Acute Ethanol Ingestion Research Articles

Interactions between uncoupling protein 2 gene polymorphisms, obesity and alcohol intake on liver function: a large meta-analysed population-based study.

Given the role of uncoupling protein 2 (UCP2) in the accumulation of fat in the hepatocytes and in the enhancement of protective mechanisms in acute ethanol intake, we hypothesised that UCP2 polymorphisms are likely to cause liver disease through their interactions with obesity and alcohol intake. To test this hypothesis, we investigated the interaction between tagging polymorphisms in the UCP2 gene (rs2306819, rs599277 and rs659366), alcohol intake and obesity traits such as BMI and waist circumference (WC) on alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in a large meta-analysis of data sets from three populations (n=20 242). The study populations included the Northern Finland Birth Cohort 1966 (n=4996), Netherlands Study of Depression and Anxiety (n=1883) and LifeLines Cohort Study (n=13 363). Interactions between the polymorphisms and obesity and alcohol intake on dichotomised ALT and GGT levels were assessed using logistic regression and the likelihood ratio test. In the meta-analysis of the three cohorts, none of the three UCP2 polymorphisms were associated with GGT or ALT levels. There was no evidence for interaction between the polymorphisms and alcohol intake on GGT and ALT levels. In contrast, the association of WC and BMI with GGT levels varied by rs659366 genotype (Pinteraction=0.03 and 0.007, respectively; adjusted for age, gender, high alcohol intake, diabetes, hypertension and serum lipid concentrations). In conclusion, our findings in 20 242 individuals suggest that UCP2 gene polymorphisms may cause liver dysfunction through the interaction with body fat rather than alcohol intake.

Vitamin C prevents the endothelial dysfunction induced by acute ethanol intake.

Investigate the effect of ascorbic acid (vitamin C) on the endothelial dysfunction induced by acute ethanol intake. Ethanol (1g/kg; p.o. gavage) effects were assessed within 30min in male Wistar rats. Ethanol intake decreased the endothelium-dependent relaxation induced by acetylcholine in the rat aorta and treatment with vitamin C (250mg/kg; p.o. gavage, 5days) prevented this response. Ethanol increased superoxide anion (O2(-)) generation and decreased aortic nitrate/nitrite levels and these responses were not prevented by vitamin C. Superoxide dismutase (SOD) and catalase (CAT) activities as well as hydrogen peroxide (H2O2) and reduced glutathione (GSH) levels were not affected by ethanol. RhoA translocation as well as the phosphorylation levels of protein kinase B (Akt), eNOS (Ser(1177) or Thr(495) residues), p38MAPK, SAPK/JNK and ERK1/2 was not affected by ethanol intake. Vitamin C increased SOD activity and phosphorylation of Akt, eNOS (Ser(1177) residue) and p38MAPK in aortas from both control and ethanol-treated rats. Incubation of aortas with tempol prevented ethanol-induced decrease in the relaxation induced by acetylcholine. Ethanol (50mM/1min) increased O2(-) generation in cultured aortic vascular smooth muscle cells (VSMC) and vitamin C did not prevent this response. In endothelial cells, vitamin C prevented the increase on ROS generation and the decrease in the cytosolic NO content induced by ethanol. Our study provides novel evidence that vitamin C prevents the endothelial dysfunction induced by acute ethanol intake by a mechanism that involves reduced ROS generation and increased NO availability in endothelial cells.

Beer Is Less Harmful for the Liver than Plain Ethanol: Studies in Male Mice Using a Binge-Drinking Model.

Mechanisms involved in the less damaging effects of beer in comparison to hard spirits have not yet been fully understood. The aim of the study was to determine if the effect of beer intake on the liver differs from that of plain ethanol and if so to determine mechanisms involved. Male C57BL/6J mice received either ethanol, beer (ethanol content: 6 g/kg body weight) or iso-caloric maltodextrin solution. Markers of steatosis, lipogenesis, activation of the toll-like receptor-4 signaling cascade and lipid export in liver and tight junction proteins in duodenum were measured 6 and 12 h after acute ethanol or beer intake. Alcohol ingestion resulted in a significant increase of hepatic triglyceride accumulation 6 and 12 h after ingestion, respectively, being markedly lower in mice fed beer. Expression of sterol regulatory element-binding protein-1c mRNA was significantly lower 12 h after alcohol or beer exposure, while fatty acid synthase mRNA expression was induced in livers of ethanol-fed mice and to a lesser extent in mice fed beer 6 h after acute alcohol ingestion. Protein levels of tight junction proteins in the small intestine were similar between groups while expression of myeloid differentiation primary response gene 88 in livers was significantly induced in ethanol- but not in beer-fed mice. Concentrations of 4-hydroxynonenal protein adducts and inducible nitric oxide synthase protein were also only induced in livers of mice fed ethanol. Protein levels of apolipoprotein B were induced in livers of beer-fed mice only. Our data suggest that beer is less harmful on the development of acute alcohol-induced liver damage than plain ethanol in male mice.

Consequências da ingestão moderada de etanol na discriminação de notas musicais

O objetivo deste estudo foi avaliar se existe relacao entre a ingestao moderada de etanol e a discriminacao das notas musicais RE, FA, e LA, em adultos jovens. Essas notas apresentam frequencias fundamentais respectivamente de 293,665 Hz, 349,228 Hz e 440 Hz, de temperamento igual, escolhidas devido estarem em localizacao central na escala musical ocidental padrao. Participaram do estudo 40 voluntarios de 18 a 29 anos, nao musicos, saudaveis, nao usuarios de farmacos ou outras substâncias toxicas, exceto o etanol de forma moderada e aguda. Por meio do softwarePsysounds, criado especificamente para esse estudo, esses voluntarios tiveram de escolher, entre duas notas musicais, uma das notas teste apresentada inicialmente. Os dados foram tratados com um teste X2 de aderencia para comparar as frequencias de acertos das notas musicais de teste nas condicoes de ingestao e de nao ingestao de alcool. As analises mostraram diferencas significantes nas frequencias de acertos para todas as notas utilizadas, sugerindo que a ingestao de etanol prejudica a discriminacao das notas musicais RE, FA e LA.

Effect of acute beer ingestion on the liver: studies in female mice.

The aim of the present study was to assess whether the effects of acute consumption of stout or pilsner beer on the liver differ from those of plain ethanol in a mouse model. Seven-week-old female C57BL/6J mice received either ethanol, stout or pilsner beer (ethanol content: 6g/kg body weight) or isocaloric maltodextrin solution. Plasma alanine transaminase, markers of steatosis, lipogenesis, activation of the toll-like receptor-4 signaling cascade as well as lipid peroxidation and fibrogenesis in the liver were measured 12h after acute ethanol or beer intake. Acute alcohol ingestion caused a marked ~11-fold increase in hepatic triglyceride accumulation in comparison to controls, whereas in mice exposed to stout and pilsner beer, hepatic triglyceride levels were increased only by ~6.5- and ~4-fold, respectively. mRNA expression of sterol regulatory element-binding protein 1c and fatty acid synthase in the liver did not differ between alcohol and beer groups. In contrast, expression of myeloid differentiation primary response gene 88, inducible nitric oxide synthases, but also the concentrations of 4-hydroxynonenal protein adducts, nuclear factor κB and plasminogen activator inhibitor-1 were induced in livers of ethanol treated mice but not in those exposed to the two beers. Taken together, our results suggest that acute ingestion of beer and herein especially of pilsner beer is less harmful to the liver than the ingestion of plain ethanol.

Cortical spreading depression and mitochondrial dysfunction with aging: lessons from ethanol abuse.

Chronic consumption of ethanol has a damaging effect in various organs and metabolic functions, including liver, kidney, heart, pancreas, and brain (Sun and Sun, 2001; Bezerra Rde et al., 2005). Additionally, it has been shown that both the acute and chronic ethanol intake induce alteration in voltage-gated channels causing behavioral and electrophysiological changes in the brain (Little, 1999). In the last few years, the effect of ethanol in the electrophysiological phenomenon, known as cortical spreading depression (CSD), has been widely assessed (Sonn and Mayevsky, 2001; Bezerra Rde et al., 2005; Abadie-Guedes et al., 2008) as an important model to predict the damaging effects of ethanol in both young and aged brains.

A pre-injury high ethanol intake in rats promotes brain edema following traumatic brain injury

Drinking is a risk factor for traumatic brain injury (TBI), and ethanol can aggravate the outcome by promoting brain edema. The mechanism involved is not fully understood. It has been confirmed that aquaporin-4 (AQP4) and vascular endothelial growth factor (VEGF) play pivotal roles in cytotoxic/vasogenic brain edema individually, and both of these proteins are downstream regulatory factors of hypoxia-inducible factor-1α (HIF-1α). In this study, we used a fluid percussion injury (FPI) model in rats to determine the effects of acute ethanol intake on the expression levels of HIF-1α, AQP4, and VEGF prior to FPI. The animals were sacrificed 1, 2, 3, and 4 days post-injury. We found that the expression levels of HIF-1α and AQP4 were significantly upregulated in the ethanol-pretreated groups, whereas the VEGF expression level was not. In addition, there was a positive correlation between HIF-1α and AQP4. The results of this study indicate that cytotoxic brain edema may play an important role in the early stage of FPI in ethanol-pre-treated animals and that HIF-1α and AQP4 might be involved.

Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship-based Approach to Understand the Variability of Central Neurological Effects of Ethanol

Pharmacokinetic/pharmacodynamic (PK/PD) relationships describe the quantitative relationships between the drug-induced effects and the concurrent corresponding drug concentrations in an individual. Since a long time, rough qualitative relationships have been described between neurological presentation and plasma ethanol concentration in acute ethanol ingestion. However, to date, precise quantitative PK/PD relationships have not been extensively studied. We studied PK/PD relationships in ethanol poisonings. Plasma concentrations were measured using an enzymatic assay. Coma depth was assessed using the Glasgow Coma Scale (GCS). Non-linear regression was used for modeling PK/PD relationships. The PK/PD relationships were well fitted with the sigmoidal Emax model. A maximal toxic effect (GCS of 3) was associated with a wide range of plasma ethanol concentrations, suggesting the saturation of drug targets at high doses. During the course of poisoning, the relationships between the depth of coma and the corresponding plasma concentrations were of sigmoidal shape. The elevated values of the Hill coefficient showed that a small decrease in plasma concentrations near the EC50 was associated with a dramatic improvement in the level of consciousness. In chronic alcoholic patients, EC50 was higher than in non-tolerant. Analyzing blood concentrations with respect of the delay elapsed since the ingestion may help predicting the time of awakening and thus the evaluation of outcome. In conclusion, PK/PD relationships are helpful in suggesting mechanisms of inter-individual variability of central neurological response to ethanol.

Acute ethanol intake induces mitogen-activated protein kinase activation, platelet-derived growth factor receptor phosphorylation, and oxidative stress in resistance arteries.

In the present study, we investigated the role of angiotensin type I (AT1) receptor in reactive oxygen species (ROS) generation and mitogen-activated protein kinases (MAPK) activation induced by acute ethanol intake in resistance arteries. We also evaluated the effect of ethanol on platelet-derived growth factor receptors (PDGF-R) phosphorylation and the role of this receptor on ROS generation by ethanol. Ethanol (1g/kg; p.o. gavage) effects were assessed within 30min in male Wistar rats. Acute ethanol intake did not alter angiotensin I or angiotensin II levels in the rat mesenteric arterial bed (MAB). Ethanol induced vascular oxidative stress, and this response was not prevented by losartan (10mg/kg; p.o. gavage), a selective AT1 receptor antagonist. MAB from ethanol-treated rats displayed increased SAPK/JNK and PDGF-R phosphorylation, responses that were not prevented by losartan. The phosphorylation levels of protein kinase B (Akt) and eNOS were not affected by acute ethanol intake. MAB nitrate levels and the reactivity of this tissue to acetylcholine, phenylephrine, and sodium nitroprusside were not affected by ethanol intake. Ethanol did not alter plasma antioxidant capacity, the levels of reduced glutathione, or the activities of superoxide dismutase and catalase in the rat MAB. Short-term effects of ethanol (50mmol/l) were evaluated in vascular smooth muscle cells (VSMC) isolated from rat MAB. Ethanol increased ROS generation, and this response was not affected by AG1296, a PDGF-R inhibitor, or losartan. Finally, ethanol did not alter MAPK or PDGF-R phosphorylation in cultured VSMC. Our study provides novel evidence that acute ethanol intake induces ROS generation, PDGF-R phosphorylation, and MAPK activation through AT(1)-independent mechanisms in resistance arteries in vivo. MAPK and PDGF-R play a role in vascular signaling and cardiovascular diseases and may contribute to the vascular pathobiology of ethanol.

Altering substrate specificity of aldehyde dehydrogenase 3A1 to enhance acetaldehyde metabolism, in vivo (585.9)

Acetaldehyde is a well‐know cytotoxin, and carcinogen. Detoxification of acetaldehyde, which is mainly carried out by the mitochondrial aldehyde dehydrogenase 2 (ALDH2), is crucial to human health. High levels of acetaldehydes are present in the saliva and in circulation after ethanol ingestion and likely contribute to the high incidence of esophageal cancer in alcoholics and in carriers of a common ALDH2 mutation (ALDH2*2) found in 540 million East Asians. Acetaldehyde is also partly responsible for behavior impairment following ethanol consumption. Therefore, means to accelerate acetaldehyde clearance will be beneficial for human health. We previously identified an activator of ALDH2 that accelerated acetaldehyde metabolism. Here we describe the recruitment of an additional ALDH isozyme, ALDH3A1, to accelerate the clearance of acetaldehyde by the use of a small molecule. ALDH2 is the main isozyme that metabolizes acetaldehyde in liver. In contrast, ALDH3A1, which is present in the stomach and mucosa of the esophagus, normally metabolizes aromatic aldehydes and is ineffective in metabolizing acetaldehyde. We identified a small molecule activator, Alda‐89, which increased the Kcat of ALDH3A1 for acetaldehyde and enhanced its catalysis. We showed that when given together with an ALDH2‐specific activator, Alda‐1, Alda‐89 induced a rapid reduction in blood ethanol and acetaldehyde levels after acute ingestion of ethanol in mice. Importantly, treatment with Alda‐1 and Alda‐89 also reduced behavioral impairment in both wild‐type and ALDH2*2 mice. The ability to recruit an enzyme to metabolize a substrate that it usually does not metabolize using a pharmacological agent may represent a novel strategy to increase metabolism of toxic agents, in vivo.Grant Funding Source: Supported by NIH AA11147 to DM‐R

A case of mouthwash as a source of ethanol poisoning: is there a need to limit alcohol content of mouthwash?

A case of mouthwash as a source of ethanol poisoning: is there a need to limit alcohol content of mouthwash?

The role of glycerol-3-phosphate dehydrogenase 1 in the progression of fatty liver after acute ethanol administration in mice

Acute ethanol consumption leads to the accumulation of triglycerides (TGs) in hepatocytes. The increase in lipogenesis and reduction of fatty acid oxidation are implicated as the mechanisms underlying ethanol-induced hepatic TG accumulation. Although glycerol-3-phosphate (Gro3P), formed by glycerol kinase (GYK) or glycerol-3-phosphate dehydrogenase 1 (GPD1), is also required for TG synthesis, the roles of GYK and GPD1 have been the subject of some debate. In this study, we examine (1) the expression of genes involved in Gro3P production in the liver of C57BL/6J mice in the context of hepatic TG accumulation after acute ethanol intake, and (2) the role of GPD1 in the progression of ethanol-induced fatty liver using GPD1 null mice. As a result, in C57BL/6J mice, ethanol-induced hepatic TG accumulation began within 2h and was 1.7-fold greater than that observed in the control group after 6h. The up-regulation of GPD1 began 2h after administering ethanol, and significantly increased 6h later with the concomitant escalation in the glycolytic gene expression. The incorporation of 14C-labelled glucose into TG glycerol moieties increased during the same period. On the other hand, in GPD1 null mice carrying normal GYK activity, no significant increase in hepatic TG level was observed after acute ethanol intake. In conclusion, GPD1 and glycolytic gene expression is up-regulated by ethanol, and GPD1-mediated incorporation of glucose into TG glycerol moieties together with increased lipogenesis, is suggested to play an important role in ethanol-induced hepatic TG accumulation.

A preliminary study on the effects of acute ethanol ingestion on default mode network and temporal fractal properties of the brain

To study the effect of acute alcohol intoxication on the functional connectivity of the default mode network (DMN) and temporal fractal properties of the healthy adult brain. Eleven healthy male volunteers were asked to drink 0.59 g/kg of ethanol. Resting state blood oxygen level dependent (rsBOLD) MRI scans were obtained before consumption, 60 min post-consumption and 90 min post-consumption. Before each rsBOLD scan, pointed-resolved spectroscopy (PRESS) (1)H-MRS (magnetic resonance spectroscopy) scans were acquired to measure ethanol levels in the right basal ganglia. Significant changes in DMN connectivity were found following alcohol consumption (p < 0.01). Both increased and decreased regional connectivity were found after 60 min, whereas mostly decreased connectivity was found after 90 min. The fractal behaviour of the rsBOLD signal, which is believed to help reveal complexity of small-scale neuronal circuitry, became more ordered after both 60 and 90 min of alcohol consumption (p < 0.01). The DMN has been linked to personal identity and social behavior. As such, our preliminary findings may provide insight into the neuro-functional underpinnings of the cognitive and behavioral changes observed during acute alcohol intoxication. The reduced fractal dimension implies a change in function of small-scale neural networks towards less complex signaling.

Postresistance Exercise Ethanol Ingestion and Acute Testosterone Bioavailability

Alcohol (ethanol) and resistance exercise can independently affect circulating bioavailable testosterone concentration. The purpose of this study was to examine the testosterone bioavailability and the anabolic endocrine milieu in response to acute ethanol ingestion after a bout of heavy resistance exercise. Eight resistance-trained men (mean ± SD: 25.3 ± 3.2 yr, 87.7 ± 15.1 kg, 177 ± 7 cm) completed two identical acute heavy resistance exercise tests (AHRET: six sets of 10 repetitions of Smith machine squats) separated by 1 wk. Post-AHRET, participants consumed either 1.09 g of grain ethanol per kilogram lean mass (EtOH condition) or no ethanol (placebo condition). Blood samples were collected immediately before exercise (PRE), immediately after exercise (IP), and every 20 min postexercise for 300 min. Samples after IP were pooled into phases (20-40 min, 60-120 min, and 140-300 min after exercise) and analyzed for total testosterone (TT) and free testosterone (FT), sex hormone-binding globulin (SHBG), cortisol, and estradiol. Peak blood ethanol concentration (0.088 ± 0.015 g·dL) was achieved 60-90 min postexercise. TT and FT were elevated significantly (P ≤ 0.05) at IP for both conditions. At 140-300 min postexercise, TT, FT, and free androgen index were significantly higher for EtOH (TT: 22.5 ± 12.5 nmol·L; FT: 40.5 ± 7.6 pmol·L) than for placebo (TT: 13.9 ± 6.8 nmol·L; FT: 22.7 ± 10.0 pmol·L). No differences between conditions were noted for SHBG, cortisol, or estradiol. Postexercise ethanol ingestion affects the hormonal milieu including testosterone concentration and bioavailability during recovery from resistance exercise.

Characterization of Functional Polymorphisms and Glucocorticoid-Responsive Elements in the Promoter of TDO2, a Candidate Gene for Ethanol-Induced Behavioural Disorders

In response to acute ethanol consumption, tryptophan 2,3-dioxygenase (TDO) induces the kynurenine pathway (KP) through a glucocorticoid-mediated mechanism, which could lead to a dramatic accumulation of neurotoxic metabolites in association with serotonin depletion. As a result, interindividual variability in ethanol-induced behavioural disorders, such as black-outs and violent impulsive behaviours (BOVIBs) following binge drinking, could be partly explained by genetic polymorphisms affecting the KP. The aim of this study was to identify polymorphisms on the promoter of the TDO2 gene that could affect expression and/or activity of TDO through glucocorticoid induction. Polymorphisms were screened using a PCR-sequencing strategy applied to 31 alcohol-dependent patients and 49 unrelated healthy volunteers, and functionally analysed with bioinformatic prediction tools and gene reporter assays in HepG2 and A549 cell lines. We identified 12 polymorphisms in the human TDO2 promoter region, 2 of them corresponding to previously unknown single-nucleotide polymorphisms (SNPs) and 3 of them located in putative glucocorticoid-responsive elements (GREs). Gene reporter assays using HepG2 and A549 cell lines confirmed the presence of several functional GREs in the promoter region of TDO2 and revealed that some of the identified polymorphisms affect the promoter activity under glucocorticoid receptor over-expression and dexamethasone exposure conditions. Correlational studies in larger samples could help to determine whether these polymorphisms are responsible for variations of expression and/or activity of TDO, in particular under conditions where release of glucocorticoids is increased, such as acute ethanol intake. If confirmed, such results would be of major interest in explaining part of the interindividual variability observed in behavioural responses to acute ethanol consumption.

Acute ethanol administration inhibits Toll-like receptor 4 signaling pathway in rat intestinal epithelia

Excess alcohol intake, as in binge drinking, increases susceptibility to microbial pathogens. Alcohol impairs macrophage function by suppression of the Toll-like receptor 4 (TLR4) pathway. This study investigated the effects of acute ethanol intake on the TLR4 pathway in rat intestinal epithelia, which usually encounters luminal antigens at first and participates in the development of intestinal immunity. Twenty Wistar rats were randomly assigned to an ethanol group given ethanol as a 25% (v/v) solution in water at 7.5 g/kg, or a control group given saline, by oral gavage daily for 3 days. The epithelial histology and ultrastructure, the intestinal microflora, peripheral and portal venous plasma lipopolysaccharide (LPS) levels, and somatostatin (SST) levels in the peripheral plasma and small intestine were evaluated. Somatostatin receptor 2 (SSTR2), TLR4, TANK binding kinase-1 (TBK1), activated nuclear factor-κB (NF-κB), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in the intestinal mucosa were assayed. LPS responsiveness with or without SST pretreatment was assayed in vitro by quantification of TLR4, TBK1, activated NF-κB, IFN-γ and TNF-α in isolated intestinal epithelia. Mucosal damage was observed in the ethanol group by light and electron microscopy. Escherichia coli cultures were unchanged in rat intestine of the ethanol group compared with controls, but lactobacilli cultures were reduced (p < 0.05). LPS levels increased in peripheral and portal venous plasma (p < 0.05), but mucosal TLR4, TBK1, nuclear NF-κB, IFN-γ and TNF-α were unchanged in the ethanol group. LPS treatment in vitro up-regulated the level of TLR4, TBK1 and nuclear NF-κB as well as the production of IFN-γ and TNF-α in isolated intestinal epithelia in the control (p < 0.05), but not the ethanol group. The stimulatory effects of LPS on intestinal epithelia isolated from the control group were significantly inhibited by SST pretreatment (p < 0.05). The peripheral plasma and intestinal levels of SST and the mucosal expression of SSTR2 in the ethanol group were significantly higher than in the control group (p < 0.05). These findings suggest the hyposensitivity of intestinal epithelial TLR4 to LPS induced by acute alcohol abuse probably through ethanol per se and ethanol-enhanced intestinal mucosal SST pathway may be a novel mechanism for increased susceptibility to intestinal pathogens.

Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: A role for angiotensin type 1 receptor

Ethanol intake is associated with increase in blood pressure, through unknown mechanisms. We hypothesized that acute ethanol intake enhances vascular oxidative stress and induces vascular dysfunction through renin–angiotensin system (RAS) activation. Ethanol (1g/kg; p.o. gavage) effects were assessed within 30min in male Wistar rats. The transient decrease in blood pressure induced by ethanol was not affected by the previous administration of losartan (10mg/kg; p.o. gavage), a selective AT1 receptor antagonist. Acute ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels. Ethanol induced systemic and vascular oxidative stress, evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels, NAD(P)H oxidase‐mediated vascular generation of superoxide anion and p47phox translocation (cytosol to membrane). These effects were prevented by losartan. Isolated aortas from ethanol-treated rats displayed increased p38MAPK and SAPK/JNK phosphorylation. Losartan inhibited ethanol-induced increase in the phosphorylation of these kinases. Ethanol intake decreased acetylcholine-induced relaxation and increased phenylephrine-induced contraction in endothelium-intact aortas. Ethanol significantly decreased plasma and aortic nitrate levels. These changes in vascular reactivity and in the end product of endogenous nitric oxide metabolism were not affected by losartan. Our study provides novel evidence that acute ethanol intake stimulates RAS activity and induces vascular oxidative stress and redox-signaling activation through AT1-dependent mechanisms. These findings highlight the importance of RAS in acute ethanol-induced oxidative damage.

Acute and chronic ethanol intake: Effects on spatial and non-spatial memory in rats

Abusive alcohol consumption produces neuronal damage and biochemical alterations in the mammal brain followed by cognitive disturbances. In this work rats receiving chronic and acute alcohol intake were evaluated in a spontaneous delayed non-matching to sample/position test. Chronic alcohol-treated rats had free access to an aqueous ethanol solution as the only available liquid source from the postnatal day 21 to the end of experiment (postnatal day 90). Acute alcoholic animals received an injection of 2 g/kg ethanol solution once per week. Subjects were evaluated in two tests (object recognition and spatial recognition) based on the spontaneous delayed non-matching to sample or to position paradigm using delays of 1 min, 15 min and 60 min. Results showed that chronic and acute alcohol intake impairs the rats' performance in both tests. Moreover, chronic alcohol-treated rats were more altered than acute treated animals in both tasks. Our results support the idea that chronic and acute alcohol administration during postnatal development caused widespread brain damage resulting in behavioral disturbances and learning disabilities.

Role of acute ethanol exposure and TLR4 in early events of sepsis in a mouse model

Sepsis is a major cause of death worldwide. The associated risks and mortality are known to significantly increase on exposure to alcohol (chronic or acute). The underlying mechanisms of the association of acute ethanol ingestion and poor prognosis of sepsis are largely unknown. The study described here was designed to determine in detail the role of ethanol and TLR4 in the pathogenesis of the sepsis syndrome. The effects of acute ethanol exposure and TLR4 on bacterial clearance, spleen cell numbers, peritoneal macrophage numbers, and cytokine production were evaluated using wild-type and TLR4 hyporesponsive mice treated with ethanol and then challenged with a nonpathogenic strain of Escherichia coli. Ethanol-treated mice exhibited a decreased clearance of bacteria and produced lesser amounts of most pro-inflammatory cytokines in both strains of mice at 2 h after challenge. Neither ethanol treatment nor a hyporesponsive TLR4 had significant effects on the cell numbers in the peritoneal cavity and spleen 2 h postinfection. The suppressive effect of acute ethanol exposure on cytokine and chemokine production was more pronounced in the wild-type mice, but the untreated hyporesponsive mice produced less of most cytokines than untreated wild-type mice. The major conclusion of this study is that acute ethanol exposure suppresses pro-inflammatory cytokine production and that a hyporesponsive TLR4 (in C3H/HeJ mice) decreases pro-inflammatory cytokine levels, but the cytokines and other mediators induced through other receptors are sufficient to ultimately clear the infection but not enough to induce lethal septic shock. In addition, results reported here demonstrate previously unknown effects of acute ethanol exposure on leukemia inhibitory factor and eotaxin, and provide the first evidence that interleukin (IL)-9 is induced through TLR4 in vivo.

Enhancement of the hypothalamic–pituitary–adrenal axis but not cytokine responses to stress challenges imposed during withdrawal from acute alcohol exposure in Sprague–Dawley rats

Alcohol withdrawal is associated with reduced activity, increased anxiety, and other signs of distress. The goal of the current studies was to determine whether acute ethanol exposure would alter hypothalamic-pituitary-adrenal (HPA) axis reactivity and cytokine responses to stress challenges imposed during the withdrawal period. Male Sprague-Dawley rats were intubated with 4 g/kg of ethanol to simulate acute binge-like ethanol intake. After characterizing the blood ethanol concentrations (BECs; Experiment 1), exploratory activity in a novel environment was explored at 10, 14 and 18 h after ethanol (Experiment 2) to characterize altered activity patterns indicative of withdrawal. In Experiment 3, rats were exposed to footshock during withdrawal to examine whether prior ethanol exposure would alter cytokine and HPA axis responses to stress. Experiments 4 and 5 investigated HPA axis sensitivity and gene expression changes during restraint imposed during withdrawal. Prior ethanol exposure produced a period of stress hyper-reactivity evidenced by an enhanced HPA axis response (increased corticosterone and adrenocorticotropic hormone) observed during withdrawal. While this hyper-reactivity in response to two different stress challenges (novel environment and restraint) was accompanied by profound behavioral changes indicative of withdrawal, no alterations in cytokine changes evoked by stress were observed. Taken together, these findings provide support for the hypothesis that alcohol withdrawal enhances HPA axis reactivity to stress challenges, though not likely as the result of heightened inflammatory signaling, and may have implications for understanding the mechanisms by which stress impacts relapse drinking in humans.