EXPERIMENTAL STUDY
Acute ethanol exposure fails to elicit preconditioning-like protection in in situ rabbit hearts because of its continued presence during ischemia
Maike Krenz, MD*,
Christopher P. Baines, PhD*,
Xi-Ming Yang, MD*,
Gerd Heusch, MD, FACC, FESC*  ,
Michael V. Cohen, MD, FACC*  and
James M. Downey, PhD*
* Department of Physiology, University of South Alabama, Mobile, Alabama, USA
Department of Medicine, University of South Alabama, Mobile, Alabama, USA
Department of Pathophysiology, University of Essen Medical School, Essen, Germany
Manuscript received April 5, 2000;
revised manuscript received August 28, 2000,
accepted October 12, 2000.
Reprint requests and correspondence: Dr. Michael V. Cohen, Department of Physiology, College of Medicine, MSB 3024, University of South Alabama, Mobile, Alabama 36688
mcohen{at}usamail.usouthal.edu
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Abstract
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OBJECTIVES
Is the timing of exposure critical for ethanol’s ability to induce cardioprotection?
BACKGROUND
Acute ethanol exposure has been reported to mimic ischemic preconditioning in vitro, but it failed to protect in situ. We hypothesized that these conflicting findings were related to ethanol’s presence during ischemia in situ.
METHODS
The effect on infarct size (triphenyltetrazolium chloride) of acute ethanol exposure (0.35, 0.7, and 1.4 g/kg IV) 10 min before ischemia was measured in open-chest rabbits after 30 min of regional ischemia and reperfusion and was compared to ethanol’s ability to reduce infarct size in isolated hearts in which the timing of ethanol exposure could be varied.
RESULTS
Ethanol exposure in situ shortly before ischemia did not reduce infarct size. Moreover, ethanol abolished protection from both ischemic preconditioning and mitochondrial KATP channel activation. In contrast, in buffer-perfused hearts exposed to 10 to 50 mmol/liter ethanol for 5 min followed by washout before ischemia, infarct size was significantly reduced. When ethanol exposure was prolonged until the end of ischemia in isolated hearts, protection was abolished. Conversely, protection was seen when ethanol was infused in situ followed by removal of the heart and perfusion with ethanol-free buffer prior to ischemia in a Langendorff preparation. When 50 min were allowed to metabolize the ethanol prior to ischemia, protection could also be shown in situ.
CONCLUSIONS
Ethanol exposure followed by washout or sufficient time to metabolize the alcohol prior to ischemia induces preconditioning-like myocardial protection. However, if present throughout ischemia, ethanol actually blocks all preconditioning-related protection.
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Abbreviations and Acronyms
| | ANOVA | = one-way analysis of variance | | IPC | = ischemic preconditioning | | IV | = intravenous | | PKC | = protein kinase C |
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In recent studies, chronic ethanol consumption induced cardioprotection against ischemia that persisted for 18 h after ethanol withdrawal. In hearts isolated from alcohol-fed guinea pigs, improved contractile recovery and reduced creatine kinase release after ischemia correlated with translocation of protein kinase C (PKC)  (1). This protection was reminiscent of the "delayed" form of preconditioning in which a brief ischemic episode triggers protection that requires 12 to 24 h to develop and lasts for several days (2). Acute ethanol exposure may mimic classical preconditioning as well: ethanol was protective to isolated rat cardiomyocytes, and inhibition of the PKC isozyme abolished this protection (3), as seen in ischemic preconditioning (IPC) (4).
Only one study has tested the effects of acute ethanol exposure on infarct size in the more clinically relevant in situ preparation. Surprisingly, intravenous (IV) ethanol infused shortly prior to ischemia in open-chest dogs did not affect infarct size (5). Apart from possible species differences and the controversial role of PKC in IPC in dogs (6–8), ethanol’s failure to protect might be related to the timing of its exposure. We therefore tested both in situ and in vitro whether ethanol could reduce infarction when the exposure was either transient or sustained and whether ethanol specifically interfered with the mechanism of IPC.
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Materials and methods
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All procedures were approved by the Institutional Animal Care and Use Committee and were in accordance with recommendations published in the Guide for the Care and Use of Laboratory Animals, National Academic Press, Washington, DC, 1996.
New Zealand White rabbits of either sex weighing between 1.5 and 2.6 kg were anesthetized with IV pentobarbital sodium (30 mg/kg) in parts A–C of the study.
Part A: in situ ethanol exposure and infarction.
A major branch of the left coronary artery was prepared with a snare. Catheters filled with heparinized saline (10 U/ml) were placed into the left carotid artery to monitor arterial blood pressure and into the right jugular vein to withdraw blood samples and administer drugs. Arterial pH, PO2 and PCO2 were maintained within the physiological range (blood gas analyzer ABL 5, Radiometer, Copenhagen, Denmark). Throughout the experiment, additional anesthesia was administered as needed (5 to 15 mg pentobarbital/15 min). A heating pad maintained rectal temperature between 38.5° and 39.5°C. The rabbits were allowed to stabilize for 20 min after surgery before the protocols were begun (Fig. 1). All hearts experienced 30 min of regional ischemia followed by 3 h of reperfusion. Either 0.35, 0.7, or 1.4 g/kg ethanol was infused over 10 min, starting 20 min prior to the onset of ischemia.
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Figure 1 Experimental protocols in in situ preparations (part A). Timing of the different interventions is shown in relation to the index ischemia. IPC = ischemic preconditioning.
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To precondition the hearts, a 5-min period of regional ischemia was followed by 20 min of reperfusion prior to the index ischemia. In the IPC+ethanol group, 0.7 g/kg ethanol was infused during the first 10 min of the 20 min of reperfusion. In the diazoxide group, a bolus of 10 mg/kg diazoxide was given 11 min before ischemia. In the diazoxide+ethanol group, the 10-min ethanol infusion (0.7 g/kg) was started 1 min after the diazoxide bolus. In this group, ischemia was produced directly after the end of the ethanol infusion. In the genistein+staurosporine group, genistein (5 mg/kg) and staurosporine (50 µg/kg) were given as boluses 9 min and 5 min before ischemia, respectively. In the ethanol+genistein+staurosporine group the above protocol was preceded by a 10-min ethanol infusion (0.7 g/kg) started 20 min prior to the onset of ischemia. In the final group, ethanol (0.35 g/kg) was infused over 10 min starting 1 h before the onset of ischemia.
Part B: in vitro ethanol exposure and infarction.
A major branch of the left coronary artery was prepared with a snare as above. The heart was excised and perfused in the Langendorff mode with Krebs-Henseleit buffer (CaCl2, 2.5; NaCl, 118.5; KCl, 4.7; MgSO4, 1.2; KH2PO4, 1.2; NaHCO3, 24.8, and glucose 10 mmol/liter). Perfusion pressure was set at 75 mm Hg. A saline-filled latex balloon connected to a pressure transducer (Maxxim Medical, Athens, Texas) was inserted into the left ventricle. Baseline end-diastolic pressure was set at 5 mm Hg. Hearts were paced at 200 beats/min if the spontaneous rate was slower. Isolated hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Ethanol was infused for 5 min at either 10, 20, or 50 mmol/liter followed by a 10-min washout period prior to ischemia (Fig. 2). In the two groups with long ethanol exposure, either 10 or 50 mmol/liter ethanol was infused for 45 min beginning 15 min before the onset of ischemia.
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Figure 2 Experimental protocols in the in vitro and hybrid preparations (parts B and C). Timing of the different interventions is shown in relation to the index ischemia.
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Part C: hybrid preparation of in situ ethanol exposure followed by in vitro infarction.
Rabbits were surgically prepared as described for part A and received either no infusion for control studies or an IV infusion of ethanol (0.7 g/kg) over 10 min. Ten minutes later the heart was excised and perfused with ethanol-free Krebs-Henseleit buffer as described for part B. After 10 min of stabilization after mounting, the hearts experienced 30 min of regional ischemia and 2 h of reperfusion (Fig. 2).
Serum ethanol
Serum ethanol concentrations in part A were measured with a diagnostic test kit (Sigma Diagnostics, St. Louis, Missouri).
Risk zone and infarct size
After completion of studies all suspended hearts were perfused with 0.9% saline. Next, the coronary snare was retightened, and 1–10-µm zinc cadmium sulfide fluorescent particles (Duke Scientific, Palo Alto, California) were infused to delineate the nonfluorescent area at risk. Hearts were frozen, cut into 2-mm transverse slices, incubated for 20 min in 1% triphenyltetrazolium chloride in 100 mmol/liter phosphate buffer (pH 7.4, 37°C), and immersed in 10% formalin. The borders between fluorescent and nonfluorescent regions were marked under ultraviolet light to identify the risk zone. Infarct and risk zone areas were planimetered. Infarct size is presented as a percent of risk zone.
Chemicals.
For part A, diazoxide (Research Biochemicals International, Natick, Massachusetts) and staurosporine (Sigma Chemical, St. Louis, Missouri) were each dissolved in 1 ml dimethyl sulfoxide. Genistein (Alexis, San Diego, California) was prepared in a 1:1:2 solution of ethylene glycol (PEG 400), ethanol, and 0.9% saline solution. In parts A and C, 95% v/v ethanol (Fisher Scientific, Fair Lawn, New Jersey) was infused intravenously. For part B, 95% v/v ethanol was diluted in Krebs buffer.
Statistics.
Data are expressed as mean ± SEM. One-way analysis of variance (ANOVA) combined with Tukey’s post hoc test was used to test for differences in infarct size and baseline hemodynamics between groups. For differences in hemodynamics within groups, ANOVA with replication was used. For all tests, p < 0.05 was considered significant (SYSTAT, Version 5.0).
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Results
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Part A: in situ ethanol exposure and infarction.
Body weight, heart weight and size of risk zone were not different between groups (data not shown). Baseline hemodynamics were not different among groups (Table 1). Three doses of ethanol (0.35, 0.7, and 1.4 g/kg) were tested. Infusion of ethanol did not change heart rate and blood pressure. Diazoxide decreased blood pressure.
Infarct size in untreated hearts was 40.4 ± 3.1% of the risk zone (Fig. 3). A 10-min infusion of ethanol started 20 min prior to the onset of ischemia at the doses of 0.35, 0.7, and 1.4 g/kg did not limit infarct size (44.0 ± 3.0, 44.9 ± 3.4, and 60.3 ± 10.7%, respectively; Fig. 3). However, 0.35 g/kg ethanol infused 1 h before ischemia significantly reduced infarct size to 26.3 ± 3.9% (Fig. 3), suggesting that the ethanol serum level had to drop below a certain threshold level by the onset of ischemia before ethanol’s protection could be expressed. At the onset of ischemia, ethanol serum levels were 126 ± 11 mg/dl in the group exposed to 1.4 g/kg ethanol, 64 ± 5 mg/dl after 0.7 g/kg ethanol infusion, and 56 ± 5 mg/dl ( 12 mmol/liter) following 0.35 g/kg ethanol. When 0.35 g/kg ethanol was infused 1 h before ischemia, the ethanol serum level had dropped to 28 ± 2 mg/dl (6 mmol/liter) at the onset of ischemia.
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Figure 3 Effect of ethanol (E) on infarct size in the in situ preparation (part A). Open symbols, individual experiments; closed symbols, group means ± SEM. If the 10-min ethanol infusion were started 20 min prior to ischemia, infarct size was not affected. In contrast, a 10-min infusion of 0.35 g/kg ethanol started 1 h prior to ischemia significantly reduced infarct size in comparison to control. *p < 0.05 vs. Control.
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We tested whether an IPC-like protective effect of ethanol might have been masked by a nonspecific toxic effect of the alcohol during ischemia. Administration of the two potent IPC blockers staurosporine and genistein had no effect on infarct size in the heart not exposed to ethanol (42.0 ± 5.7%, Fig. 4). Furthermore, infarct size was not significantly increased by this combination in the presence of ethanol (47.0 ± 5.0%). If the putative IPC-like protection induced were being counterbalanced by a nonspecific toxic effect, then elimination of any possible IPC by the combination of staurosporine and genistein should have unmasked the toxic effect. This was not seen.
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Figure 4 Effects of ethanol (E) alone or with staurosporine (S) + genistein (G) on infarct size in the in situ preparation (part A). Open symbols, individual experiments; closed symbols, group means ± SEM. Combining genistein and staurosporine did not affect infarct size either in the absence or presence of ethanol.
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Both IPC and diazoxide reduced infarct size in situ (14.7 ± 3.3 and 18.4 ± 5.0%, respectively), but ethanol abolished protection from both interventions (51.0 ± 8.8 and 45.3 ± 4.0%, respectively, Fig. 5).
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Figure 5 Effects of ethanol (E), ischemic preconditioning (IPC), and diazoxide (D) on infarct size in the in situ preparation (part A). Open symbols, individual experiments; closed symbols, group means ± SEM. Ethanol abolished the reduction in infarct size induced by either IPC or diazoxide. *p < 0.05 vs. Control.
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Part B: in vitro ethanol exposure and infarction.
Body weight, heart weight and size of risk zone were not different between groups (data not shown). The baseline hemodynamics were also not different among groups (Table 2). Fifty but not 20 or 10 mmol/liter ethanol reduced developed pressure and coronary flow and increased heart rate. The prolonged infusion of 50 mmol/liter ethanol depressed both flow and pressure.
In control hearts, infarct size averaged 33.0 ± 2.8% of the risk zone (Fig. 6). Transient exposure to 10, 20, and 50 mmol/liter ethanol prior to ischemia reduced infarct size to 17.9 ± 3.2, 18.4 ± 3.5, and 16.8 ± 3.4%, respectively. When infusion was prolonged to include the ischemic period, neither 10 nor 50 mmol/liter ethanol limited infarct size (31.5 ± 3.8 and 39 ± 5.7%, respectively; Fig. 6).
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Figure 6 Effects of ethanol (E) on infarct size in the in vitro preparation (part B). Open symbols, individual experiments; closed symbols, group means ± SEM. Ten, 20, and 50 mmol/liter ethanol reduced infarct size when washed out prior to ischemia, whereas protection was lost when ethanol (10 or 50 mmol/liter) was continued throughout ischemia. *p < 0.05 vs. Control.
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Part C: in situ ethanol exposure followed by in vitro infarction.
In this protocol ethanol was infused intravenously for 10 min prior to excision of the heart and perfusion with ethanol-free buffer. When these in vitro hearts underwent ischemia, infarction was reduced (8.8 ± 2.7%; Fig. 7) as compared to that in hearts from untreated rabbits (31.4 ± 3.5%; Fig. 7). These data indicate that ethanol has the capacity to precondition the in situ heart, but effects of prolonged exposure can mask that protection.
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Figure 7 Effects of ethanol infusion in the open-chest rabbit followed by an ischemic insult in the Langendorff mode (hybrid preparation, part C). Open symbols, individual experiments; closed symbols, group means ± SEM. Ethanol exposure before excision of the hearts did confer protection as compared to hearts removed from untreated rabbits.
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Discussion
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The present data indicate that only transient preischemic ethanol exposure triggers cardioprotection in rabbits. When ethanol is present above a certain threshold during ischemia either in vitro or in situ, protection is lost. This loss of protection appears to be the consequence of a specific interference of ethanol with the mechanism of IPC.
Protection depends on the timing of ethanol exposure.
If the heart is exposed to a 5-min coronary occlusion and then reperfused, it quickly adapts itself to become resistant to infarction from a subsequently more severe ischemic insult (9). This protection, termed classical preconditioning, lasts for less than 1 h in anesthetized rabbits and then subsides (10). Twenty-four hours later a second wave of preconditioning appears, which is less potent but persists for several days (2). Previous studies in isolated guinea pig (11,12) and rat (12) hearts have demonstrated cardioprotection following chronic ethanol exposure. Ethanol was fed to the animals over many weeks and then withdrawn prior to study, suggesting a delayed type of preconditioning. Recent studies in rat hearts and cardiomyocytes (3) have revealed that acute ethanol exposure could also offer protection by a mechanism similar to that of classical preconditioning. However, infarct size was not determined in these studies, thus making it difficult to correlate ethanol’s protection to that of IPC.
In the present study, substitution of ethanol for a preconditioning ischemic period followed by washout prior to ischemia exerted a powerful anti-infarct effect in the isolated rabbit heart. These data support the hypothesis that acute ethanol exposure indeed mimics classical IPC. However, this protection is conditional. Importantly, ethanol failed to attenuate infarct size in the in situ rabbit model (part A) when ischemia closely followed the alcohol infusion. These findings are in concordance with a recent report from Itoya et al. (5). In their study, ethanol was also given 10 min before coronary artery occlusion in open-chest dogs, and this did not affect infarct size. In both their study and our experiments, ethanol serum levels were still high at the onset of ischemia. As seen in the present study, ethanol was capable of triggering a preconditioned state in the in situ heart, as confirmed by the small infarcts in hearts removed after ethanol infusion and subjected to ischemia in the absence of ethanol (part C). Furthermore, when we infused 0.35 g/kg ethanol in the open-chest model and then waited 50 min before starting ischemia, ethanol serum levels dropped sufficiently to remove the inhibitory effect of ethanol and to allow appearance of the preconditioned state.
Ethanol administration may increase plasma catecholamines and myocardial oxygen consumption in the in situ model (13–15). This basic difference between in situ and in vitro models, however, cannot totally explain the effects of ethanol in our experiments because protection was observed in the in situ protocol in which 50 min elapsed between alcohol administration and ischemia.
The timing of ethanol exposure is critical for the agent’s ability to reduce infarct size in situ. There seems to be a distinct threshold (between 6 and 12 mmol/liter in the in situ rabbit model) above which ethanol blocks its own initially induced protection. The threshold for inducing protection has yet to be determined. Chen et al. (3) observed protection in rat cardiomyocytes acutely exposed to 10 to 50 mmol/liter ethanol and then subjected to simulated ischemia either in the presence or absence of ethanol. In a limited series of three isolated rat hearts, exposure to 10 mmol/liter ethanol before and throughout global ischemia was also protective as assessed by creatine kinase release during reperfusion (3). In the present study, we also exposed isolated rabbit hearts to 10 mmol/liter ethanol. Short exposure followed by washout prior to ischemia was protective. However, unlike the case with rat hearts, protection was not evident when 10 mmol/liter ethanol was also present during ischemia. The threshold for blocking IPC-like behavior may well differ among species.
Ethanol exposure during ischemia interferes with the signaling cascade of IPC.
In our isolated heart experiments, transient exposure to ethanol had an anti-infarct effect that was equipotent with that of IPC. Isoform-selective translocation and activation of PKC is regarded as a critical step in the signaling pathway of classical (4) and delayed preconditioning in rabbits (16). Protection in rat cardiomyocytes following preincubation with ethanol and washout before ischemia was blocked by selective inhibition of PKC (3), as was protection from IPC (4).
Given the similarities between IPC and ethanol-induced protection we tested whether the loss of protection observed when ethanol was present during ischemia might have been the result of interference with IPC’s signaling cascade. The presence of high concentrations of ethanol during ischemia completely blocked protection from IPC in our in situ preparation, suggesting that ethanol during ischemia specifically blocks the IPC mechanism.
The combination of staurosporine and genistein produces the most potent blockade of IPC’s protection documented to date (17,18). Interestingly, the double blockade in the presence of ethanol infusion did not increase infarct size over that seen with ethanol alone. We had predicted that if IPC-related protection were removed, we might unmask a nonspecific toxic action of ethanol that would have then extended the infarcts. Because extension of infarct was not seen, we conclude that ethanol’s presence during ischemia selectively blocked the IPC mechanism.
We attempted to determine at which step of the signaling cascade of IPC does ethanol block protection. Ethanol infusion in situ was combined with diazoxide, an opener of mitochondrial KATP channels that are touted as end-effectors of IPC (19–21), and ethanol blocked diazoxide’s protection. If the mitochondrial KATP channels were the end-effectors, then abrogation of diazoxide’s protection would indicate an interaction with the channels themselves. Unfortunately, there is new evidence that mitochondrial KATP channels may not be the end-effectors of IPC, but may only be an upstream link in the signaling cascade (22).
Clinical implications.
Whether acute exposure to ethanol will protect a patient’s (in situ) heart becomes very dependent on the amount taken and the time before the onset of ischemia. Previous studies have reported reduced coronary mortality in individuals claiming moderate ethanol consumption and also loss of this protection at higher levels of consumption (23,24). Protection at moderate ethanol consumption is probably related to favorable effects on plasma lipids and hemostasis (23,25), as well as to a possible delayed preconditioning effect (1,11,12). However, the current findings suggest that the presence of ethanol above some threshold level during an ischemic episode will not only abolish the alcohol’s own acute preconditioning-like protection, but will also block any other protection the patient may have acquired. There is substantial evidence that a significant number of patients with acute myocardial infarction actually enjoy the benefits of a preconditioned state—be it from antecedent angina (26), delayed preconditioning from prior ethanol exposure, or drugs such as opioids (27). The presence of ethanol would be expected to obviate such effects, and, therefore, should be avoided in this setting.
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Footnotes
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This study was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute (Bethesda, Maryland); Deutsche Forschungsgemeinschaft (Bonn, Germany); Professor G. Heusch is on sabbatical leave from the University of Essen, Germany, and was supported by the Volkswagen-Stiftung (Hannover, Germany).
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T. Yamaguchi, C. Dayton, T. Shigematsu, P. Carter, T. Yoshikawa, D. C. Gute, and R. J. Korthuis
Preconditioning with ethanol prevents postischemic leukocyte-endothelial cell adhesive interactions
Am J Physiol Heart Circ Physiol,
September 1, 2002;
283(3):
H1019 - H1030.
[Abstract]
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H.-Z. Zhou, J. S. Karliner, and M. O. Gray
Moderate alcohol consumption induces sustained cardiac protection by activating PKC-epsilon and Akt
Am J Physiol Heart Circ Physiol,
July 1, 2002;
283(1):
H165 - H174.
[Abstract]
[Full Text]
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P. S. Pagel, J. G. Krolikowski, F. Kehl, B. Mraovic, J. R. Kersten, and D. C. Warltier
The Role of Mitochondrial and Sarcolemmal KATP Channels in Canine Ethanol-Induced Preconditioning In Vivo
Anesth. Analg.,
April 1, 2002;
94(4):
841 - 848.
[Abstract]
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K. J. Mukamal and M. A. Mittleman
Acute ethanol exposure fails to elicit preconditioning-like protection in in situ rabbit hearts because of its continued presence during ischemia
J. Am. Coll. Cardiol.,
October 1, 2001;
38(4):
1271 - 1271.
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Abstract
Materials and methods