Cardioprotective effects of anesthetic preconditioning in rats with ischemia-reperfusion injury: propofol versus isoflurane

Cardioprotective effects of anesthetic preconditioning in rats with ischemia-reperfusion injury: propofol versus isoflurane 1 first-author 2 3 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:CSA8@china.com891201@mail.chimei.org.tw †E-mail:CSA8@china.com891201@mail.chimei.org.tw CSA8@china.com 4 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:CSA8@china.com891201@mail.chimei.org.tw †E-mail:CSA8@china.com891201@mail.chimei.org.tw CSA8@china.com Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100069, China Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100069, China Department of Pathophysiology, Capital Medical University, Beijing 100069, China Department of Pathophysiology, Capital Medical University, Beijing 100069, China Reproductive Medical Center, Capital Medical University, Beijing 100069, China Reproductive Medical Center, Capital Medical University, Beijing 100069, China Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan 710, China Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan 710, China Objective: 2 We compare the cardioprotective effects of anesthetic preconditioning by propofol and/or isoflurane in rats with ischemia-reperfusion injury. Methods: 2 Male adult Wistar rats were subjected to 60 min of anterior descending coronary artery occlusion followed by 120 min of reperfusion. Before the long ischemia, anesthetics were administered twice for 10 min followed by 5 min washout. Isoflurane was inhaled at 1 MAC (0.016) in I group, whereas propofol was inhaled intravenously at 37.5 mg/(kg·h) in P group. A combination of isoflurane and propofol was administered simultaneously in I+P group. Results: 2 In control (without anesthetic preconditioning, C group), remarkable myocardial infarction and apoptosis accompanied by an increased level of cardiac troponin T were noted 120 min after ischemia-reperfusion. As compared to those of control group, I and P groups had comparable cardioprotection. In addition, I+P group shares with I and P groups the comparable cardioprotective effects in terms of myocardial infarction and cardiac troponin T elevation. Conclusion: 2 A combination of isoflurane and propofol produced no additional cardioprotection. Anesthetic Heart Propofol Isoflurane Apoptosis INTRODUCTION 1 Myocardial ischemic injury is a potential perioperative threat. Ischemia possesses two sides of myocardial properties ranging from the cell death on one side to beneficial effects of preconditioning on the other side. Preconditioning agents such as inhalation and intravenous anesthetics induce a pronounced cardioprotection and thus may decrease the deleterious effects of myocardial ischemia in perioperative medicine. Indeed, many human studies (de Hert et al., 2002 2002 ; 2004 2004 ; Conzen et al., 2003 2003 ) and animal experiments (Novalija et al., 1999 1999 ; Warltier et al., 1988 1988 ) have demonstrated that different anesthetic regimens provide cardioprotection in cardiac surgery by mimicking ischemic preconditioning. Propofol (2,6-diisopropylphenol) is a lipid-soluble anesthetic agent that has a chemical structure similar to that of phenol-based free radical scavengers such as vitamin E (Aarts et al., 1995 1995 ; Kokita et al., 1998 1998 ). It is commonly used as an intravenous anesthetic in cardiac surgery and has been shown to decrease postischemic myocardial dysfunction (Kokita and Hara, 1996 1996 ), infarct size (Ebel et al., 1999 1999 ), and histologic degeneration (Ko et al., 1997 1997 ). In the absence of myocardial ischemia, the common inhalation anesthetic isoflurane reduces infarct size in animal studies by causing opening of K ATP channels (Kersten et al., 1996 1996 ; 1997 1997 ). Before aortic cross-clamping in patients undergoing coronary artery bypass surgery, pretreatment with isoflurane improves cardiopulmonary bypass outcome (Haroun-Bizri et al., 2001 2001 ). In addition, preconditioning isoflurane may offer some additional cardioprotection in coronary artery bypass graft surgery (Belhomme et al., 1999 1999 ). The present work has two purposes. The first is to assess the cardioprotective effects of propofol versus isoflurane preconditioning in rats with myocardial ischemia-reperfusion. The second is to determine whether combined propofol and isoflurane anesthesia is able to provide additional cardioprotection in rats with myocardial ischemia-reperfusion. MATERIALS AND METHODS 1 This study was conducted in accordance with our institutional guidelines on the use of live animals for research and the experimental protocol was approved by the Animal Care and Use Committee of our medical center laboratory. Surgical preparation 2 Male Wistar rats (Academy of Military Medical Sciences Center for Laboratory Animal, Beijing, China) with body weight of 250~300 g were used. The rats were anesthetized by intraperitoneal administration of urethane (Sigma, St. Louis, Missouri, USA). The left femoral vein was cannulated with a polyethylene (PE50)-tubing for fluid or drug administration. Sodium lactate Ringer’s solution (China Otsuka Pharmaceutical Co., Ltd, Beijing, China) was infused continuously at a rate of 4 ml/h for the entire period of experimentation. Needle electrodes were embedded subcutaneously in a lead II configuration to monitor electrocardiogram (ECG). The rats were artificially ventilated after orotracheal intubations. Arterial pH and P CO 2 were maintained within normal physiological limits by adjusting the respiratory rate or tidal volume. A catheter connecting to a pressure transducer for left ventricular pressure reading was placed into the left ventricle through the right carotid artery. A thoracotomy was performed at the left second intercostal space and the heart was suspended in a pericardial cradle. A prominent branch of the left anterior descending (LAD) of coronary artery was identified, and a 5-0–prolene ligature snare was looped around LAD of coronary artery inferior to the left atrial appendage for later occlusion. Coronary occlusion was achieved by tightening the snare. The presence of epicardial cyanosis and ST-segment elevation in the ECG verified myocardial ischemia. Reperfusion was achieved by releasing the snare and was confirmed by visual observation of myocardial reactive hyperemia. Experimental design 2 The experimental design is illustrated in Fig. 1 1 . A 30-min period was demanded for stabilization after the snare around LAD of coronary artery was performed. All the rats underwent a 60-min LAD occlusion (ischemia) followed by 2 h of reperfusion. Preconditioning was elicited before the onset of myocardial ischemia. Rats were randomly divided into 4 groups. In control (C) group, all rats received 60 min of ischemia followed by 120 min of reperfusion. In I group, all animals received 2 cycles of 10-min inhalation of isoflurane (Abbott Laboratories, Illinois, USA) at concentration of 1.4% (w/v) followed by a 5-min washout, which corresponds to 1.0 minimum alveolar concentration (MAC) (Quasha et al., 1980 1980 ). The dose of isoflurane was adopted from previous studies (Ludwig et al., 2004 2004 ; Toller et al., 2000 2000 ), which used this anesthetic for the purpose of preconditioning. In P group, all rats received an intravenous dose of propofol (37.5 mg/(kg·h), Fresenius Kabi Austria GmbH, Austria) twice for 10 min followed by a 5-min washout, which corresponds to 6 mg/(kg·h) for clinical patients. In I+P group, all rats received 2 cycles of 10-min inhalation of isoflurane and 2 intravenous infusion of propofol for 10 min followed by a 5-min washout. Cardiovascular parameter measurements 2 All the variables were recorded at the following time points: t 1 : baseline (before the preconditioning; 30 min after stabilization); t 2 : treatment (before LAD occlusion, 30 min after preconditioning); t 3 : 60 min ischemia; t 4 : 120 min reperfusion. Global systolic function was measured in terms of left ventricular systolic pressure (LVSP) and maximum rate of rise of left ventricular pressure d P /d t (d P /d t max ). Global left ventricular end-systole was defined as the point of minimum d P /d t (d P /d t min ) and left ventricular end-diastole pressure (LVDP) as the beginning of the sharp upslope of the LV d P /d t tracing. Both mean arterial pressure (MAP) and heart rate (HR) were all continuously recorded. Determination of myocardial infarction 2 At the end of experiments, the LAD of coronary artery was reoccluded and 2 ml of 0.6% (w/v) Evans blue dye was infused via the left atrial appendage. This maneuver identified the area at risk (AAR) for infarction that remained unstained. Meanwhile, the normally perfused zone was stained in deep blue. The heart was excised quickly and frozen for 1 h at −20 °C. Then the left ventricles separated from the heart were cut into transverse slices of equal thickness (1 mm) and taken photographs. The slices were incubated in 10% (w/v) 2,3,5-triphenyltetrazalium chloride (TTC) for 20 min at 37 °C. These slices were then placed in 10% (w/v) neutral buffered formalin for 48 h to increase the contrast between stained and unattained tissues. Because TTC was hydrogenised by dehydrogenase of viable myocardium in the AAR, it was stained in deep red, whereas the tissue of infarct area appeared pale grey. The slices were photographed again. The infarct area and the AAR were determined by planimetry using Adobe Photoshop 8.0 computer software. Myocardial infarct size was expressed as a percentage of infarct area in the AAR as follows: Infarct size (%)=(∑Infarct area/∑AAR)×100%. Cardiac troponin T (cTnT) measurement 2 cTnT measurement was conducted at the following time points: t 1 , t 2 , t 3 and t 4 . Measurement of cTnT was done by the hospital clinical chemistry laboratory, and the analysts were unaware of the conduct of this study. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay 2 TUNEL assay was performed using the myocardial sections for histological verification. Color was developed using 3,3-diaminobenzidine tetrachloride (DAB, Sigma, USA). Sections were treated with xylene and ethanol to remove paraffin and for dehydration. They were then washed with phosphate buffered solution (PBS) and incubated in 3% (v/v) H 2 O 2 solution for 20 min. The sections were treated with 5 μg/ml proteinase K for 2 min at room temperature, and re-washed with PBS (1 mol/L, pH 7.4). The sections were then treated with a TUNEL reaction mixture (Roche Mannhein, Germany) at 37 °C for 1 h, and then were washed with distilled water. They were then incubated in anti-fluorescein antibody conjugated with horse-radish peroxidase (HRP) at room temperature for 30 min, washed, and then using the apoptosis detection system fluorescence kit (Promega, WI, USA) according to the manufacturer’s instructions. The nuclei of apoptotic and non-apoptotic cells were counterstained with 0.05% (w/v) DAB as a chromogen. The labeled cells were analyzed by fluorescence microscopy. Each section was evaluated independently without knowledge of the experimental conditions. Statistical analysis 2 Statistical analysis was performed using SPSS 12.0 for windows software. Results are expressed as mean±standard deviation (SD). Data of myocardial function over time within each group were analyzed using analysis of variance (ANOVA) with repeated measures on one factor. Differences between groups were analyzed using a one-way ANOVA. If an overall significance among groups was found, least significant difference (LSD) for intergroup comparisons was performed. Changes within and between groups were considered statistically significant with P < 0.05. RESULTS 1 Hemodynamic parameters 2 Table 1 1 summarizes the levels of hemodynamic parameters for the four groups of animals at four time points. All the levels of hemodynamic parameters did not differ among groups throughout the observation interval. There was no significant intra- or intergroup difference in HR, MAP, LVSP, LVDP, d P /d t max , or d P /d t min over time (Table 1 1 ). t 1 (baseline)=30 min after stabilization; t 2 (treatment)=30 min after preconditioning or start of coronary artery occlusion; t 3 (1-h ischemia)=1 h after ischemia; t 4 (2-h reperfusion)=2 h after reperfusion 2 4 HR (beat per min) 4 MAP (mmHg) 4 LVSP (mmHg) 4 LVDP (mmHg) 4 d P /d t min (mmHg/ms) 4 d P /d t max (mmHg/ms) C I P I+P C I P I+P C I P I+P C I P I+P C I P I+P C I P I+P t 1 434±29 429±26 424±24 414±32 85±8 92±11 88±10 93±11 116±7 124±5 115±14 121±13 0.5±1.5 −0.3±2.4 0.1±1.9 0.7±1.4 −4.1±0.6 −4.9±0.5 −4.2±1.0 −4.5±0.9 6.4±1.0 6.3±0.8 6.7±1.0 6.3±1.2 t 2 407±59 425±40 415±27 407±24 83±8 87±6 87±15 93±14 113±15 114±12 128±11 123±7 1.2±0.9 0.5±1.5 0.7±1.7 1.2±1.8 −4.3±1.7 −4.9±0.6 −4.8±0.8 −4.9±0.6 5.7±2.0 6.4±0.8 6.5±1.5 6.1±0.7 t 3 397±62 406±41 393±32 394±24 86±8 89±18 88±13 99±12 111±16 108±15 115±9 120±8 0.8±0.8 −0.3±1.2 −0.8±2.6 0.2±1.6 −3.9±1.7 −4.5±0.8 −4.6±0.7 −4.7±0.4 5.5±2.1 5.8±1.1 5.8±1.1 6.0±0.6 t 4 410±45 401±43 402±31 391±35 75±18 84±12 79±12 81±13 112±8 112±15 118±14 117±14 1.2±1.1 −0.6±1.8 0.2±2.6 0.9±3.2 −4.2±1.2 −4.8±0.8 −4.8±1.0 −4.7±0.8 5.8±1.4 6.0±1.1 6.0±1.5 5.8±1.1 Cardiac troponin T (cTnT) levels 2 Fig. 2 2 shows the plasma levels of cTnT for the four groups at four time points. In C group, the cTnT values at t 4 were significantly higher than those at t 1 ( P < 0.01). In addition, the values of plasma cTnT obtained at t 4 for I or P group were significantly lower than those for C group ( P < 0.01). However, as compared to those of I or P group at t 4 , I+P group had insignificant difference ( P > 0.05). In terms of cTnT, there was an insignificant difference between I- t 4 and P- t 4 group ( P > 0.05). Myocardial infarct size and TUNEL-positive cell numbers 2 Figs. 3 3 and 4 4 show the myocardial infarct size and TUNEL-positive cells numbers, respectively, for the four groups obtained at 120 min after the start of reperfusion. It can be seen from these two figures that the values of both myocardial infarct size and TUNEL-positive cells numbers for either I or P group were significantly lower than those of C group ( P < 0.01). However, the values of both myocardial infarct size and TUNEL-positive cells numbers for I+P group were indifferent from those of I or P group ( P > 0.05). Again, in terms of myocardial infarct size or TUNEL-positive myocyte numbers, there was an insignificant difference between I and P group ( P > 0.05). DISCUSSION 1 In the present study, we show that propofol-based intravenous regimen or inhalation anesthesia with isoflurane appears to provide equal myocardial protection in myocardial ischemia-reperfusion model when using plasma levels of cTnT, the number of myocardial apoptotic cells, and myocardial infarct size as indices of myocardial damage. Our study confirms the results of several previous studies that pretreatment with isoflurane (Cason et al., 1997 1997 ; Ismaeil et al., 1999 1999 ; Piriou et al., 2000 2000 ; Roscoe et al., 2000 2000 ) or propofol (Ebel et al., 1999 1999 ; Ko et al., 1997 1997 ; Kokita and Hara, 1996 1996 ) protects the myocardium from a subsequent prolonged ischemia and thus mimics the cardioprotective effects of ischemic preconditioning. In addition, we report that the combined isoflurane and propofol pretreatment does not produce additional cardioprotection during ischemia-reperfusion. Several mechanisms have been proposed for isoflurane-induced preconditioning. For example, blocking adenosine (A1) receptors abolished isoflurane-induced cardioprotection against myocardial stunning (Kersten et al., 1996 1996 ) and infarction in rabbits (Ismaeil et al., 1999 1999 ) and human atrial trabecular muscle (Roscoe et al., 2000 2000 ). Isoflurane-induced preconditioning was prevented by 5-hydroxydeanoate and gadolinium, suggesting the involvement of mechanogated channels in this phenomenon (Piriou et al., 2000 2000 ). Administration of K ATP channel blocker before isoflurane administration completely blocked the cardioprotection (Tanaka et al., 2003 2003 ). Isoflurane preconditioning may act via release of small quantities of free radicals to protect myocardium against infarction in rabbits (Mullenheim et al., 2002 2002 ; Tanaka et al., 2002 2002 ). Radicals are released from the mitochondria as a consequence of K ATP channel opening (Duranteau et al., 1998 1998 ; Kowaltowski et al., 2001 2001 ; McPherson and Yao, 2001a 2001a ). Activation of opiate receptors by morphine leads to activation of mitochondrial K ATP channels followed by an increase of intracellular free radical formation (McPherson and Yao, 2001a 2001a ; 2001b 2001b ). Furthermore, protein kinase C can be activated by free radicals (Gopalakrishna and Anderson, 1989 1989 ). Thus, it is likely that protein kinase C is an important factor in the signal transduction cascade of isoflurane preconditioning (Baines et al., 1999 1999 ). Other lines of evidence have accumulated to suggest that large quantities of reactive oxygen species released during reperfusion after coronary artery occlusion damage proteins responsible for intracellular homeostasis, produce tissue injury (Ambrosio et al., 1993 1993 ; Bolli et al., 1988 1988 ; Zweier et al., 1987 1987 ), depress contractile function, and increase myocardial infarct size. Propofol, a free radical scavenger, is being used increasingly for cardiac anesthesia and has been known to decrease postischemic myocardial mechanical dysfunction, infarct size, and histological degeneration (Ebel et al., 1999 1999 ; Ko et al., 1997 1997 ; Kokita and Hara, 1996 1996 ). Propofol infusion during the reperfusion period produced a cardioprotective effect and inhibited apoptosis of cardiomyocytes in the ischemia-reperfusion model, with prolonged cold ischemia, in isolated rat hearts (Choi et al., 2007 2007 ). Propofol also suppresses the activity of neutrophils, and may therefore produce its beneficial effects by reducing free radicals, Ca 2+ influx, and neutrophil activity (Scarabelli et al., 2001 2001 ). It has been shown that levels of systemic cytokines, such as tumor necrosis factor-α, increased after cardiopulmonary bypass (Tomasdottir et al., 2003 2003 ). It has also been shown that propofol can attenuate apoptosis in tumor necrosis factor-α-induced endothelial cells and enhance the bioavailability of nitric oxide (Luo et al., 2005 2005 ). Coronary endothelial cell apoptosis precedes myocyte apoptosis (Sayin et al., 2002 2002 ). Hence, attenuation of vascular endothelial cell apoptosis by propofol could have resulted in reduced cardiomyocytes apoptosis during myocardial ischemia and reperfusion. Other studies have failed to show a protective effect on myocardial function during ischemia and reperfusion (Ebel et al., 1999 1999 ). It can be derived from the afore-mentioned descriptions that isoflurane inhalation preconditioning is mainly mediated by activation of K ATP channels in coupled with stimulation of adenosine receptors. On the other hand, intravenous propofol preconditioning may be mainly mediated by scavenging free radicals and attenuated systemic inflammation (or overproduction of several pro-inflammatory cytokines). The present results show that isoflurane and propofol, although having different cardioprotective mechanisms, appear to provide equal myocardial protection in the myocardial ischemia-reperfusion model when using cTnT, and myocardial apoptosis and infarct size as markers of myocardial damage in rats. Furthermore, the current study provides data to show that the combined isoflurane and propofol preconditioning does not produce additional cardioprotection during myocardial ischemia-reperfusion. In fact, the contention that volatile anesthetic and intravenous anesthetic provide equal cardioprotection during myocardial ischemia-reperfusion in rats is not supported by many other investigators. For example, sevoflurane has been found to provide greater protection of the myocardium than propofol in patients undergoing off-pump coronary artery bypass surgery (Conzen et al., 2003 2003 ). Sevoflurane shows potential to be superior to propofol in porcine animal model of severe acute ischemia induced by occlusion of the thoracic aorta (Annecke et al., 2007 2007 ). The discrepancy may be explained by species difference. The current results show that propofol did not cancel the cardioprotective effects of isoflurane preconditioning. As mentioned in the former section, isoflurane preconditioning may rely on the release of small quantity of free radicals, which may be scavenged by propofol. Propofol cardioprotection is dose-dependent both in the clinics (Xia et al., 2006 2006 ) and experiments (Xia et al., 2004 2004 ). It is likely that in the joint isoflurane-propofol group, the protective effects observed may solely come from propofol cardioprotection via its antioxidant property, providing that the dose of propofol used is high enough. Cardiomyocyte death caused by apoptosis is a primary factor in the pathogenesis of ischemia and reperfusion (van Empel et al., 2005 2005 ). In the ischemia-reperfusion model described in this paper, only the increased TUNEL-positive cells were observed during ischemia-reperfusion procedure. Other definite sequence of apoptotic events such as caspase-3 activation, mitochondrial damage, or an increasing number of dead cardiac myocytes in response to ischemia and reperfusion was not provided. Nevertheless, as shown in the current study, the increased TUNEL-positive cardiomyocytes were significantly reduced by ischemia and reperfusion preconditioning. CONCLUSION 1 Our results demonstrate that isoflurane inhalation or intravenous propofol protects the myocardium from a subsequent prolonged ischemia and mimics the cardioprotective effects of ischemic preconditioning. Isoflurane shares with propofol the same preconditioning potential in preventing myocardial ischemia-reperfusion injury. 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Direct measurement of free radical generation following reperfusion of ischemic myocardium . Proc Natl Acad Sci USA , 1987 . 84 ( 5 ): 1404 - 1407 . DOI: 10.1073/pnas.84.5.1404 http://doi.org/10.1073/pnas.84.5.1404 . Direct measurement of free radical generation following reperfusion of ischemic myocardium We would like to thank Prof. Chih-Chung Wang, Chi Mei Medical Center, Tainan, Taiwan, China for extensive helpful discussion. 10.1631/jzus.B0920119 2009-04-24 2009-08-04 2009-07-06 2022-01-05 Copyright © 2009, Journal of Zhejiang University Science 2009 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 10 10