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© 2002 International Anesthesia Research Society
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Abstract |
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Chronic consumption of small doses of ethanol protects myocardium from ischemic injury. We tested the hypothesis that mitochondrial and sarcolem-mal adenosine triphosphate-dependent potassium (KATP) channels mediate these beneficial effects. Dogs (n = 76) were fed with ethanol (1.5 g/kg) or water mixed with dry food bid for 6 or 12 wk, fasted overnight before experimentation, and instrumented for measurement of hemodynamics. Dogs received intracoronary saline (vehicle), 5-hydroxydecano-ate (a mitochondrial KATP channel antagonist; 6.75 mg/kg over 45 min), or HMR-1098 (a sarcolemmal KATP channel antagonist; 45 µg/kg over 45 min) and were subjected to a 60 min coronary artery occlusion followed by 3 h of reperfusion. A final group of dogs was pretreated with ethanol and chow for 6 wk before occlusion and reperfusion. Myocardial infarct size and transmural coronary collateral blood flow were measured with triphenyltetrazolium chloride staining and radioactive microspheres, respectively. The area at risk of infarction was similar between groups. A 12-wk pretreatment with ethanol significantly reduced infarct size to 13% ± 2% (mean ± SEM; n = 8) of the area at risk compared with control experiments (25% ± 2%; n = 8), but a 6-wk pretreatment did not (21% ± 2%; n = 8). 5-hydroxydecanoate and HMR-1098 abolished the protective effects of 12-wk ethanol pretreatment (24% ± 2% and 29% ± 3%, respectively; n = 8 for each group) but had no effect in dogs that did not receive ethanol (22% ± 2% and 23% ± 4%, respectively; n = 8 for each group). No differences in hemodynamics or transmural coronary collateral blood flow were observed between the groups. The results indicate that mitochondrial and sarcolemmal KATP channels mediate ethanol-induced preconditioning in dogs independent of alterations in systemic hemodynamics or coronary collateral blood flow.
IMPLICATIONS: Mitochondrial and sarcolemmal KATP channels mediate ethanol-induced preconditioning independent of alterations in systemic hemodynamics or coronary collateral perfusion in vivo.
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Introduction |
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Adenosine triphosphate-dependent potassium (KATP) channels have been strongly implicated in myocardial protection against irreversible ischemic injury (1). This ischemic preconditioning (IPC) may result from activation of an intracellular signal transduction pathway that includes adenosine subtype 1 (A1) receptors (2), inhibitory guanine nucleotide binding proteins (3), and protein kinase C (PKC) (4). Experimental evidence obtained in rodents indicates that chronic ingestion of small amounts of ethanol also protects the myocardium from ischemic damage (5,6) by activating A1 (6) or
1-adrenergic (7) receptors and the 
isoform of PKC (8). These data suggest that signaling pathways responsible for IPC and chronic ethanol exposure-induced myocardial protection may be similar. We (9) recently demonstrated that chronic, intermittent ethanol consumption reduces myocardial infarct size in dogs independent of alterations in systemic hemodynamics and coronary collateral blood flow and termed this process chronic ethanol-induced preconditioning (CEPC). These beneficial effects were abolished by the nonselective KATP channel antagonist glyburide, indicating that KATP channels are involved in mediating CEPC. A role for mitochondrial KATP (mitoKATP) channels in IPC has been identified (10), and recent results obtained in rats implicate these channels in CEPC, as well (11). The role of sarcolemmal KATP (sarcKATP) channels in CEPC is unknown. We tested the hypothesis that chronic, intermittent ethanol ingestion reduces experimental myocardial infarct size by activation of mitoKATP and sarcKATP channels in vivo using the selective antagonists sodium 5-hydroxydecanoate (5-HD) and HMR-1098 (Aventis Pharma AG, Bridgewater, NJ) (12, 13), respectively. |
Methods |
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All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of Wisconsin. All conformed to the Guiding Principles in the Care and Use of Animals of the American Physiological Society and the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (Revised, 1996).
Mongrel dogs weighing between 25 and 30 kg were randomly assigned to receive dry dog chow (Lab Canine Diet, Richmond, IN) mixed with ethanol (1.5 g/kg) or an equal volume of water bid for 6 or 12 wk (9,14). Drinking water was provided ad libitum. We (9) have previously shown that the administration of ethanol using this method produces peak blood ethanol concentrations of 52 ± 4 mg/dL 45 min after eating. Dogs were fasted overnight before experimentation and did not receive ethanol on the day of experimentation.
Dogs were anesthetized with sodium barbital (200 mg/kg) and sodium pentobarbital (15 mg/kg) and ventilated with an air and oxygen mixture (fraction of inspired oxygen = 0.25) after intubation of the trachea, as previously described (9,15). Acid-base status and arterial blood gas tensions were maintained within the normal range by adjustment of respiratory rate and tidal volume throughout the experiment. After calibration, a double pressure transducer-tipped catheter (SPC-771, Millar Instruments Inc, Houston, TX) was inserted into the aorta and left ventricle (LV) through the left carotid artery to measure arterial and LV pressures. The maximal rate of increase of LV pressure (dP/dtmax) was obtained by electronic differentiation of the LV pressure-wave form. The femoral artery and vein were cannulated for the withdrawal of reference blood flow samples and fluid administration, respectively. A thoracotomy was performed in the left fifth intercostal space. A heparin-filled catheter was inserted into the left atrial appendage for the administration of radioactive microspheres. A 1.0-cm segment of the left anterior descending coronary artery (LAD) was dissected immediately distal to the first diagonal branch, and a silk ligature was placed around this vessel for production of coronary artery occlusion and reperfusion. Hemodynamic data were continuously monitored throughout the experiment, recorded on a polygraph, and digitized using a computer interfaced with an analog-to-digital converter.
At the conclusion of each experiment, the LAD was again occluded and cannulated at the occlusion site (15). Ten milliliters each of saline and patent blue dye were injected at equal pressure in the LAD and left atrium to delineate the anatomic area at risk (AAR) and the normal zone, respectively. The heart was fibrillated, removed, and sliced into serial 6- to 7-mm wide transverse sections. The unstained AAR was separated from the normal area, and the two regions were incubated for 20 min at 37°C in 1% 2,3,5-triphenyltetrazolium chloride on 0.1 mol/L phosphate buffer adjusted to a pH value of 7.4. Infarcted and noninfarcted myocardium within the AAR were separated and weighed after being stored overnight in 10% formaldehyde. Infarct size was expressed as a percentage of AAR.
Carbonized plastic microspheres (15 ± 2 µm [SD]) labeled with 95Nb, 141Ce, and 103Ru were used to measure myocardial perfusion, as previously described (15). Briefly, microspheres were administered into the left atrium as a bolus and flushed in with 10 mL of warm (37°C) saline. A few seconds before injection, a timed collection of reference arterial blood flow was started from the femoral arterial catheter at a rate of 7 mL/min for 3 min. Transmural tissue samples were selected from the ischemic region and subdivided into subepicardial, midmyocardial, and subendocardial layers of approximately equal thickness. Samples were weighed and placed in scintillation vials, and the activity of each isotope was determined. Similarly, the activity of each isotope in the reference blood flow sample was assessed. Tissue blood flow (mL · min-1 · g-1) was calculated as Qr · Cm/Cr, where Qr is the rate of withdrawal of the reference blood flow sample (mL/min), Cm is the activity (cpm/g) of the myocardial tissue sample, and Cr is the activity of the reference blood flow sample. Transmural blood flow was considered to be the average of the subepicardial, midmyocardial, and subendocardial blood flows.
The experimental design used in the present investigation is illustrated in Figure 1. Baseline hemodynamics were recorded 90 min after completion of the surgical preparation. All dogs were subjected to a 60-min LAD occlusion followed by 3 h of reperfusion. In six separate groups of experiments, dogs that consumed ethanol or water (control) mixed with dog chow for 12 wk were randomly assigned to receive intracoronary infusions of 0.9% saline, 5-HD (150 µg · kg-1 · min-1 in 10 mL of 0.9% saline over 45 min), or HMR-1098 (1 µg · kg-1 · min-1 in 10 mL of 0.9% saline over 45 min) 60 min before LAD occlusion and reperfusion. We have previously shown that these doses of 5-HD and HMR-1098 abolish volatile anesthetic-induced preconditioning in dogs (16). A final group of dogs was pretreated with ethanol for 6 wk, received an intracoronary infusion of 0.9% saline, and was subjected to a 60-min LAD occlusion and reperfusion. Dogs that developed intractable ventricular fibrillation, and those with a subendocardial coronary collateral blood flow 
0.15 mL · min-1 · g-1, were excluded from subsequent data analysis (1).
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Statistical analysis of data within and between the groups was performed with the analysis of variance with repeated measures followed by the Student’s t-test with Bonferroni’s correction for multiplicity. Changes within and between the groups were considered statistically significant when P < 0.05. Data are expressed as mean ± SEM.
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Results |
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All dogs consumed the assigned diet during the 6 or 12 wk pretreatment period. Seventy-six dogs were used to obtain 56 successful experiments. Eleven dogs were excluded from analysis because of intractable ventricular fibrillation during LAD occlusion or reperfusion (1 control, one 12-wk ethanol pretreatment, three 5-HD, four 12-wk ethanol pretreatment and 5-HD, one HMR-1098, and one 12-wk ethanol pretreatment and HMR-1098). Nine dogs were excluded because their subendocardial coronary collateral blood flow exceeded 0.15 mL · min-1 · g-1 (one control, two 5-HD, two 6-wk ethanol pretreatment, one 12-wk ethanol pretreatment, one 12-wk ethanol pretreatment and 5-HD, one HMR-1098, and one 12-wk ethanol pretreatment and HMR-1098).
No differences in baseline systemic hemodynamics were observed between the experimental groups (Table 1). Consumption of ethanol bid for 6 or 12 wk did not affect systemic hemodynamics. The intracoronary administration of 5-HD or HMR-1098 in the presence or absence of 12-wk ethanol pretreatment was also devoid of hemodynamic effects. Significant (P < 0.05) increases in LV end-diastolic pressure and decreases in dP/dtmax were observed during LAD occlusion and reperfusion. Heart rate, mean arterial and LV systolic pressures, and rate-pressure product were unchanged during LAD occlusion and reperfusion. No differences in systemic hemodynamics were observed between the groups during occlusion or reperfusion.
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The AAR of the LV was similar between groups (control 39% ± 2%, 6-wk ethanol pretreatment 38% ± 2%, 12-wk ethanol pretreatment 40% ± 2%, 5-HD 38% ± 3%, 12-wk ethanol pretreatment and 5-HD 45% ± 3%, HMR-1098 38% ± 3%, and 12-wk ethanol pretreatment and HMR-1098 36% ± 2%). The 12-wk pretreatment with ethanol significantly reduced myocardial infarct size to 13% ± 2% of the AAR (Figs. 2–5) compared with control experiments (25% ± 2%). In contrast, the 6-wk pretreatment with ethanol did not affect infarct size (21% ± 2%). 5-HD and HMR-1098 abolished the protective effects of 12-wk ethanol pretreatment (24% ± 2% and 29% ± 3%, respectively) but had no effect in dogs that did not receive ethanol (22% ± 2% and 23% ± 4%, respectively). Consumption of ethanol for 6 or 12 wk did not affect baseline regional myocardial perfusion. No differences in transmural coronary collateral blood flow (Table 2) were observed between groups.
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Significantly (P < 0.05) different from 5-HD; 
Significantly (P < 0.05) different from 12-WK ETOH+5-HD; 
Significantly (P < 0.05) different from HMR; ¶Significantly (P < 0.05) different from 12-WK ETOH+HMR.
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Discussion |
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Chronic consumption of small amounts of ethanol improves survival in patients after acute myocardial infarction (17), but the mechanisms responsible for this protective effect have not been fully elucidated. We (9) and others (5–8,11) have shown that chronic, moderate ethanol consumption protects myocardium from irreversible ischemic injury by a signal transduction pathway that is similar to that implicated in IPC. The present results confirm these previous findings, indicating that chronic ethanol ingestion reduces the extent of myocardial infarction. In contrast to 12 weeks of pretreatment, 6-week exposure to ethanol did not protect against infarction. These data confirm previous observations (6) that indicate that a minimum duration of ethanol consumption appears to be required for CEPC to occur. The reduction in infarct size produced by chronic ethanol ingestion observed in dogs occurred independently of alterations in systemic hemodynamics and transmural coronary collateral blood flow. Nevertheless, a role for coronary vascular endothelium has been suggested in IPC (18) and cannot be strictly excluded in CEPC solely on the basis of the measurements of regional coronary perfusion in vivo conducted in the present investigation. Other studies conducted in rats (5,7,11) and guinea pigs (6–8) did not quantify regional myocardial perfusion during experimentation nor assess blood ethanol concentrations during pretreatment. The present results also indicate that the beneficial effect of a 12-week pretreatment with ethanol was blocked by 5-HD and HMR-1098, suggesting that CEPC is mediated by both mitoKATP and sarcKATP channels in dogs.
A recent study (11) demonstrated that exposure to 18% ethanol in drinking water for 10 months enhanced the recovery of LV function and reduced creatine kinase release in Langendorff-prepared rat hearts subjected to global ischemia and reperfusion when compared with those pretreated with water alone. These salutary actions were abolished by 5-HD, implicating mitoKATP channels in this process. In contrast to the continuous administration of ethanol in drinking water described by these authors (11), the present investigation used the intermittent administration of ethanol with ad libitum access to fresh drinking water during the pretreatment period. This method of administration may more closely resemble moderate ethanol consumption with meals in humans. Myocardial protection associated with this method of administration occurred after ethanol had been withheld the night before experimentation, which is in contrast to the presence of an average blood ethanol concentration of 3 mmol/L immediately before experimentation as described by Zhu et al. (11). Acute exposure to ethanol concentrations as small as 10 mmol/L has recently been shown to produce direct protective effects against ischemic damage in ventricular myocytes and isolated hearts (19,20) and enhance the functional recovery of stunned myocardium in vivo (21). Thus, it remains possible that these previous results (11) were influenced to some degree by the presence of ethanol immediately before experimentation.
The intracellular signal transduction cascade responsible for CEPC is incompletely understood. A role for A1 receptor activation was implicated in this process (6), and an important connection between A1 receptors and KATP channels has been established during IPC (2). Adenosine-mediated priming of mitoKATP channels was also recently suggested as a critical element in IPC (22). A similar mechanism may be activated to produce CEPC. Chronic, moderate ethanol ingestion translocates the isoform of PKC (8). Activation of this isoform of PKC is also important in the intracellular signaling that occurs during IPC (4), is directly linked to KATP channels (23), and is synergistically enhanced by the administration of adenosine (24). The previous and present investigations suggest that the signaling pathways responsible for CEPC and IPC share a number of common features, including a role for mitoKATP channels in the reduction of irreversible ischemic injury. The results further suggest that sarcKATP channels were also involved in canine CEPC because the selective HMR-1098 sarcKATP channel antagonist abolished the protective effects of ethanol pretreatment. Whether sarcKATP channels play an important role in IPC remains highly controversial (25). The sarcKATP channel independently mediates IPC in dogs (26) but not rats (27) or rabbits (28), and evidence for the involvement of both channels in IPC has been presented (26,29). Both sarcKATP and mitoKATP channels have also been implicated in myocardial protection against infarction associated with the administration of the volatile anesthetic desflurane in dogs (16). These latter data suggest that cross talk between these two channels may occur during IPC (25) or anesthetic-induced preconditioning (16). Such a phenomenon may also account for the involvement of both sarcKATP and mitoKATP channels in CEPC, but this hypothesis remains to be examined.
The present results should be interpreted within the constraints of several potential limitations. The specificity of 5-HD for mitoKATP channels has not been definitively established in canine myocardium, but several previous studies suggest that 5-HD preferentially blocks mitoKATP channels at a concentration (30–33) similar to that achieved (approximately 450 µmol/L) during intracoronary administration in the present investigation. Similar concentrations of 5-HD also abolished the protective effects of the selective mitoKATP channel opener diazoxide (10) and inhibited mitochondrial flavoprotein oxidation produced by the KATP channel agonist pinacidil in the absence of alterations in sarcKATP channel current (33). In addition, 5-HD antagonized the beneficial effects of the KATP channel agonist cromakalim without affecting action potential duration (32), an action known to be mediated by sarcKATP channels (34). However, the effects of chronic ethanol ingestion on the activity of mitoKATP channels in vitro were not specifically examined in the present investigation and will require further study using flavoprotein fluorescence techniques to define. The administration of 5-HD did not produce systemic hemodynamic effects or affect coronary collateral blood flow in dogs in the presence and absence of ethanol pretreatment. Thus, the possibility that drug toxicity resulting from the administration of 5-HD influenced the results seems unlikely. HMR-1098 is the water-soluble salt of the selective sarcKATP channel antagonist HMR-1883 (12). Recent data indicate that HMR-1098 is highly selective for sarcKATP channels (13) at a concentration similar to that achieved in the present investigation (approximately 1 µmol/L; estimated assuming a coronary blood flow of 40 mL/min). Nevertheless, the specificity of HMR-1098 has not been examined in canine myocardium, and it remains possible that this drug may not be entirely selective for sarcKATP channels. The present results also require qualification because oral ingestion of the dose of ethanol used in this investigation may produce larger blood ethanol concentrations in humans than dogs, although the pharmacokinetics of ethanol seem to be similar between these species.
In summary, the present results demonstrate that chronic, intermittent consumption of subintoxicating amounts of ethanol reduces myocardial infarct size. This protective effect was abolished by the selective mitoKATP and sarcKATP channel antagonists 5-HD and HMR-1098, indicating that these channels mediate CEPC in dogs.
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Acknowledgments |
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Supported, in part, by grants AA-12331, HL-03690, HL-63705, HL-54820, and GM-08377 from the United States Public Health Service, Bethesda, Maryland.
The authors thank David A. Schwabe and John P. Tessmer for technical assistance.
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