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Anesth Analg 2008; 107:755-761
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31817f0e61
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CARDIOVASCULAR ANESTHESIOLOGY

Section Editor:
Charles W. Houge JrSection Editor Martin J. London Section Editor Jerrold H. Levy

Low-Dose Sevoflurane Inhalation Enhances Late Cardioprotection from the Anti-Ulcer Drug Geranylgeranylacetone

Hiroshi Kitahata, MD*, Junpei Nozaki, MD{dagger}, Shinji Kawahito, MD*, Takehito Tomino, BS*, and Shuzo Oshita, MD*

From the *Department of Anesthesiology, The University of Tokushima Graduate School, Institute of Health Biosciences, Tokushima, Japan; and {dagger}Department of Anesthesiology, Naruto Hospital, Tokushima.

Address correspondence and reprint requests to Hiroshi Kitahata, MD, PhD, The University of Tokushima Graduate School, Institute of Health Biosciences, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Address e-mail to hiroshi{at}clin.med.tokushima-u.ac.jp.

Abstract

BACKGROUND: We investigated in rabbits whether sevoflurane enhances late cardioprotection induced by geranylgeranylacetone (GGA), a gastric antiulcer drug.

METHODS: S(+)-ketamine and xylazine-anesthetized rabbits were assigned to one of seven experimental groups: a control (vehicle only) group, a GGA group, a sevoflurane group, a GGA+sevoflurane group, a sodium 5-hydroxydecanoate (5HD) group, a GGA + 5HD group, and a heat stress group. All rabbits were subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Rabbits were pretreated with IV vehicle, GGA (10 mg/kg), or heat stress (42°C for 15 min) 24 h before coronary occlusion. Sevoflurane (0.5 minimum alveolar concentration) or 5HD (5 mg/kg) were administered before myocardial ischemia. Myocardial infarct size and the area at risk for ischemia were measured, and heat shock protein (Hsp) 70 levels in each experimental group were determined.

RESULTS: Compared with vehicle only, GGA significantly reduced the size of myocardial infarction in relation to the area at risk (39 ± 10% vs 59 ± 9%, P < 0.02). Sevoflurane enhanced the GGA-induced cardioprotection (23 ± 17%, P < 0.05 vs GGA). The cardioprotective effect of GGA was abolished by administration of 5HD (56 ± 15%, P < 0.01). GGA enhanced Hsp 70 expression compared with that in the control group (0.69 ± 0.15 vs 0.36 ± 0.05, P < 0.02). Administration of GGA with sevoflurane resulted in the same level of Hsp 70 expression as GGA (0.69 ± 0.16, P > 0.98).

CONCLUSIONS: GGA appears to reduce myocardial infarct size in association with increased Hsp 70 expression. Sevoflurane enhances the GGA-induced cardioprotective effect.

Various types of physiological stress upregulate the synthesis of a multigene family of proteins called heat shock proteins (Hsps). Hsps act as molecular chaperones that facilitate the folding, assembly, and disassembly of other proteins in addition to other cellular functions, including repair or degradation of denatured proteins.1 Hsps are named according to their molecular size, for example, Hsp 70, Hsp 90, Hsp 40, and Hsp 27. One of the most studied of this class of proteins is Hsp 70. In the heart, sublethal heat stress induces Hsp 70 synthesis.2–4 The resulting increased level of Hsp 70 has been shown to enhance myocardial tolerance to subsequent ischemia-reperfusion injury. In addition, over-expression of Hsp 70 in transgenic mice or in gene-transfected rat hearts improves myocardial function and reduces infarct size after ischemia-reperfusion.5,6 The mechanisms involved in this form of cardioprotection remain unclear. It has been reported that the widely used anti-gastric ulcer drug geranylgeranylacetone (GGA) directly induces Hsp 70 synthesis in cultured gastric mucosal cells.7 Furthermore, oral administration of GGA has been shown in a Langendorff rat heart model to enhance Hsp 70 expression and to improve myocardial function after myocardial ischemia.8

Administration of volatile anesthetics, including sevoflurane, improves myocardial function and reduces myocardial infarct size after ischemia-reperfusion in vitro and in vivo.9–12 Activation of mitochondrial adenosine triphosphate-regulated potassium (KATP) channels, through multiple signaling pathways including protein kinase C (PKC), has been implicated as a pivotal mechanism mediating anesthetic-induced preconditioning.9–12 One investigation showed that sevoflurane confers additive cardioprotective effects to ischemic late preconditioning and that activation of KATP channels plays an important role in this interaction.13 Whether preconditioning from volatile anesthetics modulates late cardioprotection conferred by Hsp has not been described. The purpose of this study was to investigate in rabbits whether GGA induces Hsp70 expression in the heart and whether an increased Hsp70 level provides cardioprotection against myocardial ischemia and reperfusion injury. Furthermore, we sought to evaluate the mechanism of GGA-induced myocardial protection and to test the hypothesis that sevoflurane enhances late cardioprotection by GGA.

METHODS

The study experiments and procedures were approved by the Animal Care Committee of The University of Tokushima and were performed in strict accordance with the guidelines of the Animal Care Committee of The University of Tokushima.

General Preparation
Male Japanese White rabbits (2.2–3.4 kg) were anesthetized with IM xylazine (5 mg/kg) and S(+)-ketamine (50 mg/kg). Before surgical procedures were performed, adequate depth of anesthesia was ensured by the absence of pedal and palpebral reflexes. After tracheostomy, the animal lungs were mechanically ventilated (Model 122, mechanical ventilator, New England Medical Instruments, Medway, MA) with 100% oxygen and a tidal volume and respiratory rate adjusted to maintain end-tidal CO2 in the physiological range as confirmed by arterial blood gas tensions. End-tidal gas concentrations were measured continuously (Capnomac Ultima multigas analyzer, Datex, Helsinki, Finland). A heparin-filled catheter was inserted into the right carotid artery for measurement of arterial blood pressure, and another was inserted into the right jugular vein for fluid or drug administration. Animals underwent continuous infusion of lactated Ringer solution (15 mL · kg–1 · h–1) during the experiment. Anesthesia was maintained by infusion of xylazine (1 mg · kg–1 · h–1) and S(+)-ketamine (3 mg · kg–1 · h–1). Additional boluses of xylazine and S(+)-ketamine were administered when necessary during surgery. Body temperature (38–39°C) was maintained with a heating blanket. The electrocardiogram was continuously monitored in two limb leads. Hemodynamic variables were continuously monitored throughout the experiment and were recorded on a computer interfaced with an analog-to-digital converter (PowerLab, ADInstruments, Bella Vista, Australia).

Left thoracotomy was performed at the fourth intercostal space, and the heart was exposed. A prominent branch of the left circumflex artery was selected, and a 4/0 silk suture was placed around this artery approximately halfway between the base and apex for performing coronary artery occlusion and reperfusion. Each animal received 1000 U of heparin before coronary artery occlusion. Coronary artery occlusion was confirmed by the appearance of regional cyanosis on the epicardium, by regional myocardial dyskinesis in the ischemic area, and by electrocardiographic ST segment elevation. Reperfusion was confirmed by the appearance of epicardial hyperemia.

Experimental Protocol
The experimental protocol is illustrated in Figure 1. Sixty-three Japanese White rabbits were used for this study. Rabbits were randomly assigned to 1 of 7 experimental groups: a control (vehicle only) group (n = 11), a GGA group (n = 10), a sevoflurane group (n = 8), a GGA+sevoflurane group (n = 8), a sodium 5-hydroxydecanoate (5HD) group (n = 8), a GGA + 5HD group (n = 8), and a heat stress group (n = 10). All rabbits underwent each pretreatment 24 h before myocardial ischemia and reperfusion while anesthetized with IM S(+)-ketamine (50 mg/kg). Rabbits in the control group, sevoflurane group, and 5HD group were pretreated IV with drug vehicle 24 h before coronary artery occlusion. In the GGA group, GGA+sevoflurane group, and GGA + 5HD group, GGA was given IV 24 h before coronary artery occlusion. GGA was dissolved with 0.4% lecithin in deionized water mixed to a final concentration of 2 mg/mL. A catheter was inserted into a marginal ear vein, and vehicle (5 mL/kg) or GGA (10 mg/kg) was injected over 15 min. GGA was kindly provided by Eisai Co., Tokyo, Japan. Rabbits in the heat stress group were subjected to heat stress (rectal temperature 42°C for 15 min via heating pads) 24 h before coronary artery occlusion. All rabbits were then allowed to recover for 24 h.


Figure 17
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  		Figure 1. Experimental protocol used in the seven experimental groups. GGA = geranylgeranylacetone; SEV = sevoflurane; 5HD = sodium 5-hydroxydecanoate; MAC = minimum alveolar concentration.

 

After the pretreatment with vehicle or GGA, 0.5 minimum alveolar concentration (MAC) sevoflurane was administered for 30 min and discontinued 30 min before coronary artery occlusion (sevoflurane group and GGA+sevoflurane group). Two groups received mitochondrial KATP channel blocker 5HD (5 mg/kg) 30 min before coronary occlusion (5HD group and GGA + 5HD group). All rabbits were subjected to 30-min coronary artery occlusion followed by 3 h of reperfusion.

Measurement of Infarct Size
Myocardial infarct size was measured as previously described.14 After completion of each experiment, the coronary artery was reoccluded, and 3 mL of 10% Evans Blue dye was injected into the jugular vein. Each rabbit was killed, and the heart was removed. The left ventricle was dissected and cut into 6 transverse slices of equal thickness from the apex to the base (2 mm). The area at risk (AAR) for ischemia and reperfusion injury was determined for each slice on the basis of negative Evans Blue staining. The AAR was separated from normal area, as determined by Evans Blue staining, and was then incubated in 1% 2,3,5-triphenyltetrazolium chloride in isotonic pH 7.4 phosphate buffer at 37°C for 20 min. The slices were fixed in 10% formaldehyde overnight, and the infarcted (pale) tissue was carefully differentiated from viable (red) tissue within the AAR. The slices were dried, and the infarcted and viable tissues within the AAR were weighed. Infarct size was expressed as a percentage of the AAR. Rabbits with an AAR <20% of the left ventricular (LV) weight were excluded from the analyses.

Measurement of Heat Shock Proteins
Expression of Hsp 70 was determined in a subexperiment by means of Western immunoblotting. Twenty-two additional animals were randomly assigned to 1 of 5 experimental groups: a control (vehicle) group (n = 4), a GGA group (n = 5), a sevoflurane group (n = 5), a GGA+sevoflurane group (n = 4), and a heat stress group (n = 4). Rabbits were pretreated as described above for each group, and the hearts were removed without performance of coronary artery occlusion. The left ventricle was then separated and frozen in liquid nitrogen.

The LV tissue was homogenized with two volumes of 100 mM Trice-HCl (pH 7.2) containing 6 M urea, 10 mM ethylene diamine tetraacetic acid, 10 mM ethyleneglycotetraacetic acid, and 0.2 mM phenylmethylsulfonyl sulfate and centrifuged at 15,000 rpm for 20 min at 4°C. The protein concentration of the myocardial tissue was quantified by using the Lowery method (Bio-Rad Laboratories, Richmond, CA, USA). The samples were diluted in dissociation buffer (40% glycerol, 10% sodium dodecyl sulfate, 10% 2-mercaptoethanol, 0.001% bromophenol blue, and 260 mM Tris-HCl at pH 6.8), vortexed, and boiled at 95°C for 3 min. Tissue extracts (20 µg protein per lane) were subjected to electrophoresis on a 7.5% polyacrylamide gel, and separated proteins were transferred to a polyvinylidene difluoride membrane. The gel was stained with Coomassie Brilliant Blue R-250 (Bio-Rad Laboratories) and dried. After nonspecific binding sites were blocked with 4% purified milk casein, the membranes were incubated for 1 h with mouse monoclonal IgG antibody to Hsp 70 (SPA-810, Stressgen Biotechnologies Corp., Victoria, Canada) at 1:600 dilution. After a repeat washing, the membrane was incubated with anti-mouse IgG horseradish peroxidase-linked whole body antibody (Amersham Biosciences, Piscataway, NJ, USA) at 1:20000 dilution for 1 h. The membranes were washed and developed to enhance chemiluminescence (Amersham Biosciences) detection and exposed to radiograph film (Amersham Biosciences). After scanning, the relative levels of Hsp 70 were determined for optical density with the use of an image analysis program (NIH Image for Windows) and were normalized to the actin bands on Coomassie-stained gels.4

Statistical Analysis
Data are expressed as mean ± sd. Differences within and among groups were evaluated by repeated measures analysis of variance followed by the Student-Newman-Keuls test. P values of <0.05 were considered statistically significant.

RESULTS

Two animals were excluded because of fatal ventricular fibrillation that occurred during coronary artery occlusion (control group, n = 1) or at the beginning of reperfusion (heat stress group, n = 1). Six animals were excluded because the AAR weight/LV weight was <20% (control group, n = 1; sevoflurane group, n = 1; GGA group, n = 2; GGA+sevoflurane group, n = 1; and heat stress group, n = 1). Three animals were excluded because of technical problems during surgical preparation (control group, n = 1; GGA + 5HD group, n = 1; and heat stress group, n = 1). One animal in the control group was excluded because its systolic blood pressure was <30 mm Hg. We obtained complete myocardial infarct size data from 51 animals (control group, n = 7; GGA group, n = 8; sevoflurane group, n = 7; GGA+sevoflurane group, n = 7; 5HD group, n = 8; GGA + 5HD group, n = 7; heat stress group, n = 7).

Systemic Hemodynamics
Systemic hemodynamic variables are listed in Table 1. There were no significant differences in baseline variables among experimental groups. Mean arterial blood pressure and the rate-pressure product were reduced by 0.5 MAC sevoflurane inhalation, but these hemodynamic variables returned to baseline values during the 30-min sevoflurane washout period. Thirty minutes of coronary artery occlusion and 3 h of reperfusion led to decreases in heart rate, mean arterial blood pressure, and rate-pressure product in each experimental group.


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  		Table 1. Systemic Hemodynamics

 

Myocardial Infarct Size
Body weight, AAR weight, and the AAR weight/LV weight ratio are presented in Table 2, and no significant differences among groups were observed. Myocardial infarct size data, expressed as percentages of the AAR, are presented in Figure 2. Infarct size was significantly (P < 0.02) smaller in the GGA group (39 ± 10%) than in the control group (59 ± 9%). Sevoflurane (0.5 MAC) alone did not decrease myocardial infarct size compared with that in the control group (sevoflurane group: 58 ± 11%, P > 0.96); however, GGA pretreatment combined with sevoflurane administration led to a reduction in myocardial infarct size (GGA+sevoflurane group: 23 ± 17%) compared with that in the control (P < 0.001), sevoflurane (P < 0.001) and GGA (P < 0.05) groups. Heat stress 24 h before myocardial ischemia and reperfusion produced strong myocardial protection resulting in a reduction in myocardial infarct size (heat stress group: 29 ± 11%, P < 0.001) compared with that in the control group. Administration of 5HD had no effect on myocardial infarct size (5HD group: 58 ± 5%, P > 0.83) compared with that in the control group. The cardioprotective effect of GGA was abolished by administration of 5HD resulting in no difference in myocardial infarct size (GGA + 5HD group: 56 ± 15%, P > 0.94) compared with that in the control group.


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  		Table 2. Left Ventricular Area at Risk

 

Figure 27
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  		Figure 2. Myocardial infarct size expressed as a percentage of the left ventricular area at risk in the seven experimental groups. GGA = geranylgeranylacetone; SEV = sevoflurane; 5HD = sodium 5-hydroxydecanoate; HS = heat stress; AAR = area at risk. Data are mean ± sd *P < 0.05 versus control group. {dagger}P < 0.05 versus GGA group. §P < 0.05 versus SEV group.

 

Expression of Hsp70
Representative examples of the Western blot results for Hsp 70 are shown in Figure 3A. Densitometric assessment of Hsp 70 indicated that GGA significantly enhanced Hsp 70 expression (0.69 ± 0.15, n = 5) compared with that in the control and sevoflurane groups (0.36 ± 0.05, n = 4, P < 0.02; 0.40 ± 0.16, n = 5, P < 0.02) (Fig. 3B). Expression of Hsp 70 in the GGA+sevoflurane group was similar to that measured in the GGA group (0.69 ± 0.16, n = 4, P > 0.98). Hsp 70 expression in the GGA group and GGA+sevoflurane group was weak in comparison to that in the heat stress group (1.16 ± 0.13, n = 4, P < 0.001).


Figure 37
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  		Figure 3. Representative Western blot of heat shock protein (Hsp) 70 in five experimental groups (A). Quantification by densitometric analysis of Hsp 70 expression in the five experimental groups (B). The relative levels of Hsp 70 were determined for optical density and were normalized to the actin bands on Coomassie-stained gels. Control (n = 4); GGA = geranylgeranylacetone (n = 5); SEV = sevoflurane (n = 5); GGA+SEV = GGA + sevoflurane (n = 4); HS = heat stress (n = 4). Data are mean ± sd *P < 0.05 versus control and SEV groups. {dagger}P < 0.05 versus GGA and GGA + SEV groups.

 

DISCUSSION

In the present study, IV administration of GGA 24 h before ischemia induced Hsp 70 expression and resulted in myocardial protection against ischemia and reperfusion injury. This cardioprotective effect of GGA was negated by administration of 5HD. Inhaling a low-concentration of sevoflurane did not reduce myocardial infarct size compared with that in control animals; however, the cardioprotective effect of GGA was enhanced when rabbits pretreated with GGA were exposed to 0.5 MAC sevoflurane for 30 min before ischemia. We also confirmed that prior exposure to heat stress provided cardioprotection against myocardial ischemia and reperfusion injury and induced high-level myocardial Hsp 70 expression. These results suggest that the mechanism of GGA-induced myocardial protection may involve mitochondrial KATP channels and that sevoflurane preconditioning enhances late cardioprotection induced by GGA.

Hsp 70 and Cytoprotective Effects
Hutter et al.3 and Marber et al.4 showed a direct correlation between the amount of Hsp 70 expressed and myocardial protection in rat and rabbit hearts. Furthermore, over-expression of Hsp 70 in gene-transfected hearts or in transgenic animals increases cardioprotective tolerance against ischemic stress.5,6 Thus, our results confirm these findings that suggest a link between expression of Hsp 70 and cardioprotection. The mechanism of Hsp 70-induced cardioprotection seems to involve interference with apoptotic pathways. Hsp 70 competes with caspase-9 for the caspase recruitment domain of apoptotic-protease-activating factor 1 (Apaf-1) and prevents oligomerization of Apaf-1, leading to inhibition of the formation of a functional apoptosome.15,16 Over-expression of Hsp 70 also enhances the content and activity of mitochondrial manganese superoxide dismutase, an enzyme that preserves mitochondria, and improves mitochondrial respiratory function during ischemia and reperfusion.17,18 Consistent with our findings, Hoag et al.19 and Pell et al.20 further showed that KATP channel activation may be integral to delayed cardioprotection conferred by heat stress in the rabbit heart.

Cardioprotective Effect of GGA
The effects of GGA on Hsp 70 was first examined in cultured gastric mucosal cells.7 Oral administration of GGA was shown to enhance Hsp 70 induction and to suppress ischemia and reperfusion injury in rat liver. Priming of hepatocytes with GGA causes an enhanced heat shock response through activation of heat shock factor 1, resulting in inhibition of hepatocyte apoptosis.21 Oral administration of GGA was further shown to enhance Hsp 70 induction through the activation of PKC in isolated perfused rat heart, resulting in improved myocardial function after ischemia.22 These results, along with the data from this experiment, suggest that the cardioprotection secondary to GGA is due in part to enhanced Hsp 70 expression. More recently, others have shown that the preserved mitochondrial respiratory function with GGA-induced Hsp expression has a role in cardioprotection against ischemia-reperfusion and opening of the mitochondrial KATP channel may be involved in these processes.23 Our finding that the mechanism of GGA-induced cardioprotection may involve the mitochondrial KATP channels is consistent with these reported findings.

Volatile anesthetics have been shown to exert cardioprotective effects when administered before coronary artery occlusion, a phenomenon termed anesthetic-induced preconditioning. The efficacy of volatile anesthetics is dose-dependent, and the cardioprotective potency differs among inhaled anesthetics.9,24,25 Sevoflurane has been shown to improve functional recovery of the heart and to reduce myocardial infarct size in the experimental model.13,26–28 Toller et al.,29 however, showed in dogs that 1 MAC sevoflurane does not protect against myocardial infarction when discontinued 30 min before ischemia. Piriou et al.25 observed no significant reduction in the myocardial infarct size in rabbits when they were exposed to 1 MAC sevoflurane for 30 min followed by a 15-minute washout period before myocardial ischemia. A similar lack of cardioprotection by sevoflurane with a washout period was recently observed in patients undergoing coronary artery bypass surgery.30 These findings suggest that the cardioprotective effect of sevoflurane depends on the interval from washout to induction of myocardial ischemia as well as the experimental model. Our findings that 30-min exposure to a low concentration of sevoflurane (0.5 MAC) with a 30-min washout period before ischemia failed to reduce the myocardial infarct size in rabbits do not contradict previously reported findings.

Several studies have indicated that sevoflurane induces translocation and phosphorylation of isoforms of PKC, which are required to activate mitochondrial KATP channels and produce myocardial ischemic protection.10,12 Julier et al.31 showed preconditioning with sevoflurane preserves myocardial function in patients undergoing coronary artery bypass graft surgery and produces translocation of PKC isoforms in human myocardium. The activation of mitochondrial KATP channels through PKC has been shown to be an essential mechanism mediating anesthetic-induced preconditioning and ischemic preconditioning.9–12

Sevoflurane has been shown to provide additive cardioprotective effects to acute and late myocardial ischemic preconditioning.13,29 Our results further indicate that sevoflurane enhances late cardioprotection by GGA. Sevoflurane-induced preconditioning improves mitochondrial function through the activation of mitochondrial KATP channels.32 GGA protects mitochondrial function in myocardial cells,23 and the increased myocardial protection from GGA with sevoflurane compared with GGA alone is likely due to enhanced improvement of mitochondrial function during myocardial ischemia. Although there are many similarities between ischemic and anesthetic preconditioning, distinct differences in gene expression were found in studies using microarray technology.33,34 Ischemic preconditioning up-regulated Hsp 70 and Hsp 27, whereas anesthetic preconditioning down-regulated Hsp 70 precursor and Hsp 90. This finding implies different mechanisms of myocardial protection by anesthetic preconditioning and by GGA associated with Hsp 70 expression, consequently, sevoflurane may produce additive cardioprotection with GGA through the different pathway.

There are several limitations to the present study. First, GGA induced Hsp 70 expression and produced myocardial protection against myocardial ischemia; however, a direct relation between induced Hsp 70 and cardioprotection has not been proved. Second, the rabbits in this study were anesthetized with S(+)-ketamine and xylazine. It has been found that racemic ketamine has an inhibitory effect on myocardial ischemic preconditioning but that its S(+)-ketamine enantiomer does not.35 We therefore chose S(+)-ketamine as the basal anesthetic for our study. We, however, cannot completely exclude an interaction between the basal anesthetic and GGA or sevoflurane-based myocardial protection. The size of the AAR is influenced by the magnitude of coronary collateral perfusion. Rabbits have minimal collateral coronary artery blood flow and the experimental model we used has been extensively investigated in similar studies.36 Furthermore, the AAR was similar among experimental groups, suggesting that the current results were not affected by collateral coronary blood flow.

Footnotes

Supported in part by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (#13671587, #16790878).

Accepted for publication April 25, 2008.

The authors have no conflicts of interest, sources of financial support, corporate involvement, patent holdings, etc., to report.

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2008 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press