Effects Of Moderate Ethanol Consumption Research Articles

Abstract P2026: Moderate Ethanol Consumption Causes Right Ventricular Hypertrophy And Pulmonary Hypertension Via The Pro-inflammatory Endothelin-interleukin Pathway

The substantial increase in ethanol consumption since the Covid-19 pandemic has re-emphasized the need for extensive preclinical research on the cardiac and pulmonary effects of ethanol. Current knowledge is mostly based on ethanol effects on left ventricular (LV) function and blood pressure. Therefore, this preclinical study dealt with the effects of moderate ethanol consumption on right ventricular (RV) and pulmonary artery (PA) structure and function, and the implicated mechanisms in a pulmonary hypertension susceptible rat strain. Two groups of Sprague-Dawley (CD strain) male rats (n=7-8 each) received balanced liquid diet containing 5% ethanol (w/v) or pair-fed with isocaloric liquid diet for 8 weeks. This ethanol regimen resulted in clinically relevant blood ethanol concentration (39.8 + 1.9 mg/dL). Echocardiographic analysis showed progressive decreases in PA acceleration time/ejection time and increases in mean PA pressure (hallmarks of pulmonary hypertension) in ethanol-fed rats. Further, transthoracic echocardiography in long-axis orientation showed a significant increase in the RV internal diameter/left ventricular internal diameter during diastole (RVID-d/LVID-d), indicative of RV dilation in chronic ethanol-treated rats. Echocardiographic LV Mass/body weight and post-mortem Fulton’s index were higher in ethanol-fed rats, suggesting ethanol induced simultaneous LV and RV hypertrophy. Further, ethanol increased mean arterial pressure (measured at the end of the 8-weeks study). Ex vivo biochemical analyses showed upregulation of the vasoconstrictor/pro-inflammatory protein endothelin-1 (ET-1) and its downstream target IL-6 in the RV and lungs of ethanol-fed rats. Finally, ethanol reduced lung endothelin ETB receptor expression but had no effect on the ETA receptor, leading to higher ETA/ETB receptor ratio. Collectively, this study yields new insight into ethanol-evoked RV and pulmonary artery remodeling via the upregulation of the ET-1-IL-6 pathway.

Effects of moderate ethanol consumption as a function of n-6:n-3 dietary ratio on lipid profile, inflammation, and liver function in mice

ObjectiveIt is critical to understand how moderate ethanol exposure interacts with dietary components such as essential fatty acids to influence inflammatory processes underlying CVD pathogenesis. The purpose of this study was to examine the effects of moderate ethanol consumption and dietary n-6:n-3 fatty acid composition on markers associated with CVD in mice. MethodsTwenty-three C57BL/6J mice consumed an 18% ethanol solution or 26.9% maltose dextrin solution (isocaloric control) for 12 weeks. Within each group, the mice were fed either a high n-6 (n-6:n-3 = 50:1) diet or a balanced n-3 (n-6:n-3 = 1:1) diet ad libitum. Following the exposure period, serum samples were analyzed to assess lipid profile, inflammatory markers, antioxidant capacity, DNA damage, and liver function enzyme activity. ResultsThe control group gained more weight than the ethanol group (P = 0.020). In ethanol-exposed mice, HDL was significantly increased (P = 0.009). C-reactive protein (CRP; P < 0.001), high mobility group box 1 protein (HMGB1; P = 0.011), 8-oxo-deoxyguanosine (8-oxo-dG; P = 0.019), ALT (P = 0.002) and AP (P = 0.021) were lower in the ethanol group. There was a significant main effect of the n-3 diet on total antioxidant capacity (TAC; P < 0.001) and 8-oxo-dG (P = 0.047). ConclusionThese findings indicate that moderate ethanol consumption and a balanced n-6:n-3 diet improve several inflammatory and lipid markers associated with CVD. Observed differences in weight gain between groups should be considered when interpreting these results.

Effects of Moderate Ethanol Consumption with a n‐3 Diet on Inflammation and Total Antioxidant Capacity in Mice

Excessive alcohol intake is known to elevate risk for cardiovascular diseases (CVD); however, several studies have reported that moderate alcohol consumption may not contribute additional risk or may provide a protective effect against CVD. It is critical to understand how moderate ethanol exposure interacts with other essential dietary components such as n-3 fatty acids to influence inflammation underlying CVD pathogenesis. The purpose of this study was to examine the effects of moderate ethanol consumption as a function of dietary n-6:n-3 fatty acid composition on markers associated with inflammation and total antioxidant capacity (TAC) in mice. Twenty-three mice (12 male, 11 female) consumed an 18% ethanol solution or 26.9% maltose dextrin solution (non-ethanol isocaloric control) for 12 weeks. In each group, half of the mice were fed either a high n-6 (n-6:n-3 = 50:1) diet or a balanced n-3 (n-6:n-3 = 1:1) diet ad libitum. There were no differences in initial body weight between the two groups; however, the control group gained significantly more weight than the ethanol group (P = 0.020) associated with higher maltose dextrin fluid intake (P < 0.001). C-reactive protein and high mobility group box 1 protein were significantly lower in the ethanol group compared to the control group (P < 0.001 and P = 0.029, respectively). There was a significant main effect of n-3 diet on total antioxidant capacity (TAC; P < 0.001) and no significant effect of ethanol on TAC. These findings indicate that moderate consumption of alcohol may improve inflammatory markers associated with CVD in mice; however, the results should be interpreted with caution due to the differences in weight gain between groups.

Effects of Moderate Ethanol Consumption with a n‐3 Diet on Lipid Profile and Liver Function in Mice

Several studies have found a non‐linear relationship between alcohol consumption and cardiovascular disease (CVD) risk, suggesting that low or moderate consumption of alcohol may provide cardioprotective effects, while excessive alcohol consumption increases the risk of CVD. Studies also suggest that increased dietary consumption of n‐3 fatty acids may reduce CVD risk. The purpose of this study is to examine the effects of moderate ethanol consumption as a function of dietary n‐6:n‐3 fatty acid composition on markers associated with cardiovascular disease and liver dysfunction in mice. Twenty‐three mice (12 male, 11 female) consumed an 18% ethanol solution or 26.9% maltose dextrin solution (non‐ethanol isocaloric control) for 12 weeks. In each group, half of the mice were fed either a high n‐6 (n‐6:n‐3 = 50:1) diet or a balanced n‐3 (n‐6:n‐3 = 1:1) diet ad libitum. There were no differences in initial body weight between the two groups; however, the control group gained significantly more weight than the ethanol group (P = 0.020) associated with higher maltose dextrin fluid intake (P &lt; 0.001). In the control group, the balanced n‐3 diet resulted in significantly lower aspartate aminotransferase (AST) levels (P = 0.010) compared to the high n‐6 diet. In the ethanol group, the balanced n‐3 diet resulted in lower levels of serum triglycerides (P = 0.086), total cholesterol (P= 0.096), and low‐density lipoprotein (LDL) levels (P = 0.053) that were approaching significance. These findings indicate that a diet with a balanced n‐6 to n‐3 ratio may improve several lipid profile markers associated with CVD in mice who concurrently consume moderate amounts of alcohol.Support or Funding InformationNIH AA023291

Inflammation Biomarkers in Older Adult Rats Consuming Moderate Levels of Ethanol

Previous epidemiological studies and experimental data from rodent models have reported a non‐linear relationship between consumption of alcohol and cardiovascular disease risk and colorectal health. These studies indicate that light‐to‐moderate alcohol consumption, in contrast to excessive alcohol use, may provide cardiovascular health benefits as well as a protective effects on risk for colorectal cancer. Although prior studies have examined the effects of moderate ethanol consumption primarily in young adult animals, it is unknown if the results can be extrapolated to older adults or if these effects may be more pronounced in aging animals due to declining indices of health.. This study examined the effects of moderate ethanol consumption on lipid profile and colonic gene expression in older rats. Twenty‐four non deprived middle aged (420 days old) Wistar rats (n=12/group) were allowed to voluntarily consume a 20% v/v ethanol solution on alternate days for 13 weeks or were given access to water as their sole source of fluid (non‐ethanol exposed control). Moderate ethanol consumption significantly increased HDL cholesterol levels (P = 0.016) and ApoA1 (P = 0.048) compared to control. There were no differences in serum triglyceride, total cholesterol, LDL cholesterol, oxidized LDL and glucose between the groups. Blood C‐reactive protein (CRP) was decreased significantly (P = 0.034) in ethanol‐exposed animals. Blood high‐mobility group protein 1 (HMGB1) showed a decreased trend in the ethanol group (P = 0.083). In colon, gene expression of aldehyde dehydrogenase (Aldh) displayed an increased trend in ethanol‐exposed rats (P = 0.073). Colonic superoxide dismutase (Sod) was upregulated with ethanol intervention (P = 0.050). Colonic gene expression of cyclooxygenase 2 (Cox‐2), RelA, b‐catenin, CD68, and Pparr were not different between the groups. These results suggest that moderate consumption of ethanol in older rats may potentially contribute to improved cardiovascular and colorectal cancer risk by improving blood cholesterol, decreasing blood markers of inflammation in and increasing antioxidant enzyme expression in colon.Support or Funding InformationNIH AA023291

Effects of Moderate Ethanol Consumption on Lipid Metabolism and Inflammation Through Regulation of Gene Expression in Rats.

Epidemiological studies and experimental data from rodent models have reported a non-linear relationship between consumption of alcohol and cardiovascular disease (CVD) risk that suggests that light-to-moderate drinking as opposed to excessive consumption may provide some cardiovascular benefits. The present study examined potential mechanisms by which moderate alcohol consumption may provide a protective effect against CVD. Wistar rats exposed for 3 months to a 20% ethanol intermittent-access voluntary drinking paradigm displayed a reduction in epididymal fat, blood glucose and non-HDL and total cholesterol. These effects were accompanied by decreased expression of Hmgcr, Srebp-2, Cox-2 and RelA, indicating downregulation of genes involved in cholesterol synthesis and inflammation. Twenty-four male Wistar rats voluntarily consumed a 20% v/v ethanol solution on alternate days for 13 weeks (ethanol-treated) or were given access to water alone (non-ethanol-exposed control). There was no difference in body weight gain between the two groups, however, epididymal fat weight was lower in ethanol-fed rats (P = 0.030). Blood glucose, total cholesterol, non-high-density lipoprotein (HDL) and oxidized low-density lipoprotein (LDL) levels were lower in the ethanol group compared to controls (P < 0.05). There was a significant reduction in the expression of hydroxymethylglutaryl-coenzyme A reductase and sterol regulatory element-binding protein-2 in ethanol-treated rats (P < 0.05), suggesting that ethanol may have lowered cholesterol levels via downregulation of genes involved in cholesterol synthesis. Paraoxonase-1, which is associated with inhibition of LDL cholesterol oxidation, was upregulated in the ethanol group (P = 0.029). Ethanol-treated rats exhibited significantly lower levels of high-mobility box group protein 1 (P ≤ 0.05). Cyclooxygenase-2 and RelA gene expression were significantly lower in ethanol-treated rats (P < 0.05), indicating possible anti-inflammatory effects. These findings suggest that moderate ethanol consumption may potentially contribute to improved cardiovascular outcomes by reducing body fat, improving blood cholesterol and blood glucose, and modulation of gene expression involved in inflammation and/or cholesterol synthesis.

Effects of Moderate Ethanol Consumption on Lipid Metabolism and Inflammation through Regulation of Gene Expression in Rats

Evidence supports a J or U‐shaped correlation with consumption of alcohol and cardiovascular disease (CVD) risk and suggests that light to moderate drinking as opposed to excessive consumption may provide some cardiovascular benefits. The present study examined the underlying mechanisms of how moderate alcohol consumption provides a protective effect against cardiovascular disease. Twenty‐four 109 day old, male Wistar rats were divided into a control group and a treatment group (n=12/group). The treatment group was administered a 20% v/v ethanol solution on alternate days for 12 weeks. There was no difference in body weight gain between the two groups, however, epididymal fat weight was lower in ethanol‐fed rats (P=0.030). Blood glucose was lower in the ethanol group compared to control (P=0.030). Total cholesterol levels (P=0.036) and LDL‐cholesterol levels (P=0.031) were also lower in the ethanol group. There was a significant reduction seen in the expression of hydroxymethylglutaryl‐coenzyme A reductase (Hmgcr) and sterol regulatory element‐binding protein‐2 (Srebp‐2) in the ethanol group (P=0.026 and P=0.034, respectively), suggesting that ethanol lowers cholesterol levels via downregulation of genes involved in cholesterol synthesis. Paraoxonase‐1 (Pon‐1), which is associated with inhibition of LDL‐cholesterol oxidation, was upregulated in the ethanol group (P=0.029). Cyclooxygenase‐2 (Cox‐2) and nuclear factor NF‐kappa‐B p65 subunit (Rela) gene expression was significantly decreased in ethanol‐treated rats (P=0.016 and P=0.047, respectively), indicating possible anti‐inflammatory effects. These findings suggest that moderate ethanol consumption may reduce the risk of CVD by reducing body fat, improving blood cholesterol and blood glucose, and modulation of gene expression involved in inflammation.Support or Funding InformationThis study was funded by NIH AA02329 and supported by San Diego State University N302L Advanced Nutrition Laboratory.

Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P) Rats.

Heavy alcohol consumption has detrimental neurologic effects, inducing widespread neuronal loss in both fetuses and adults. One proposed mechanism of ethanol-induced cell loss with sufficient exposure is an elevation in concentrations of bioactive lipids that mediate apoptosis, including the membrane sphingolipid metabolites ceramide and sphingosine. While these naturally-occurring lipids serve as important modulators of normal neuronal development, elevated levels resulting from various extracellular insults have been implicated in pathological apoptosis of neurons and oligodendrocytes in several neuroinflammatory and neurodegenerative disorders. Prior work has shown that acute administration of ethanol to developing mice increases levels of ceramide in multiple brain regions, hypothesized to be a mediator of fetal alcohol-induced neuronal loss. Elevated ceramide levels have also been implicated in ethanol-mediated neurodegeneration in adult animals and humans. Here, we determined the effect of chronic voluntary ethanol consumption on lipid profiles in brain and peripheral tissues from adult alcohol-preferring (P) rats to further examine alterations in lipid composition as a potential contributor to ethanol-induced cellular damage. P rats were exposed for 13 weeks to a 20% ethanol intermittent-access drinking paradigm (45 ethanol sessions total) or were given access only to water (control). Following the final session, tissues were collected for subsequent chromatographic analysis of lipid content and enzymatic gene expression. Contrary to expectations, ethanol-exposed rats displayed substantial reductions in concentrations of ceramides in forebrain and heart relative to non-exposed controls, and modest but significant decreases in liver cholesterol. qRT-PCR analysis showed a reduction in the expression of sphingolipid delta(4)-desaturase (Degs2), an enzyme involved in de novo ceramide synthesis. These findings indicate that ethanol intake levels achieved by alcohol-preferring P rats as a result of chronic voluntary exposure may have favorable vs. detrimental effects on lipid profiles in this genetic line, consistent with data supporting beneficial cardioprotective and neuroprotective effects of moderate ethanol consumption.

Ethanol impairs intestinal barrier function in humans through mitogen activated protein kinase signaling: a combined in vivo and in vitro approach.

BackgroundEthanol-induced gut barrier disruption is associated with several gastrointestinal and liver disorders.AimSince human data on effects of moderate ethanol consumption on intestinal barrier integrity and involved mechanisms are limited, the objectives of this study were to investigate effects of a single moderate ethanol dose on small and large intestinal permeability and to explore the role of mitogen activated protein kinase (MAPK) pathway as a primary signaling mechanism.MethodsIntestinal permeability was assessed in 12 healthy volunteers after intraduodenal administration of either placebo or 20 g ethanol in a randomised cross-over trial. Localization of the tight junction (TJ) and gene expression, phosphorylation of the MAPK isoforms p38, ERK and JNK as indicative of activation were analyzed in duodenal biopsies. The role of MAPK was further examined in vitro using Caco-2 monolayers.ResultsEthanol increased small and large intestinal permeability, paralleled by redistribution of ZO-1 and occludin, down-regulation of ZO-1 and up-regulation of myosin light chain kinase (MLCK) mRNA expression, and increased MAPK isoforms phosphorylation. In Caco-2 monolayers, ethanol increased permeability, induced redistribution of the junctional proteins and F-actin, and MAPK and MLCK activation, as indicated by phosphorylation of MAPK isoforms and myosin light chain (MLC), respectively, which could be reversed by pretreatment with either MAPK inhibitors or the anti-oxidant L-cysteine.ConclusionsAdministration of moderate ethanol dosage can increase both small and colon permeability. Furthermore, the data indicate a pivotal role for MAPK and its crosstalk with MLCK in ethanol-induced intestinal barrier disruption.Trial RegistrationClinicalTrials.gov NCT00928733

The neuroprotective effect of acute moderate alcohol consumption on caspase-3 mediated neuroapoptosis in traumatic brain injury: The role of lysosomal cathepsin L and nitric oxide

Our aim in this study was to investigate the effect of moderate acute alcohol administration on cysteine protease mediated neuronal apoptosis and nitric oxide production in the traumatic brain injury. A total of 29 adult Sprague–Dawley male rats weighing 250–300g were used. The rats were allocated into four groups. The first group was the control (sham-operated) group in which only a craniotomy was performed, the others were alcohol, trauma and trauma+alcohol groups. Caspase-3 enzyme activity in the trauma group increased significantly in comparison with the control group. The alcohol given group showed a decreased caspase-3 enzyme activity compared to the trauma group. The level of caspase-3 enzyme activity in the alcohol+trauma group decreased in comparison to the trauma group. SF/FEL ratio of cathepsin-L enzyme activity in the trauma group was significantly higher than in the control group. Our results indicate that moderate alcohol consumption may have protective effects on apoptotic cell death after traumatic brain injury. Protective effects of moderate ethanol consumption might be related to inhibition of lysosomal protease release and nitric oxide production.

Ethanol protects from injury due to ischemia and reperfusion by increasing vascularity via vascular endothelial growth factor

The cardioprotective effects of moderate ethanol consumption have been known for years and have generally been ascribed to long-term effects of alcohol on blood lipids. However, other mechanisms, particularly ethanol-induced increase in blood vessel density, may also be involved. Our goal was to understand the relationship between ethanol consumption, new blood vessel formation in vivo and protection from injury due to ischemia and ischemia/reperfusion. Using paired ethanol fed and control rats, we assessed capillary density in the heart, brain and skeletal muscle by immunostaining and quantified expression of vascular endothelial growth factor (VEGF) by Western blot analysis and immunocytochemistry. Numbers of vessels were significantly increased in the brain, heart and skeletal muscle of animals fed ethanol-rich diets. VEGF (and its receptors) were upregulated in these organs. These effects were very rapid: highly significantly increased vascularization was seen within 2 weeks of commencing alcohol feeding. A neutralizing VEGF antibody, bevacizumab, inhibited new blood vessel formation induced by moderate doses of ethanol. Ethanol consumption increased vascularization and promoted skeletal muscle regeneration following hindlimb ischemia; these effects were prevented by bevacizumab. Finally, ethanol consumption protected myocardium following experimental ischemia/reperfusion. Conclusion: Experimental ethanol ingestion rapidly increases VEGF production, significantly increasing the capillary bed in the heart, brain, and skeletal muscle. Moreover, the ethanol-induced increase of blood vessel density is protective against ischemic events (i.e., hindlimb ischemia and myocardium ischemia/reperfusion) and promotes skeletal muscle regeneration.

The effect of ethanol and its metabolism on fibrinolysis

The role of ethanol metabolism in possible haemostatic cardioprotective effects has not yet been determined. To this end, we investigated the effect of a moderate dose of ethanol (35 g) and its metabolism, on haemostatic variables over 14 hours (h). Eighteen Caucasian males participated in a placebo-controlled, randomised, cross-over study. Blood was collected prior to alcohol consumption, and at 10 time points for 14 h. Blood ethanol peaked at 1 h and was cleared after 8 h following ethanol consumption, significantly increasing plasma acetate (p=0.0028). Ethanol did not influence the coagulation factors significantly. PAI-1act increased (p<0.0001) and tPAact (p=0.047) decreased following alcohol consumption, reaching maximum (0.69 to 22.2 IU/ml) and minimum (0.88 to 0.33 IU/ml) levels at 5 h, respectively. Significantly increased plasma clot lysis times (46.8 to 67.6 minutes) and reduced global fibrinolytic capacity of whole blood, measured as D-dimer production during incubation of blood clots (2.26 to 0.29 μg/ml), were found at 5 h. Except for PAI-1act (borderline significance; p=0.05), there was no significant difference in the fibrinolytic markers between the two groups the following morning. Moderate ethanol consumption resulted in a significant temporary fibrinolysis inhibition. Any protective effects of moderate ethanol consumption on cardiovascular disease do not appear to be due to improvement in fibrinolytic potential within the first 14 h following consumption. The use of global fibrinolytic assays is recommended for determining the true effect of ethanol on fibrinolysis.

Acute ethanol increases angiogenic growth factor gene expression in rat skeletal muscle.

Moderate ethanol consumption demonstrates a protective effect against cardiovascular disease and improves insulin sensitivity, possibly through angiogenesis. We investigated whether 1) ethanol would increase skeletal muscle growth factor gene expression and 2) the effects of ethanol on skeletal muscle growth factor gene expression were independent of exercise-induced growth factor gene expression. Female Wistar rats were used. Four groups (saline + rest; saline + exercise; 17 mmol/kg ethanol + rest; and 17 mmol/kg ethanol + exercise) were used to measure the growth factor response to acute exercise and ethanol administration. Vascular endothelial growth factor (VEGF), transforming growth factor-beta(1) (TGF-beta(1)), basic fibroblast growth factor (bFGF), Flt-1, and Flk-1 mRNA were analyzed from the left gastrocnemius by quantitative Northern blot. Ethanol increased VEGF, TGF-beta(1), bFGF, and Flt-1 mRNA at rest and after acute exercise. Ethanol increased resting Flk-1 mRNA. Ethanol increased bFGF mRNA independently of exercise. These findings suggest that 1) ethanol can increase skeletal muscle angiogenic growth factor gene expression and 2) the mechanisms responsible for the ethanol-induced increases in VEGF, TGF-beta(1), and Flt-1 mRNA appear to be different from those responsible for exercise-induced regulation. Therefore, these results provide evidence in adult rat tissue that the protective cardiovascular effects of moderate ethanol consumption may result in part through the increase of angiogenic growth factors.

Cardioprotection from ischemia by a brief exposure to physiological levels of ethanol: role of epsilon protein kinase C.

Recent epidemiological studies indicate beneficial effects of moderate ethanol consumption in ischemic heart disease. Most studies, however, focus on the effect of long-term consumption of ethanol. In this study, we determined whether brief exposure to ethanol immediately before ischemia also produces cardioprotection. In addition, because protein kinase C (PKC) has been shown to mediate protection of the heart from ischemia, we determined the role of specific PKC isozymes in ethanol-induced protection. We demonstrated that (i) brief exposure of isolated adult rat cardiac myocytes to 10-50 mM ethanol protected against damage induced by prolonged ischemia; (ii) an isozyme-selective epsilonPKC inhibitor developed in our laboratory inhibited the cardioprotective effect of acute ethanol exposure; (iii) protection of isolated intact adult rat heart also occurred after incubation with 10 mM ethanol 20 min before global ischemia; and (iv) ethanol-induced cardioprotection depended on PKC activation because it was blocked by chelerythrine and GF109203X, two PKC inhibitors. Consumption of 1-2 alcoholic beverages in humans leads to blood alcohol levels of approximately 10 mM. Therefore, our work demonstrates that exposure to physiologically attainable ethanol levels minutes before ischemia provides cardioprotection that is mediated by direct activation of epsilonPKC in the cardiac myocytes. The potential clinical implications of our findings are discussed.

Effect of Ethanol on Platelet Function

Epidemiological studies have linked an inhibition of platelet function by ethanol, among other factors, to the cardioprotective effects of moderate ethanol consumption. Platelet defects have been noted in alcoholics and in human experimental studies. Importantly, in in vivo experimental settings, ethanol diminishes thrombus formation on damaged arterial walls. Ethanol inhibits platelet activation in vitro in response to diverse agonists. Phospholipase A2 is a major site for ethanol inhibition, corresponding to a reduction in the formation of stimulatory arachidonate metabolites. Additional signal transduction pathways are likely targets for ethanol including phosphoinositide-specific phospholipase C and cyclic AMP. The role of additional cofactors in the inhibition of platelet responses by ethanol is discussed.

Inhibition of advanced glycation endproduct formation by acetaldehyde: role in the cardioprotective effect of ethanol.

Epidemiological studies suggest that there is a beneficial effect of moderate ethanol consumption on the incidence of cardiovascular disease. Ethanol is metabolized to acetaldehyde, a two-carbon carbonyl compound that can react with nucleophiles to form covalent addition products. We have identified a biochemical modification produced by the reaction of acetaldehyde with protein-bound Amadori products. Amadori products typically arise from the nonenzymatic addition of reducing sugars (such as glucose) to protein amino groups and are the precursors to irreversibly bound, crosslinking moieties called advanced glycation endproducts, or AGEs. AGEs accumulate over time on plasma lipoproteins and vascular wall components and play an important role in the development of diabetes- and age-related cardiovascular disease. The attachment of acetaldehyde to a model Amadori product produces a chemically stabilized complex that cannot rearrange and progress to AGE formation. We tested the role of this reaction in preventing AGE formation in vivo by administering ethanol to diabetic rats, which normally exhibit increased AGE formation and high circulating levels of the hemoglobin Amadori product, HbA1c, and the hemoglobin AGE product, Hb-AGE. In this model study, diabetic rats fed an ethanol diet for 4 weeks showed a 52% decrease in Hb-AGE when compared with diabetic controls (P < 0.001). Circulating levels of HbA1c were unaffected by ethanol, pointing to the specificity of the acetaldehyde reaction for the post-Amadori, advanced glycation process. These data suggest a possible mechanism for the so-called "French paradox," (the cardioprotection conferred by moderate ethanol ingestion) and may offer new strategies for inhibiting advanced glycation.

Effects of moderate alcohol consumption on the central nervous system.

The concept of moderate consumption of ethanol (beverage alcohol) has evolved over time from considering this level of intake to be nonintoxicating and noninjurious, to encompassing levels defined as "statistically" normal in particular populations, and the public health-driven concepts that define moderate drinking as the level corresponding to the lowest overall rate of morbidity or mortality in a population. The various approaches to defining moderate consumption of ethanol provide for a range of intakes that can result in blood ethanol concentrations ranging from 5 to 6 mg/dl, to levels of over 90 mg/dl (i.e., approximately 20 mM). This review summarizes available information regarding the effects of moderate consumption of ethanol on the adult and the developing nervous systems. The metabolism of ethanol in the human is reviewed to allow for proper appreciation of the important variables that interact to influence the level of exposure of the brain to ethanol once ethanol is orally consumed. At the neurochemical level, the moderate consumption of ethanol selectively affects the function of GABA, glutamatergic, serotonergic, dopaminergic, cholinergic, and opioid neuronal systems. Ethanol can affect these systems directly, and/or the interactions between and among these systems become important in the expression of ethanol's actions. The behavioral consequences of ethanol's actions on brain neurochemistry, and the neurochemical effects themselves, are very much dose- and time-related, and the collage of ethanol's actions can change significantly even on the rising and falling phases of the blood ethanol curve. The behavioral effects of moderate ethanol intake can encompass events that the human or other animal can perceive as reinforcing through either positive (e.g., pleasurable, activating) or negative (e.g., anxiolysis, stress reduction) reinforcement mechanisms. Genetic factors and gender play an important role in the metabolism and behavioral actions of ethanol, and doses of ethanol producing pleasurable feelings, activation, and reduction of anxiety in some humans/animals can have aversive, sedative, or no effect in others. Research on the cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes. Recent studies have also noted some positive effects of moderate ethanol consumption on cognitive performance in the aging human. The moderate consumption of ethanol by pregnant women can have significant consequences on the developing nervous system of the fetus. Consumption of ethanol during pregnancy at levels considered to be in the moderate range can generate fetal alcohol effects (behavioral, cognitive anomalies) in the offspring. A number of factors--including gestational period, the periodicity of the mother's drinking, genetic factors, etc.--play important roles in determining the effect of ethanol on the developing central nervous system. A series of recommendations for future research endeavors, at all levels, is included with this review as part of the assessment of the effects of moderate ethanol consumption on the central nervous system.

Effects of Moderate Alcohol Consumption on the Central Nervous System*

The concept of moderate consumption of ethanol (beverage alcohol) has evolved over time from considering this level of intake to be nonintoxicating and noninjurious, to encompassing levels defined as “statistically” normal in particular populations, and the public health-driven concepts that define moderate drinking as the level corresponding to the lowest overall rate of morbidity or mortality in a population. The various approaches to defining moderate consumption of ethanol provide for a range of intakes that can result in blood ethanol concentrations ranging from 5 to 6 mg/dl, to levels of over 90 mg/dl (i.e., 20 mM). This review summarizes available information regarding the effects of moderate consumption of ethanol on the adult and the developing nervous systems. The metabolism of ethanol in the human is reviewed to allow for proper appreciation of the important variables that interact to influence the level of exposure of the brain to ethanol once ethanol is orally consumed. At the neurochemical level, the moderate consumption of ethanol selectively affects the function of GABA, glutamatergic, serotonergic, dopaminergic, cholinergic, and opioid neuronal systems. Ethanol can affect these systems directly, and/or the interactions between and among these systems become important in the expression of ethanol's actions. The behavioral consequences of ethanol's actions on brain neurochemistry, and the neurochemical effects themselves, are very much dose- and time-related, and the collage of ethanol's actions can change significantly even on the rising and falling phases of the blood ethanol curve. The behavioral effects of moderate ethanol intake can encompass events that the human or other animal can perceive as reinforcing through either positive (e.g., pleasurable, activating) or negative (e.g., anxiolysis, stress reduction) reinforcement mechanisms. Genetic factors and gender play an important role in the metabolism and behavioral actions of ethanol, and doses of ethanol producing pleasurable feelings, activation, and reduction of anxiety in some humans/animals can have aversive, sedative, or no effect in others. Research on the cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes. Recent studies have also noted some positive effects of moderate ethanol consumption on cognitive performance in the aging human. The moderate consumption of ethanol by pregnant women can have significant consequences on the developing nervous system of the fetus. Consumption of ethanol during pregnancy at levels considered to be in the moderate range can generate fetal alcohol effects (behavioral, cognitive anomalies) in the offspring. A number of factors–including gestational period, the periodicity of the mother's drinking, genetic factors, etc.–play important roles in determining the effect of ethanol on the developing central nervous system. A series of recommendations for future research endeavors, at all levels, is included with this review as part of the assessment of the effects of moderate ethanol consumption on the central nervous system

A review of the effects of moderate alcohol intake on psychiatric and sleep disorders.

In this chapter we discuss the effects of moderate ethanol consumption on the treatment of psychiatric and sleep disorders. A review of the literature on the interactions of ethanol with neurotransmitters and psychotropic medications suggests that although ethanol affects the clinical course of psychiatric and sleep disorders by different mechanisms, it does so principally through perturbations it causes in the balance of central nervous system neurotransmitter systems, which may modify the clinical course of primary psychiatric and sleep disorders and undermine the therapeutic response to psychotropic medications. Neurotransmitter responses may also be manifested clinically by rebound phenomena, akin to a subsyndromal withdrawal, which affect sleep and precipitate anxiety and mood symptoms. In addition, ethanol also modifies the clearance and disposition of a variety of psychotropic metabolites and interferes with their clinical effectiveness. We recommend that most psychiatric patients, and all patients with sleep disorders, should abstain from even moderate ethanol use, as this may adversely affect their clinical course and response to treatment.

The Role of Moderate Ethanol Consumption in Health and Human Nutrition

The role of ethanol in human health and nutrition is complex. Ethanol is a macronutrient energy source, capable of providing calories for all of the essential biological activities of the human organism: replication, function and maintenance of individual cells; energy for physical work; and thermogenesis. Ethanol differs from the other principal dietary macronutrient energy sources, glucose, fatty acids, and amino acids in two fundamentally important ways. First, although each of the other classes of energy compounds has a macromolecular storage form [glycogen (glucose), lipids (fatty acids), and protein (amino acids)], there is no storage form for ethanol. Second, fuel consumption in multicellular organisms is coordinated and prioritized largely through the regulation of entry of the energy source into the cell. For sugars, fatty acids, and amino acids, this transport across the plasma membrane is mediated by proteins thus providing an easy mechanism of regulation. In contrast, ethanol freely diffuses across plasma membranes, not requiring protein-mediated transport. These properties of ethanol define its unique role and hierarchal position as a macronutrient in human nutrition. While chronic, excessive consumption of ethanol leads to disease, low to moderate consumption has been shown to reduce risk of certain high incidence diseases. Numerous epidemiological studies have documented that a reduced risk of coronary heart disease usually accompanies regular consumption of a moderate level of ethanol. It has also recently been reported that ethanol consumption reduces the risk of development of adult onset or Non-Insulin Dependent Diabetes Mellitus (NIDDM). The protective effect of dietary alcohol has been attributed to the increase in HDL cholesterol and associated apolipoproteins. However, the effect of alcohol on HDL and lipoproteins does not fully account for the protective role of dietary ethanol. Therefore, ethanol must have other important effects in human metabolism. Increased risk of both coronary heart disease and NIDDM has recently been shown to be associated with increased risk of several other diseases, each of which has insulin resistance as an underlying cause. Insulin resistance results in a progressive cascade of abnormalities associated with macronutrient fuel metabolism. This metabolic derangement was first described by Reaven and termed "Syndrome X." The explanation of the health-promoting effects of moderate ethanol consumption may lie in part in ethanol9s role as a macronutrient energy source and in its ability to affect the onset, development and progression of Syndrome X. This review will describe our current level of understanding of ethanol metabolism and its effects on the metabolism of other macronutrient energy sources and will discuss the possible role of ethanol in Syndrome X and reduced risk of coronary heart disease.