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Anesth Analg 2003;96:665-672 © 2003 International Anesthesia Research Society
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Abstract |
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Chronic ingestion of small doses of ethanol protects the myocardium from ischemic damage. It was demonstrated that short-term administration of ethanol (SAE) enhances the recovery of stunned myocardium in acutely instrumented, anesthetized dogs. It is unclear whether this beneficial effect of SAE also occurs in awake dogs. Therefore, we investigated the effects of SAE on regional myocardial stunning in awake dogs. Thirty-six dogs were chronically instrumented for measurement of heart rate, left atrial, aortic, and left ventricular pressure, left systolic ventricular contactility (dP/dtmax) and diastolic ventricular function (dP/dtmin), and regional myocardial wall-thickening fraction (WTF). Occluders around the left anterior descending (LAD) artery allowed the induction of reversible ischemia in the LAD-perfused myocardium. The dogs were assigned to one of three groups that differed in the dose of ethanol administered in the ethanol experiment (I, 0.125 g/kg [n = 12]; II, 0.25 g/kg [n = 12]; III, 0.5 g/kg [n = 12]). In each group, the dogs underwent two ischemic episodes (randomized crossover fashion; separate days): 10 min of LAD occlusion after the application of ethanol IV over 30 min (ethanol group) and without ethanol (control). WTF and hemodynamic variables were measured at baseline and at predetermined time points until complete recovery of myocardial stunning occurred. LAD-ischemia led to a significant decrease of LAD-WTF in all groups. There was no difference in WTF and hemodynamic variables with or without SAE during reperfusion. We conclude that SAE (0.125 g/kg, 0.25 g/kg, and 0.5 g/kg) does not significantly affect myocardial stunning in conscious dogs.
IMPLICATIONS: In contrast to previous experiments in anesthetized dogs, short-term administration of ethanol does not alter myocardial stunning in conscious dogs.
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Introduction |
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A large number of epidemiological studies have demonstrated an inverse correlation between the regular consumption of alcohol and the incidence of coronary artery disease and myocardial infarction. Evidence has been provided by socioeconomic studies, as well as by retrospective or prospective studies, that only moderate and chronic consumption is beneficial (1). Chronic ingestion of small doses of ethanol protects the myocardium from ischemic damage (2–4), whereas the acute effects of ethanol on myocardial ischemic injury remain controversial. Bolus administration of small doses of ethanol immediately before a series of brief coronary artery occlusions and reperfusion enhances the functional recovery of stunned myocardium in acutely instrumented, barbiturate-anesthetized dogs (5). However, the effects of ethanol on the functional recovery of stunned myocardium in chronically instrumented conscious dogs without ischemic preconditioning remain uncertain. This investigation of chronically instrumented conscious dogs tests the hypothesis that small doses of ethanol ameliorates myocardial stunning in the awake state.
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Methods |
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The investigation is in accordance with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (NIH Publication No. 85–23, revised 1996). It was approved by the District Government of Münster.
After overnight fasting, 36 mongrel dogs (either sex; weight 21–30 kg) received IM premedication with piritramide 1 mg/kg and ketamine 5 mg/kg. The dogs were anesthetized IV with propofol 5 mg/kg. After tracheal intubation, anesthesia was maintained with isoflurane in a mixture of oxygen (35%) in air and supplemented by fentanyl (3–5 µg · kg-1 · h-1). Perioperative antibiotic prophylaxis was achieved with cefamandole 30 mg/kg. Details of the instrumentation methods have been published (6) and therefore are only briefly summarized. A left thoracotomy was performed in the fifth intercostal space under aseptic conditions. Size 18F catheters were inserted into the descending aorta and the left atrium (LA) for pressure measurement, injection of microspheres, administration of ethanol or 0.9% saline in a random manner, and withdrawal of blood. Blood ethanol concentrations were determined by using a standard enzymatic assay (7) before coronary artery occlusion. A pressure microtransducer (Janssen Pharmaceutica, Beerse, Belgium) was inserted in the left ventricle through an apical stab wound to measure left ventricular (LV) pressure. Pulsed Doppler blood flow velocity probes (20 MHz; Baylor College of Medicine, Houston, TX) were fitted around the left anterior descending (LAD) coronary artery. To measure the regional myocardial wall-thickening fraction (WTF), a 10-MHz pulsed Doppler crystal was sutured to the myocardium in the LAD-perfused area. Proximal to the Doppler flowprobe, a pneumatic occluder was positioned around the LAD (proximal to the first main diagonal branch) to induce reversible brief ischemic episodes in the LAD-perfused myocardium. After closure of the thorax, all leads were subcutaneously tunneled and exteriorized between the scapulae.
After instrumentation, the dogs were trained daily to accustom them to the experimental environment and to ensure that they could lie quietly in the cage when connected to the data acquisition system. Aortic and LA pressures were measured using disposable pressure transducers. Pressure, flow velocity, and wall-thickening signals (Fig. 1) were processed using a six-channel pulsed Doppler system (Baylor College of Medicine). The calculation of the WTF is as follows (8):equation
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The LV micromanometer was calibrated to the pressures measured in the aorta and LA. The LV pressure signal was electronically differentiated (Gould Inc., Cleveland, OH) to obtain LV systolic contactility (dP/dtmax) and LV diastolic function (dP/dtmin). All signals were digitally recorded. Experiments were only conducted after the dogs had recovered completely from the instrumentation and measurements of blood gas values and hemodynamic variables showed normal values. It took between 10 and 12 days after surgery until complete normalization of physiological variables occurred.
In detail, the experimental design was as follows: The dogs were assigned to one of three groups, and within the groups, each dog underwent two ischemic experiments (ethanol and control). The three groups differed with respect to the dose of ethanol (B. Braun Melsungen AG, D-34209 Melsungen, Germany, Ch.-B.: 8094Z21) administered during the ethanol experiment (Group 1 [n = 12], 0.125 g/kg; Group 2 [n = 12], 0.25 g/kg; and Group 3 [n = 12], 0.5 g/kg). The respective dose of ethanol was administered IV over a period of 30 min before the induction of regional ischemia. Within the groups, the order of ethanol or control experiment was randomized for each dog, i.e., half of the dogs had the first ischemic episode without pretreatment (control) and the second ischemic episode after pretreatment with ethanol, and the other half was in the opposite order (Fig. 5).
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Control Experiment
This experiment included the measurement of baseline values in the awake state, application of saline vehicle over 30 min, and the induction of 10 min of LAD ischemia, with a follow-up of WTF until complete recovery occurred.
Ethanol Experiment
This experiment included the measurement of baseline values in the awake state, application of 0.125 g/kg, 0.25 g/kg, or 0.5 g/kg of ethanol over 30 min, and the induction of 10 min of LAD ischemia, with follow-up of WTF until complete recovery occurred.
The second ischemic episode was only induced when there was complete recovery of regional myocardial function in the LAD-perfused area; the minimum time interval between the two experiments was 6 days. Criteria for complete recovery of myocardial function were return to the baseline hemodynamic values and baseline WTF.
Regional myocardial blood flow was measured using colored microspheres (Triton Technology, San Diego, CA). For each measurement, a total of 9 x 106 microspheres suspended in a volume of 3 mL of NaCl 0.9% was injected into the LA. The reference blood sample was withdrawn from the aortic catheter at a rate of 10 mL/min. The dogs were killed by injection of potassium chloride into the LA catheter during general anesthesia when regional myocardial function had completely recovered after the second ischemic episode. The heart was dissected, and three tissue samples were obtained from the LAD-perfused left ventricle in each dog. LAD samples were taken from the immediate vicinity of the wall-thickening probes. Only samples from dogs with severe ischemic dysfunction, as determined by the wall-thickening probe, were included (no dog had to be excluded because of insufficient dysfunction). Samples were further dissected into the subendocardial, subepicardial, and mid-myocardial layers. Measurement of microspheres in the tissue samples was performed, as previously described (9). Measurement of regional myocardial blood flow to the regions described was performed four times during the experiments as follows: (a) without ethanol and without ischemia (control), (b) without ethanol during ischemia, (c) after ethanol and without ischemia, and (d) after ethanol and during ischemia.
The experiments were conducted in chronically instrumented conscious dogs to avoid the effects of acute surgical trauma, anesthesia, volume and electrolyte imbalances, and temperature on recovery from stunning. Because multiple stun maneuvers may induce extensive development of coronary collaterals thus precluding the induction of postischemic dysfunction, the number of ischemic episodes was restricted to two in each dog.
The data were analyzed using repeated-measures two-way analysis of variance followed by Bonferroni-corrected Student’s t-test as appropriate after checking normal distribution with the program SPSS® version 10.0 (SPSS, Inc, Chicago, IL); P < 0.05 was considered significant. The data are presented as mean ± SD.
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Results |
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None of the dogs had to be excluded from the analysis because of insufficient dysfunction. The maximum degree of regional ischemic dysfunction was similar during the first and the second ischemic episode in each dog.
There were no significant changes in arterial blood pressure in either group during or after ischemia. LAD occlusion led to a significant increase of heart rate and LA pressure in ethanol and control experiments in all three groups (Table 1–3). Heart rate increased to significantly larger values compared with baseline for the first 5 min during reperfusion in all experimental groups. LA pressure increased to significantly larger values compared with baseline for the first 5 min during reperfusion only in the experimental group with 0.25 g/kg (n = 12) of ethanol. The induction of regional ischemia induced a significant alteration of LV dP/dtmax and LV dP/dtmin in both experiments, which lasted for the first 10 min during reperfusion, but there was no significant difference among the groups (Table 1–3).
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During LAD occlusion, LAD flow velocity decreased to zero and increased to significantly larger values compared with baseline for the first 10 min during reperfusion (Table 1–3). There were no statistically significant differences among the three groups.
In all dogs, severe regional myocardial dysfunction occurred during LAD occlusion. The induction of regional ischemia led to a significant reduction in WTF to negative values (wall thinning) in all three groups (Fig. 1–4). There were no differences among the groups in recovery of WTF after ischemia. Baseline WTF values were reached after 24 h of reperfusion with and without ethanol in all groups.
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During LAD occlusion, the subendocardial blood flow decreased significantly in all three groups (Table 4). There were no significant differences among the groups in subendocardial blood flow to the LAD-perfused area in the absence of ischemia with and without ethanol (Table 4).
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Discussion |
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Previously, Gross et al. (5) demonstrated that acute administration of ethanol doses that produce blood concentrations less than or equal to the intoxicating level improved the functional recovery of myocardial stunning after ischemic preconditioning in acutely instrumented anesthetized dogs. Although we used the same dose of ethanol (0.25 g/kg) in the same species (dogs) as in the investigation by Gross et al. (5), we failed to demonstrate an effect of ethanol on myocardial stunning, even with 0.125 g/kg and 0.5 g/kg of ethanol. However, two major differences in the experimental setting may account for this divergent observation. First, in our investigation, chronically instrumented, awake dogs were used. Second, we did not induce ischemic preconditioning (10,11) before the ischemic episode that elicits stunning (12) because we intended to investigate the effects of different doses of ethanol on stunning only (i.e., without confounding effects of measures affecting the postischemic recovery profile) (12). The duration of 10 minutes of LAD occlusion was chosen to produce a predictable postischemic dysfunction of sufficient severity and duration and also to avoid myocardial infarction (12,13).
There are obviously major differences between the acutely instrumented open-chest experiments used by other groups and the experimental model of awake, chronically instrumented dogs used in this investigation (14). The heterogenous experimental settings, which were used to describe myocardial stunning, are associated with heterogenous pathogenetic and pathophysiological changes in the reperfused myocardium (12). In each experimental model, the recovery profile of myocardial stunning, the metabolic and biochemical changes in the myocardial cell, are inevitably different, at least in part. The use of chronically instrumented experimental models allows the investigation of myocardial stunning without pertubating influences such as anesthesia and acute surgical stress (14). The severity of myocardial stunning is greatly exaggerated by the conditions present in the barbiturate-anesthetized open-chest dog (14).
Krenz et al. (15) described effects induced by acutely administered ethanol in rabbit hearts. These effects were, in part, similar to those of ischemic preconditioning. Acute transient ethanol exposure seems to exert a preconditioning-like protection in the ischemic myocardium. Protein kinase C and mKATP channels are involved in this ethanol-induced protection but not adenosine or free radicals.
The observed protective effects of acute ethanol exposure described by Gross et al. (5) are therefore explainable by an interaction between ethanol and ischemic preconditioning in the presence of barbiturate anesthesia. Barbiturates, in general, induce a depressive effect on the cardiovascular system (16). They also have a direct negative inotropic effect on a variety of heart-isolated preparations (17). Thus, thiopental decreases the Ca2+ current in dog (17) heart muscles. The mechanism of myocardial stunning has been studied extensively in rodents and is thought to involve a decrease in Ca2+ responsiveness of the myofilaments (12). The Ca2+ hypothesis is one of the major contributors to myocardial stunning. Avoiding this influence of barbiturates on the recovery profile of myocardial stunning, we investigated this phenomenon in the conscious dog during the absence of anesthesia.
Clinical and experimental data clearly identify beneficial cardiovascular actions associated with chronic, intermittent ingestion of only small amounts of ethanol (1). Most likely, changes of the oxidant balance in the heart or an activation of KATP channels by chronic ethanol exposure are responsible for these beneficial effects (18). The myocardial cell has developed very effective protective (i.e., antioxidant) mechanisms, such as superoxide dismutase and catalase, glutathione, vitamin E, and the generation of heat shock proteins (19,20). The myocardium is able to generate increased levels of these antioxidants because of very different stressors that induce free radicals (e.g., ischemia, sepsis, toxins, and ethanol) (21), but only chronically administered, small doses of ethanol that do not intoxicate the organism cause myocardial protection (22,23). Indeed, the acute effects of ethanol on myocardial ischemic damage remain controversial. Most of the data about ethanol and the ischemic myocardium demonstrate that only chronic ingestion of small doses of ethanol protects the myocardium from ischemic damage. Acute exposure of ethanol mediates dose-dependent cardioprotective effects in some acute experimental models only (e.g., the investigation by Krenz et al. (24)). The same is true for the experiments performed by Chen et al. (22) where isolated adult rat cardiac myocytes were used. This experimental setting is different from ours; therefore, it is not possible to apply the mentioned results directly to our findings. However, the described dose-dependent effects of ethanol on isolated adult rat cardiac myocytes do not conflict with our findings because subcellular enzyme modifications of the epsilon protein kinase C may occur without macrohemodynamic changes or cardioprotection in the conscious dog.
Current knowledge indicates that acute ethanol exposure fails to mediate cardioprotective effects on the ischemic myocardium in conscious humans and in conscious chronically instrumented animals. Protective effects of acute ethanol administration against ischemic damage were only found in experiments performed in acutely instrumented animals or in isolated organs (22,23) where acutely administered ethanol in concentrations between 0.5 to 6.0 g/kg reduced the extent of myocardial infarction in rats (25,26).
Our study has some limitations. The results obtained are restricted to dogs; there may be relevant species differences in severity and duration of the ischemic response and its modulation by ethanol. Some baseline values differ (e.g., arterial blood pressure or LV dP/dt) in Groups 2 and 3. Possible explanations are the different dog breeds that were used and the awake state of the dogs during the experiments. Because the same experimental condition was used in each dog twice in a randomized manner, a direct individual comparison to the intervention (with and without ethanol) is allowed. Certainly, some other features need to be considered. The induction of repetitive episodes of coronary artery occlusion may alter the functional response to subsequent ischemic episodes. However, this is not relevant when allowing enough time to elapse between the two experiments, as in our investigation (27). More than two or multiple episodes of myocardial stunning may produce a delayed preconditioning effect that could alter the results. By assigning the dogs to the two experiments in a crossover fashion, a bias of this phenomenon in favor of one experimental group can be excluded (12).
In conclusion, small doses of ethanol did not affect functional recovery from myocardial stunning in chronically instrumented conscious dogs without ischemic preconditioning. These data confirm the results of other investigators who also failed to demonstrate protective effects of acute administration of ethanol on ischemic myocardium in the awake state (1).
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