to the Guiding Principles in the Care and Use of Animals of the American Physiological Society and were in accordance with the Guide for the Care and Use of Laboratory Animals.26

Instrumentation and Surgical Procedure
Mice were anesthetized with an i.p. injection of 60 µg/g sodium pentobarbital (Merial, Hallbergmoos, Germany), and repeated i.p. injections of 15 µg/g were given as needed. Rectal temperature was maintained at 37.0°C ± 0.2°C using a servo-controlled heating pad (FMI, Seeheim, Germany). After endotracheal intubation, the lungs were ventilated with 50% air/50% oxygen using a rodent ventilator (SAR 830/AP, CWE Inc., Ardmore, PA) operated in pressure-controlled mode. A 3-lead needle-probe electrocardiogram (ECG) was attached to continuously monitor heart rate and ST-segment elevation. For measurement of arterial blood pressure and fluid management, a saline-filled PE-10 catheter connected to a pressure transducer (Combitrans, B.Braun, Melsungen, Germany) was inserted into the right common carotid artery. Continuous flushing of the arterial catheter with 0.9% normal saline (30 µL · g–1 · h–1 in average) served to further replace fluid loss during the experimental protocol.

Ligature of the left anterior descending coronary artery (LAD) was performed as described previously.27 Briefly, after left thoracotomy at the fourth intercostal space, the LAD was exposed, and a 6-0 silk suture was passed around the LAD. Coronary artery occlusion (CAO) was achieved using the hanging weight system27 and was verified by paleness of the myocardial area at risk (AAR), changes in color of the LAD distal to the ligature from bright red to violet, and ECG ST-segment elevation. Reperfusion was verified by reversion of these same three criteria.

Experimental Protocols
Animals were randomly assigned to groups 1–7 to investigate the role of large-conductance KCa channels in APC. In a second series of experiments, animals were randomly assigned to Group 8–10 to investigate the involvement of PKA in large-conductance KCa channel-mediated APC. Group size was n = 7 in every group. The experimental protocol is illustrated in Figure 1.


Figure 15
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  		Figure 1. Schematic diagram illustrating the experimental protocol. Desflurane (DES) was administered at a dose of 1.0 MAC for 15 min. The vehicle dimethylsulfoxide (DMSO), the selective large-conductance KCa channel agonist NS1619, and the selective large-conductance KCa channel antagonist iberiotoxin (IbTX) were injected i.p. The selective protein kinase antagonist H-89 was administered intraventricularly. Triangles indicate time points of analysis of hemodynamic data as presented in Table 1.

 


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  		Table 1. Systemic Hemodynamics

 

After completion of instrumentation and surgical procedures, all animals were allowed a 15-min equilibration period. Myocardial ischemia was induced by CAO for 45 min, followed by 180 min of reperfusion. In Group 1 (CON), there was no treatment prior to CAO. In Group 2 (APC), 1.0 MAC desflurane (7.5 vol %)28 was administered 30 min prior to CAO for 15 min. Desflurane concentration was increased from 0.0 to 1.0 MAC and decreased from 1.0 to 0.0 MAC gradually over a period of 1 min. In Group 3 (DMSO), the vehicle dimethylsulfoxide (DMSO, 10 µL/g) was injected i.p. 35 min prior to CAO. In Group 4 (NS1619), the selective large-conductance KCa channel agonist29 NS1619 (100 µg dissolved in 1 mL DMSO, 1 µg/g) was injected i.p. 35 min prior to CAO. In Group 5 (IbTX), the selective large-conductance KCa channel antagonist30 Iberiotoxin (5 µg dissolved in 1 mL H2O, 0.05 µg/g) was injected i.p. 35 min prior to CAO. In Group 6 (APC + NS1619), NS1619 (1 µg/g) was injected i.p. 35 min prior to CAO and 1.0 MAC desflurane was administered 30 min prior to CAO for 15 min. In Group 7 (APC + IbTX), ibTX (0.05 µg/g) was injected i.p. 35 min prior to CAO and 1.0 MAC desflurane was administered 30 min prior to CAO for 15 min. In Group 8 (H-89), the PKA antagonist H-89 (0.5 µg/g) was injected into the left ventricle (intraventricular, i.vt.) via a 30-gauge needle 35 min prior to CAO. In Group 9 (APC + H-89), H-89 (0.5 µg/g) was injected i.vt. 35 min prior to CAO and 1.0 MAC desflurane was administered 30 min prior to CAO for 15 min. In Group 10 (H-89 + NS1619), H-89 (0.5 µg/g) and NS1619 (1 µg/g) were injected 35 and 30 min prior to CAO, respectively.

Measurement of Myocardial Infarct Size
Myocardial infarct size (IS) and AAR were determined using methods described previously.31 Briefly, after reperfusion, the LAD was reoccluded and 1 mL Evans Blue (0.1 g/mL; Sigma-Aldrich, Taufkirchen, Germany) was slowly injected into the carotid artery to delineate AAR. After injection of a lethal dose of pentobarbital (150 µg/g i.p.), the heart was rapidly removed. The left ventricle was dissected and cut into eight transverse slices of 1 mm thickness each using an acrylic heart matrix (Aster Industries, McCandles, PA). All slices were incubated with 2% triphenyltetrazolium chloride (Sigma Aldrich, Taufkirchen, Germany), fixed overnight in 10% formalin, weighed, and digitally photographed (Finepix S3 Pro, Fujifilm, Tokyo, Japan). The photographs were then analyzed with picture analysis software (AdobePhotoshop CS 8.0.1; Adobe Systems Inc., San Jose, CA), and IS, AAR, and normal zone were quantified by an investigator blinded to the treatment protocol. The resulting fractions of IS, AAR, and normal zone of each slice were multiplied by the weight of that slice. IS was calculated by the following formula: IS = weight of IS/weight of AAR x 100 (IS = IS/AAR x 100). Animals with an AAR <20% of the left ventricle were excluded from the study.

Immunocytochemistry
Immunocytochemical staining was used to localize large-conductance KCa channels in cardiac myocytes. Primary cultures of rat neonatal cardiac myocytes were established as described elsewhere.32 Briefly, neonatal cardiac myocytes were cultivated for 2–3 days in Lab-Tek Chamber Slides (Nunc, Wiesbaden, Germany), permeabilized with 0.1% Triton X-100 solution, and blocked with normal 5% donkey serum. The neonatal cardiac myocytes were incubated with rabbit polyclonal antibodies against the {alpha}-subunit of the large-conductance KCa channel (APC-021, Alomone labs, Jerusalem, Israel), goat polyclonal antibodies against VDAC2 (sc-32057, Santa Cruz, Heidelberg, Germany), and goat polyclonal antibodies against cadherin (sc-1499, Santa Cruz, Heidelberg, Germany). After incubation with secondary antibodies (Donkey-anti-rabbit-AlexaFluor 594 and donkey-anti-goat-AlexaFluor 488, Molecular probes, Invitrogen, Karlsruhe, Germany), all sections were examined with a confocal microscope (Axiovert 135 TV, Zeiss, Jena, Germany).

Data Acquisition and Statistical Analysis
Hemodynamic variables, ECG, and body temperature were continuously recorded at a sampling rate of 1000 Hz and analyzed on a personal computer (Fujitsu Siemens, Augsburg, Germany) using hemodynamic data acquisition and analysis software (Notocord® hem 3.5, Croissy sur Seine, France).

Power analysis revealed a group size of n = 6 to detect a difference in means of 25% with a power of 0.8 at {alpha}-level of 0.05. Statistical analysis of data within and among groups was performed with one-way and two-way analysis of variance (ANOVA) followed by post hoc Duncan test using Statmost software (Dataxiom Software Inc., Los Angeles, USA). Changes were considered statistically significant if P was <0.05. All data are expressed as mean ± sem.

RESULTS

Seventy-eight mice were assigned to the ischemia-reperfusion experiments. Eight animals were excluded from the study because the AAR was <20% (2 in the control group and 2 in the APC group) or because of pump failure during CAO (2 in the DMSO group, 1 in the APC + NS1619 group, 1 in the IbTX group).

Hemodynamic variables at baseline and AAR were not different among groups (Tables 1 and 2). Heart rate was significantly decreased during the application of desflurane alone or in combination with NS1619 but returned to baseline values prior to CAO. IS/AAR was 51.3% ± 6.1% in the control group (Fig. 2). Myocardial IS was significantly reduced in the desflurane group compared with the control group (7.4% ± 0.8%, P < 0.05).


Figure 25
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  		Figure 2. Myocardial infarct size (IS) expressed as a percentage of the left ventricular area at risk (AAR). Mice received desflurane, dimethylsulfoxide (DMSO), the large-conductance KCa channel agonist NS1619 or the large-conductance KCa channel antagonist iberiotoxin (IbTX) alone or in combination with desflurane, respectively. Values are mean ± sem. n = 7 in each group. APC = anesthetic-induced preconditioning. *Significantly (P < 0.05) different from CONTROL.

 


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  		Table 2. Body Weight and Planimetry

 

The activation of large-conductance KCa channels by NS1619 resulted in a significant decrease of myocardial IS (7.5% ± 1.8%, P < 0.05) compared with the control group (Fig. 2). The combination of NS1619 and desflurane resulted in a significant decrease of IS (5.1% ± 1.0%) compared the control group (P < 0.05) but this decrease was not different than that observed with the administration of either drug alone. Application of the vehicle DMSO (40.2% ± 5.3%) did not influence myocardial IS compared with the control group.

The blockade of large-conductance KCa channels with IbTX did not influence myocardial IS compared with the control group (46.2% ± 5.9%). The administration of desflurane in combination with IbTX resulted in myocardial IS that was not different compared with the control group (49.1% ± 7.5%). Thus, APC induced with desflurane was completely abrogated when large-conductance KCa channels were blocked by IbTX.

The blockade of PKA with H-89 did not influence myocardial IS compared with the control group (44.5% ± 5.9%, Fig. 3). The administration of desflurane in combination with H-89 resulted in myocardial IS that was not different compared with the control group (45.1% ± 4.0%). Thus, APC induced with desflurane was completely abrogated when PKA was blocked. However, activation of large-conductance KCa channels with NS1619 significantly reduced myocardial IS, even in the presence of PKA blockade with H-89 (9.0% ± 2.4%, P < 0.05).


Figure 35
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  		Figure 3. Myocardial infarct size (IS) expressed as a percentage of the left ventricular area at risk (AAR). Mice received desflurane, protein kinase antagonist H-89 alone or in combination with desflurane or with the large-conductance KCa channel agonist NS1619, respectively. Note that data of CONTROL and APC groups are the same as in Figure 2. Values are mean ± sem. n = 7 in each group. APC = anesthetic-induced preconditioning. *Significantly (P < 0.05) different from CON.

 

Rat neonatal cardiac myocytes were immunostained with antibodies against the {alpha}-subunit of the large-conductance KCa channel (Figs. 4a and d), the mitochondrial protein VDAC2 (Fig. 4b), and the sarcolemmal protein cadherin (Fig. 4e). Examination of 10 slices (5 high-power resolution fields per slice) revealed that {alpha}-subunits of large-conductance KCa channels colocalize with VDAC2 (Fig. 4c). In contrast, no colocalization {alpha}-subunits of large-conductance KCa channels with cadherin was detected in rat neonatal cardiac myocytes (Fig. 4f).


Figure 45
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  		Figure 4. Immunocytochemical staining of neonatal cardiac myocytes (NCM). Representative photographs of NCM’s that were immunostained for the {alpha}-subunit of large-conductance KCa channels, the mitochondrial protein VDAC2, and the sarcolemmal protein cadherin. Large-conductance KCa channels (a and d) and VDAC2 (b) are detectable only in the subsarcolemma and appear in a spotted manner. VDAC2 is not detectable at the sarcolemma. Cadherin is distributed continuously along the sarcolemma (e). Merging of the staining of VDAC2 and large-conductance KCa channel {alpha}-subunit reveals co-localization of these proteins (c). In contrast, merging of the staining of cadherin and large-conductance KCa channel {alpha}-subunit demonstrates that large-conductance KCa channels do not co-localize with the sarcolemma of NCM (f).

 

DISCUSSION

Desflurane confers profound protection against myocardial infarction in the murine in vivo model of acute myocardial infarction. IS was reduced by 86% when 1.0 MAC desflurane was administered for 15 min prior to CAO. This remarkable extent of IS reduction by desflurane was also achieved by pharmacological activation of large-conductance KCa channels with NS1619. This cardioprotective effect exceeds IS reduction induced by isoflurane in mice33 and by desflurane in rabbits.5 Different potency of volatile anesthetics to induce preconditioning34 and different durations of preconditioning, ischemia and reperfusion might additionally have contributed to the large IS reduction compared with that described in published studies.

The current study reveals that large-conductance KCa channels are crucial in mediating desflurane-induced myocardial preconditioning. We found that activation of large-conductance KCa channels mimicked desflurane induced APC and that blockade of large-conductance KCa channels completely abolished this myocardial protection. These results confirm the cardioprotective effects of activation of large-conductance KCa channels by NS1619 that have been shown within the paradigm of early and delayed IPC.16–18,35 In line with these findings, blockade of large-conductance KCa channels by IbTX17 and paxilline16 completely abolished IS reduction elicited by IPC.

In SMC, large-conductance KCa channels are located in the cell membrane, but in cardiac myocytes, they are expressed in the mitochondria.13 It is unclear whether in cardiac myocytes large-conductance KCa channels are also located in the sarcolemma and, thus, whether abrogation of APC by IbTX is due to blockade of mitochondrial and/or sarcolemmal large-conductance KCa channels. The immunocytochemical data presented in the current study provide evidence that large-conductance KCa channels are not expressed in the sarcolemma of neonatal rat cardiac myocytes. This is in agreement with the finding that large-conductance KCa currents from the sarcolemma have yet to be recorded. Taken together, these results suggest that the myocardial effects of IbTX or NS1619 might be attributable solely to mitochondrial and not sarcolemmal large-conductance KCa channels in cardiac myocytes. However, one should bear in mind that immunostaining was performed in isolated rat neonatal cardiac myocytes and more likely than not this is probably also true for isolated murine adult cardiac myocytes.

Mechanistically, activation of mitochondrial large-conductance KCa channels leads to K+ influx into the mitochondrial matrix. During preconditioning, pH is increased by net K+ uptake into the mitochondrial matrix, which causes a relative retardation of electron flow and consequent mild increase in ROS production.36 ROS are then available by diffusion to act as second messengers activating kinases as mediators of preconditioning.36 Furthermore, net K+ uptake into the mitochondrial matrix during sustained ischemia increases matrix volume, thus preserving ATP synthesis and preventing mitochondrial permeability transition11,37,38 and leading to mild uncoupling of the electron transport chain that is beneficial by preventing the deleterious burst of ROS at the onset of reperfusion.39

Opening of sarcolemmal and mitochondrial ATP-regulated K+ channels have been reported to play a pivotal role in IPC10,11 and APC.12 Although the role of sarcolemmal KATP channels in preconditioning is commonly accepted, considerable controversy remains regarding potential unspecific effects of mitochondrial KATP channel agonists and antagonists.40 Since large-conductance KCa channels are unaffected by activators or blockers of mitochondrial KATP channels (diazoxide and 5-hydroxydecanoate),21 and since sarcolemmal KCa channels are not expressed in cardiac myocytes, the current study provides evidence for the first time that mitochondrial K+ channels are crucial mediators of APC.

Mitochondrial KCa channels are activated via phosphorylation by PKA,21 and volatile anesthetics activate PKA.24,25 Thus, activation of large-conductance KCa channels by PKA may be, at least in part, responsible for large-conductance KCa channel activation during APC. Indeed, in the current study desflurane-induced preconditioning was completely abrogated when PKA was pharmacologically blocked by H-89. Direct activation of large-conductance KCa channels by NS1619, however, fully mimicked desflurane-induced preconditioning, even in the presence of the PKA blocker H-89. These data suggest that PKA mediates the activation of mitochondrial KCa channels by volatile anesthetics during desflurane-induced myocardial preconditioning and that PKA is upstream of KCa channels.

In a recent study, the mechanism of isoflurane-induced APC was investigated by using Ca2+ uptake into mitochondria as a surrogate marker of ischemic damage.41 Isoflurane diminished mitochondrial Ca2+ uptake as measured using rhod-2 fluorescence. As Ca2+ uptake was unaffected by the large-conductance KCa antagonist paxilline, the authors concluded that mitochondrial large-conductance KCa channels were unlikely to contribute to isoflurane-induced APC. Those conclusions, though, are based on indirect evidence, as K+ currents were not measured. In contrast, the current results obtained in the in vivo preparation strongly support the notion that mitochondrial large-conductance KCa channels participate in the signal transduction pathway of APC.

The results of the present study should be interpreted within the constraints of several potential limitations. Volatile anesthetics might exert cardioprotective effects due to their positive influence on O2 supply/demand ratio. In fact, heart rate was significantly decreased during the application of desflurane alone or in combination with NS1619. However, heart rate returned to baseline values prior to CAO. Thus, this hemodynamic effect of desflurane or NS1619 does not account for the observed effects on myocardial IS. However, O2 consumption was not directly quantified, and therefore reduced O2 demand cannot be totally excluded as contributing to our results. Administration of NS1619 might have increased coronary blood flow during ischemia. We did not directly measure coronary artery blood flow, and cannot exclude that increased myocardial blood supply might have contributed to our findings. However, in a canine in vivo open chest model of myocardial infarction, NS1619 did not increase myocardial collateral blood flow during ischemia.17 Since small rodents are reported to have little if any coronary collateral blood flow,42 it is highly improbable that vasodilatation during CAO might have influenced myocardial IS due to improvement of myocardial O2 supply/demand ratio. Nonspecific effects of the drugs used in the present study might, in part, have contributed to the observed results. Nonetheless, NS1619 and ibTX are the most selective of available KCa channels agonists or antagonists.43 The PKA inhibitor H-89 is considered to be selective to PKA. Since H-89 is reported to inhibit several other protein kinases,44 these additional effects might have contributed to inhibition of desflurane-induced preconditioning by H-89.

In summary, PKA-mediated activation of mitochondrial KCa channels by desflurane contributes to the beneficial effects of desflurane-induced APC. The regulation of mitochondrial homeostasis via mitochondrial KCa channels might be a candidate mechanism for mediating APC.

ACKNOWLEDGMENTS

The authors thank Katerina Pech, BS, and Jenny Muck, BS, for excellent technical assistance.

Footnotes

Accepted for publication October 16, 2007.

Supported, in part, by grant 01 KS9603 from the ministry for education and research of the Federal Republic of Germany and the interdisciplinary centre for clinical research (IZKF) of Würzburg, Germany.

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press