Chronic Effects Of Ethanol Research Articles

Effects of acute and chronic ethanol administration on thromboxane and prostacyclin levels and release in rat brain cortex

The effects of acute (3 g/kg i.p. two jours before sacrifice) and chronic (6% in drinking water and libitum for 15 days) ethanol administration to male rats (200 g body weight) on basal levels and release of TxB 2n2 and 6-keto-PGF 1α in brain cortex were studied. Also the effects of chronic ethanol (30 days) on the fatty acid composition of brain cortical tissue and liver phospholipids were investigated. Acute treatment reduced basal levels of 6-keto-PGF 1α in brain cortical tissue (rats sacrificed by microwave radiation) and decreased the accumulation of 6-keto-PGF 1α in brain cortex after post-decapitation ischemia (PDI). Basal TxB 2 levels were also reduced in brain cortex, but TxB 2 release during PDI was enhanced. Chronic treatment (15 days) induced changes of TxB 2 and 6-ketoPGF 1α levels and release during PDI in brain cortex less pronounced than those observed after acute treatment. The reduced effectiveness of chronic ethanol on brain vasoactive eicosanoids suggest adaptation processes. After chronic treatment (30 days), the fatty acid composition of brain cortex total phospholipids were not significantly modified. Changes of eicosanoid production after ethanol were thus independent from modifications of the fatty acid precursor pool(s). Ethanol-induced changes in the production of vascular eicosanoids in the CNS may be of relevance to the action of the compound on the CNS and may also have implications for the clinic.

Ethanol tolerance and enhanced calcium/calmodulin-dependent phosphorylation of synaptic membrane proteins

The chronic effects of ethanol on synaptic membrane proteins was studied in ethanol-tolerant rats. Synaptic plasma membranes and postsynaptic densities were prepared from homogenates of forebrain and incubated in vitro with [γ- 32P]adenosine triphosphate in the presence and absence of calcium and calmodulin. In ethanol-tolerant animals, enhanced phosphorylation of synaptic plasma membrane but not postsynaptic density proteins was demonstrated in the presence of calcium and calmodulin. These results suggest that the development of tolerance to ethanol may involve alteration in neuronal sensitivity to calcium.

The effects of ethanol on brain blood flow in awake dogs.

Ethanol produces a generalized decline in brain flow in awake dogs. The reduction in flow is most marked and persistent in the cerebellum. In the anesthetized animal with brain blood flow already depressed, this effect is obscured. The possible relationship of these findings to the acute and chronic effects of ethanol on the central nervous system in humans is discussed.

Ethanol and the Pancreas

The acute and chronic effects of ethanol on pancreatic structure and function are discussed. Acute necrotizing, acute edematous, acute relapsing, chronic relapsing, and painless pancreatitis have an established association with ethanol abuse. The management of these disorders is outlined.

Protein turnover in brain during the development of alcohol dependence

The chronic effect of ethanol on central nervous system protein turnover was investigated in selected regions of brain following intoxication and withdrawal in a strain of ethanol preferring mice. Mice were serially injected with [ 14C]glucose in order to achieve a constant specific radioactivity of brain glutamase. Protein turnover was calculated from the specific activities of extracted protein and free glutamate. Results from these studies show that ethanol causes a significant increase in protein turnover in all sections of brain. The brain protein turnover in animals following alcohol withdrawal also shows an increase which deviates significantly from controls in 2 of the 3 regions examined.

The effect of ethanol on hepatic sodium plus potassium activated adenosine triphosphatase activity in the rat

We studied the acute and chronic effects of ethanol on hepatic Na+, K+-ATPase activity. Graded doses of ethanol given 1 h before death acutely increased Na+, K+-ATPase activity in a dose-related manner to a maximum of 138% of control with a simultaneous serum ethanol of 35.4 mM (163 mg%). Rats chronically fed 10% ethanol as their only fluid for 5 days had normal Na+, K+-ATPase activity, however, when ethanol was withdrawn 14 h before death Na+, K+-ATPase activity fell to 60% of control. The in vitro addition of ethanol to membrane preparations from untreated rats caused an increase in Na+, K+-ATPase activity with ethanol concentrations <81 mM with decreased activity at higher concentrations. In membranes from rats treated chronically with ethanol Na+, K+-ATPase activity did not respond to in vitro ethanol while the decreased activity noted after ethanol withdrawal was reversed by in vitro ethanol. These results suggest hepatocytes respond to the acute effects of ethanol by membrane adaptation which restores Na+, K+-ATPase activity to normal in the presence of ethanol. This adaptive response is probably due to changes in membrane lipids modulating membrane fluidity.

Chronic effects of ethanol under partial inhibition of catalase activity in the rat heart: Light and electron microscopic observations

In order to test the hypothesis that cardiac catalase plays a protective role in the pathogenesis of alcoholic cardiomyopathy, ethanol, comprising 36% of dietary calories, was administered to the rats for 5 weeks under inhibited cardiac catalase activity. Rats were treated with 3-amino-1,2,4-triazole (AT), a specific enzyme inhibitor, or iso-osmotic saline as control. During ethanol feeding, cardiac catalase activity was significantly inhibited at 24 h after AT, 25.6 ± 4.7 IU/mg protein, compared to rats given isoosmotic saline, 51.0 ± 9.1 IU/mg protein ( s.d.m.) ( P < 0.001). Under light microscopy, observed were intrasarcoplasmic vacuolization and occasional foci of necrosis and fibrosis. Ultrastructural abnormalities included very extensive vesicular changes in the myocardial cells, abnormally increased interstitial fibrosis, dilatation of tubular structures of sarcoplasmic reticulum, increased numbers of lysosomes, dehiscence of intercalated disc and various mitochondrial alterations including amorphous inclusion body. None of the rats given ethanol + saline, pair-fed diet + AT or saline showed comparable changes. Thus, cardiac catalase is considered to play a metabolic and protective role in the rat myocardium chronically exposed to ethanol.

Unsuitability of control sucrose or glucose in studies of the effects of chronic ethanol administration on brain 5-hydroxytryptamine metabolism

Chronic sucrose or glucose administration enhances 5-hydroxytryptamine synthesis in rat brain, as does ethanol. This suggests that the above sugars are not suitable for use as control treatments in studies of the chronic effects of ethanol on brain 5-hydroxytryptamine metabolism.

The effect of ethanol on the metabolism of prostaglandins and related compounds.

Previous studies have shown that chronic consumption of ethanol by rats lowers the level of membrane-bound arachidonic acid (C20:4) and stimulates the in vitro measured rate of hepatic lipid peroxidation. These observations suggested that ethanol might thereby cause changes in the metabolic pathway leading to prostaglandins and related compounds. Initial studies demonstrated that chronic ethanol administration to male rats results in an impaired ability on the part of these animals to catabolize prostaglandins via renal prostaglandin dehydrogenase (PGDH) but no effect was observed on the synthesis of thromboxanes by blood platelets from these same animals. Experiments have now been carried out in an attempt to further assess the acute and chronic effects of ethanol on the metabolism of prostaglandins and prostacyclin. Generally, these results suggest a lack of an acute effect of ethanol and a dose dependency for the chronic effects.

Chronic effects of alcohols on mouse biomembranes.

Our recent work has been directed at determining the role of membrane lipids in the chronic effects of ethanol. The hypothesis that alcohols act at hydrophobic sites has been in favor ever since the work of Meyer and Overton, because the aliphatic alcohols fit nicely on plots showing correlation of potency with lipid solubility (1). Much more recently, Seeman (2) has shown that ethanol and its close relatives expand the membranes of red blood cells, with potencies proportional to their lipid solubility in the membrane. Either the lipids or the hydrophobic portions of the proteins could be the site of action of alcohols in biomembranes. If lipid solubility determines potency, it follows that a membrane-acting drug should affect every cell in the body. Any specificity of action of such drugs very likely reflects the relative sensitivity of various cells to perturbations of their membranes. Neurons would be expected to be the most sensitive cells in the body, since their membranes perform all the functions of general transport and in addition must carry out ion transport with a speed and precision that seems beyond the abilities of other cell types. Some specificity may also be due to differential solubility of drugs in lipids of different composition. It now seems likely that there is a good deal of variety of membrane lipid composition, not only between cells but at different regions of the same cell. The subsynaptic membrane is likely to differ from the membrane of an axon. Microscopic inhomogeneities exist in the region of the membrane proteins, many of which are apparently surrounded by a layer of boundary lipid. Thus there are many possibilities for differential actions of a membrane-acting drug on different cells. It is easy to imagine how much more complicated this field of investigation will become when we get past the early exploratory stage and begin to deal with specific actions of drugs on different parts of membranes. But for the moment, it is of interest just to sketch out the outlines of what a drug might do if it acts simply by occupying space in cell membranes and thus disrupting the function of the embedded proteins.KeywordsElectron Paramagnetic ResonancePhysical DependenceLipid SolubilityMembrane Lipid CompositionAlcohol Withdrawal SyndromeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Prevention by pyrazole of the effects of chronic ethanol administration on the redox states of the hepatic nicotinamide–adenine dinucleotide (phosphate) couples and on liver and brain tryptophan metabolism in the rat

Chronic administration of pyrazole in the diet of rats does not cause toxicity and prevents the chronic effects of ethanol on: (1) the redox states of the hepatic NAD(P) couples; (2) liver tryptophan pyrrolase activity; (3) brain tryptophan and 5-hydroxytryptamine metabolism.

Biochemical markers of ethanol effects on brain.

Because sialic acid is a potential biochemical marker of membrane development or alteration, we compared acute and chronic ethanol effects on sialic acid. Experiments were conducted with 50 adult male Wistar rats (approximately 400 gm), housed in groups of five. Rats drank ad libitum a vitamin-fortified diet (Nutrament) that was adulterated with ethanol; ethanol intake averaged for each rat 10-18 gm/kg/day. Controls were fed an equal total volume, made isocaloric with sucrose. Rats were sacrificed weekly for four weeks, and an acute challenge dose of ethanol (2 gm/kg, intraperitoneally) was given 45 minutes before sacrifice of both control and ethanol-consuming rats. Some controls were challenged only with saline. We replicated our earlier findings of regional differences in sialic acid and in cerebellar deoxyribose (measured as a necessary adjunct in the autoanalyzer modification of the Warren-Delmotte methods). In the saline-challenged controls, levels of both compounds were higher at four weeks than after one week. Similar increases occurred also in the chronic ethanol-consuming group, but not in the ethanol-challenged controls, which had significantly lower values. Results in saline-challenged controls suggest that the chronic treatment either 1) created a tolerance which protected cells from damage by the challenge dose of ethanol, or 2) killed neurons, thus promoting proliferation of glial cells.

Effect of ethanol tolerance on release of acetylcholine and norepinephrine by rat cerebral cortex slices.

The release of acetylcholine (ACh) by rat cerebral cortex slices, with and without electrical stimulation, and the effect of ethanol (EtOH) on this release were examined during the acquisition and loss of EtOH tolerance in vivo. ACh was measured by pyrolytic monodemethylation and gas–liquid chromatography. Electrical stimulation of control slices in medium containing diisopropyl phosphofluoridate (1.26 μM) and atropine (0.3 μM) increased ACh release by 88 ± 12%. Addition of 0.11 M EtOH to the medium had negligible effect on ACh release from unstimulated slices, but reduced the effect of stimulation to 51 ± 10%. After chronic treatment with EtOH by gavage or in a liquid diet, rats became tolerant to EtOH in vivo as shown by reduced impairment on the moving belt test. Slices from tolerant rats showed increased release of ACh in response to electrical stimulation and less inhibition of this response by added EtOH. The changes had disappeared by 2 weeks after cessation of EtOH treatment.Similar findings were obtained by measurement of release of [14C]ACh from slices preloaded with [14C]choline, except that electrical stimulation in the absence of EtOH appeared to cause a smaller increase in slices from chronic EtOH animals than from controls. This may reflect differences in isotope dilution. Release of [3H]norepinephrine was less affected by EtOH than that of ACh. The findings suggest that tolerance to EtOH is accompanied by increased ACh release by cortical neurones, as well as decreased direct inhibitory effect of EtOH on this, but do not permit any conclusion about the relative importance of such changes in various parts of the brain.

Acute and Chronic Effects of Ethanol on Fluid Transport in the Human Small Intestine

The effect of acute and chronic administration of ethanol on jejunal and ileal water and electrolyte transport was studied in healthy volunteers by the triple lumen intestinal perfusion technique. The acute perfusion of a glucose-free electrolyte solution containing 2 to 10 g per 100 ml of ethanol in the jejunum or ileum did not cause any significant alterations of sodium or water transport. In contrast, the administration of a folate-deficient diet and ethanol for 2 weeks produced a marked reduction in sodium and water absorption or a small net secretion (control, mean +/-SE: H2O = 0.91 +/- 0.06 ml per min, Na = 130 +/- 8 micronEq per min per 30 cm of intestine versus H2O = -0.13 +/- 0.14 ml per min, Na = -20 +/- 29 micronEq per min per 30 cm, P less than 0.001). These changes were not accompanied by a reduction in serum folate levels. The administration of ethanol with a folate-supplemented diet also produced significant but less pronounced changes in sodium and water transport control: H2O = 1.33 +/- 0.2 ml per min, Na = 185 +/- 34 micronEq per min per 30 cm of intestine versus H2O = 0.48 +/- 0.17 ml per min, Na =65 +/- 16 micronEq per min per 30 cm of intestine, P less than 0.05). From this study it appears that the diarrhea seen in chronic alcoholics can be explained in part by the effect of ethanol on intestinal sodium transport, without any accompanying changes in serum folate levels.

Mechanism of the protective action of cysteine and penicillamine against acetaldehyde-induced mitochondrial injury

The inhibition of several mitochondrial functions by acetaldehyde, a metabolite of ethanol oxidation, was previously shown to be almost completely relieved by cysteine. To study the mechanism of this protective effect, several derivatives of cysteine were also tested. Free sulfhydryl and amino groups appear to be required for maximal protection against the inhibition by acetaldehyde since no protective effect was found with N-acetylcysteine or S-methylcysteine. Cysteine interacts readily with acetaldehyde whereas N-acetylcysteine and S-methylcysteine do not. Penicillamine (β,β-dimethylcysteine) also relieved the inhibition by acetaldehyde, but prior incubation of penicillamine with acetaldehyde was required. Penicillamine was not as effective as cysteine, a finding which correlates with the weaker interaction of penicillamine with acetaldehyde. The greater stability of penicillamine compared to cysteine may be an advantage in studies of the effects of sulfhydryl amino acids on acute and chronic effects of ethanol and acetaldehyde.

Lack of alteration in regional brain adenosine-3′, 5′-cyclic monophosphate levels after acute and chronic treatment with ethanol

Previously reported studies have suggested that acute and chronic treatment with ethanol induces alterations in adenosine-3′, 5′-cyclic monophosphate (c-AMP) levels in the brain. Because the methods used in those studies to minimize postmortem accumulation of c-AMP are now considered to be inadequate, the effects of ethanol were reinvestigated using focused microwave irradiation to prevent postmortem c-AMP accumulation. These studies were extended to include measurements in seven areas of the rat brain after acute administration of ethanol and in animals rendered ethanol-dependent. Three treatment groups were examined: acutely treated while intoxicated (6 g/kg, p.o.), ethanol-dependent while intoxicated, and ethanol-dependent while undergoing a withdrawal syndrome. No changes in c-AMP levels were observed in any of the brain areas studied after any of the ethanol treatments. The data suggest that changes in c-AMP levels in the brain do not play any role in the acute and chronic effects of ethanol.

The basis for differences in ethanol-induced myocardial depression in normal subjects.

The acute effects of ethanol (ETOH) on cardiac function in 32 normal subjects has been studied utilizing systolic time intervals. Seven (group I) 13 (group II), and 12 subjects (group III), reported an average daily consumption of less than 1 oz, 1-2 oz, and more than 2 oz of ETOH, respectively. Progressively higher control values from group I to group III in PEP, PEPI, ICT and PET/LVET were observed (PEP-I vs PEPI-III: P smaller than 0.05; PEP/LVET-I vs PEP/LVET-II and PEP/LVET-III: P smaller than 0.05). There was progressively less change in these variables following acute ETOH (P smaller than 0.02-0.05 in group I; P equals NS in group III, group II intermediate). This indicates some degree of chronic myocardial impairment in group II and especially in group III, which tends to be proportionate to the degree of chronic ETOH exposure. These data are not necessarily disparate with previous reports of little or even a salutary hemodynamic effect of ETOH in normal subjects. Thus, the relative stability of LVET post ETOH, coupled with the observed increase in heart rate, is consistent with previous reports of ETOH-induced rate-dependent increments in cardiac output with unchanging stroke volumes, in spite of the presence of acute myocardial depression. The observations reported herein demonstrate the probable incremental influence of ETOH consumption in a chain of events which may culminate in alcoholic cardiomyopathy.

Acute and chronic effects of ethanol on intestinal lipid metabolism

To assess the effects of ethanol on intestinal lipid metabolism, fatty acid oxidation and triacylglycerol synthesis were measured in intestinal slices incubated with ethanol. Ethanol, when used in concentrations likely to be achieved in the upper jejunum after moderate drinking, inhibited both palmitate and acetate oxidation, CO 2 production and triacylglycerol synthesis, whereas it enhanced the esterification of fatty acid with ethanol. The concentrations required for the inhibitory effect were much higher than those needed to saturate enzyme systems known to participate in ethanol oxidation. In vivo administration of ethanol-containing diets produced persistent changes of the intestinal slices with respect to fatty acid oxidation and triacyl-glycerol synthesis. Acute intragastric administration of ethanol (3 g/kg) one hour prior to sacrifice, inhibited both processes in slices obtained from the jejunum, but not in those derived from the ileum. By contrast, chronic ethanol feeding increased the ability for fatty acid oxidation and triacylglycerol synthesis both in the jejunum and in the ileum. This stimulatory effect was associated with significant enhancement of palmitoyl-CoA synthetase activity, suggesting increased fatty acid activation. The inhibition by ethanol in high concentrations of intestinal fatty acid oxidation and triacylglycerol synthesis probably reflects epithelial cell damage; by contrast, prolonged administration of ethanol results in a persistent enhancement of lipid metabolism which may reflect the presence of a different cell population in the intestine.

Intestinal Lymph Formation and Fat Absorption Stimulation by Acute Ethanol Administration and Inhibition by Chronic Ethanol Feeding

The acute administration of ethanol, either in lipid emulsions administered intraduodenally or in liquid diets given by gastric tube, increased the flow of intestinal lymph and the output of proteins and dietary lipids into the lymph, mainly in the 1st hr after administration. During this time, the intraduodenal administration of ethanol (0.75 g per kg of body weight), without exogenous lipids, increased the flow of lymph without changing the lymph lipid output. Stimulation of the lymph flow with neostigmine or by increasing the fluid load also enhanced the output of lymph proteins and the transport of exogenous lipids from the intestinal lumen into the lymph. To study the chronic effects of ethanol, rats were pair-fed liquid diets containing either ethanol (36% of calories) or isocaloric carbohydrate for 3 to 4 weeks. Thereafter, the lymph changes were measured after administration of equal lipid loads with and without ethanol. The administration of an acute ethanol dose to rats chronically fed alcohol moderately increased the lymph flow, but did not change the output of dietary lipids. Furthermore, rats chronically fed alcohol responded to a dietary challenge devoid of ethanol with increases in both lymph flow and dietary lipid output which were not as great as those of pair-fed controls. Thus, acute ethanol administration has a marked stimulatory effect both on the formation of intestinal lymph and on the transport of deitary fat. By contrast, chronic ethanol feeding inhibits these acute effects of ethanol, and, in addition, appears to have moderate inhibitory effect on lipid absorption.

Effect of acute and chronic ethanol treatment on hepatic triglyceride release from the rat perfused liver

Rats were fed ethanol (30% of total calory intake) for 5 weeks (chronic ethanol treatment), while isocaloric sucrose replaced ethanol in controls. Livers from both ethanol-treated and control rats were perfused with ethanol (acute ethanol treatment), and without ethanol. The hepatic lipid levels and the release of triglycerides and lipoproteins from the livers to the perfusates were measured. Neither chronic nor acute ethanol treatment changed the liver lipid levels. Chronic ethanol treatment reduced the release of triglycerides and preβ-lipoproteins. Acute administration of ethanol increased the release of triglycerides and lipoprotiens in chronically ethanol-treated rats. The chronic effect of ethanol may be related to reduced protein synthesis in these livers, while the acute effect may be secondary to the established effect of ethanol on triglyceride synthesis or to a direct effect on hepatic triglyceride release.