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K Lindros

Publications and source records attributed to K Lindros.

18 recordsLinked to original sources
PubMed2000

Metronidazole increases intracolonic but not peripheral blood acetaldehyde in chronic ethanol-treated rats.

BACKGROUND: Metronidazole leads to the overgrowth of aerobic flora in the large intestine by reducing the number of anaerobes. According to our previous studies, this shift may increase intracolonic bacterial acetaldehyde formation if ethanol is present. Metronidazole is also reported to cause disulfiram-like effects after alcohol intake, although the mechanism behind this is obscure. Therefore, the aim was to study the effect of long-term metronidazole and alcohol treatment on intracolonic acetaldehyde levels and to explore the possible role of intestinal bacteria in the metronidazole related disulfiram-like reaction. METHODS: A total of 32 rats were divided into four groups: controls (n = 6), controls receiving metronidazole (n = 6), ethanol group (n = 10), and ethanol and metronidazole group (n = 10). All rats were pair-fed with the liquid diet for 6-weeks, whereafter blood and intracolonic acetaldehyde levels and liver and colonic mucosal alcohol (ADH) and aldehyde dehydrogenase (ALDH) activities were analyzed. RESULTS: The rats receiving ethanol and metronidazole had five times higher intracolonic acetaldehyde levels than the rats receiving only ethanol (431.4 +/- 163.5 microM vs. 84.7 +/- 14.4 microM,p = 0.0035). In contrast, blood acetaldehyde levels were equal. Cecal cultures showed the increased growth of Enterobacteriaceae in the metronidazole groups. Metronidazole had no inhibitory effect on hepatic or colonic mucosal ADH and ALDH activities. CONCLUSIONS: The increase in intracolonic acetaldehyde after metronidazole treatment is probably due to the replacement of intestinal anaerobes by ADH-containing aerobes. Unlike disulfiram, metronidazole neither inhibits liver ALDH nor increases blood acetaldehyde. Thus, our findings suggested that the mechanism behind metronidazole related disulfiram-like reaction might be located in the gut flora instead of the liver.

Acetaldehyde↗
PubMed1998

Acetaldehyde inhibits NF-kappaB activation through IkappaBalpha preservation in rat Kupffer cells.

BACKGROUND AND AIMS: Treatment with acetaldehyde dehydrogenase inhibitors leads to increased liver acetaldehyde levels and prevents hepatic inflammation and necrosis in ethanol-fed rats. This is accompanied by IkappaBa preservation and decreased activation of nuclear factor (NF)-kappaB. The present in vitro study was aimed to clarify whether acetaldehyde has an effect on degradation of IkappaBalpha and activation of NF-kappaB in LPS-stimulated rat Kupffer cells. METHODS: Kupffer cells were isolated from male Sprague-Dawley rats and preincubated with various concentrations of acetaldehyde (25-100 microM). Thereafter the cells were stimulated with LPS, and cytosolic and nuclear fractions were prepared. IkappaBalpha and p65 proteins and activation of NF-kappaB were evaluated. RESULTS: In LPS-stimulated rat Kupffer cells, acetaldehyde diminished proteolytic degradation of IkappaBalpha, inhibited nuclear translocation of cytosolic p65 protein, and, accordingly, markedly decreased NF-kappaB activation. CONCLUSIONS: Acetaldehyde is clearly involved in the stabilization of IkappaBalpha protein and suppression of NF-kappaB activation in rat Kupffer cells. Acetaldehyde may form an adduct with IkappaBalpha, thus making the protein less susceptible to degradation.

Acetaldehyde↗
PubMed1996

The effect of ethanol or hepatotoxin exposure on rat transferrin desialylation.

Serum carbohydrate-deficient transferrin (CDT) is being increasingly used as a biological indicator for excessive alcohol consumption. However, the mechanisms behind the changes in the carbohydrate moiety of transferrin are unclear, although they have been suggested to be mediated by acetaldehyde or liver damage. To study this, an animal model involving alterations in serum isotransferrin concentrations would be needed. The present work examined the changes in the carbohydrate moiety of transferrin in rats after different degrees of ethanol exposure, the effects of chronically elevated acetaldehyde levels, and also the changes, produced with liver toxins (galactosamine) and carbon tetrachloride). Ethanol was administered both in the drinking fluid and by intubation, reaching a dose of 11 g/kg/day over 7 weeks, or 16 g/kg/day over 4 weeks. Serum samples from rats maintained on high ethanol for 10 weeks by intragastric infusion were also analysed. Some rats simultaneously had cyanamide administered to elevate acetaldehyde levels. However, neither ethanol nor acetaldehyde had any effect on transferrin. Intraperitoneal galactosamine, but not carbon tetrachloride, induced transferrin desialylation. Thus, in the rat, neither chronic ethanol consumption nor elevated acetaldehyde induces changes in transferrin microheterogeneity.

Acetaldehyde↗
PubMed1996

Toxicity of ethanol in low concentrations. Experimental evaluation in cell culture.

PURPOSE: To define the threshold ethanol concentration that is toxic to cultured cells. METHODS: Three malignant cell lines and freshly isolated normal rat hepatocytes were exposed to 0-50% (vol.) ethanol (concentrations used were 0, 5, 10, 15, 20, 25, 30, 40 and 50%) on tissue culture plates for 0.25-60 min (exposure times used were 0.25, 5, 10, 20, 30, 40 50 and 60 min). Cytotoxicity was estimated by trypan blue exclusion test and from 3H-thymidine incorporation. RESULTS: All cells were killed by a 15-s exposure to 30-40% ethanol while a concentration as low as 15-20% gave a total response after 5-10-min exposures. After a one-hour exposure of F9 carcinoma cells and hepatocytes, a total or nearly total response was achieved with 10% ethanol. The cytotoxic effect was thus dependent both on the exposure time and on the concentration of ethanol. There were no significant differences in ethanol tolerance among the cell types. CONCLUSION: Ethanol seemed to kill cells in the cell culture effectively in much lower concentrations than those currently used in tumour ablation.

Animals↗
PubMed1988

Acute cardiovascular and metabolic effects of acetate in men.

We studied the potential contribution of acetate to the cardiovascular effects of ethanol in 12 healthy male volunteers. Sodium acetate, or sodium chloride in control experiments, was infused i.v. at the rate of 0.033 mEq/kg/min for 60 min. Left ventricular function was examined by M-mode echocardiography and systolic time intervals during infusion and for 60 min thereafter. Blood acetate rose during infusion from 0.19 +/- 0.02 (mean +/- SEM) to a maximum of 0.99 +/- 0.08 mmol/liter. Changes in serum free fatty acids, glycerol, and ketone bodies indicate that acetate inhibited peripheral lipolysis. The volume of urine excreted during the acetate experiment (305 +/- 37 ml) was significantly larger (p less than 0.01) than during the chloride experiment (181 +/- 21 ml). Left ventricular function did not differ between the experiments during the infusions even though at 45 min heart rate was increased by acetate (7%; p less than 0.01, between infusions). After the infusion period, at 75 min the treatment by acetate increased cardiac output from the baseline by 17% (p less than 0.05, between infusions), and decreased peripheral arterial resistance (19%, p less than 0.05), and diastolic blood pressure (10%, p less than 0.01). Circumferential fiber shortening velocity was increased during the acetate experiment maximally by 7% (p less than 0.01) from the baseline at 120 min. These data indicate that acetate is an arterial vasodilator and a mild diuretic and may slightly improve myocardial performance in the concentrations encountered during ethanol metabolism in men.

Acetates↗
PubMed1984

Distribution and utilization of alcohol-derived acetate in the rat.

The metabolism of endogenous and alcohol-derived acetate was studied in intact male Wistar rats. Acute alcohol administration increased the concentration of acetate in the hepatic vein from 0.3 to 2.2 mM, in the hepatic portal vein from 0.6 to 1.2 mM, and in arterial blood from 0.2 to 1.0 mM. These effects were almost independent of the alcohol dose. The blood acetate levels remained elevated during the course of alcohol oxidation but rapidly returned to endogenous levels when alcohol oxidation terminated. In hepatic tissue, a slight trend toward higher acetate level with increasing alcohol doses was observed. No significant adaptation to acetate metabolism was observed in rats examined after 7 weeks of forced alcohol consumption. The highest endogenous acetate concentration was observed in heart muscle (0.7 mumol/g), and this concentration was not influenced by alcohol in spite of a fourfold increase in the concentration in arterial blood, demonstrating the high capacity of heart muscle to produce and utilize acetate.

Acetates↗
PubMed1983

Cardiovascular effects of acetaldehyde accumulation after ethanol ingestion: their modification by beta-adrenergic blockade and alcohol dehydrogenase inhibition.

Left ventricular function was examined by echocardiography and systolic time intervals in nine healthy male volunteers, who ingested ethanol 0.35 g/kg 4 hr after a 50-mg peroral dose of calcium cyanamide, an aldehyde dehydrogenase inhibitor. Accumulation of acetaldehyde in blood was accompanied by marked increases in heart rate (53%) and cardiac output (78%) as well as by decreases in diastolic arterial blood pressure (19%) and peripheral vascular resistance (46%). Ejection fraction and maximum circumferential fibre shortening velocity increased by 25 and 47%, respectively; the preejection period/ejection time ratio decreased by 31%. 4-Methylpyrazole, an alcohol dehydrogenase inhibitor, efficiently reduced blood acetaldehyde levels when injected intravenously (7 mg/kg) at the height of the reaction. It was as effective as intravenous propranolol (0.1 mg/kg) in attenuating the hyperdynamic circulation and stabilized arterial blood pressure better than propranolol. We conclude that even a very mild alcohol intoxication (30-50 mg/100 ml) causes a marked enhancement of cardiac function, in addition to vasodilation, in subjects with impaired acetaldehyde oxidation. These changes are reversed by preventing acetaldehyde formation through alcohol dehydrogenase inhibition.

Acetaldehyde↗
PubMed1982

Possible cardiovascular hazards of the alcohol-calcium carbimide interaction.

Healthy volunteers taking ethanol after pretreatment with calcium carbimide, a drug commonly used in treatment of alcoholism, were studied by echocardiography. Marked facial flushing and accumulation of acetaldehyde after ethanol were accompanied by circulatory acceleration corresponding in magnitude to at least moderate physical exercise. The heart rate (+/- SD) rose from 58 +/- 6 to 107 +/- 11 beats/min (p less than .001) the cardiac output from 4.1 +/- 0.6 to 9.4 +/- 1.1 L/min (p less than .001), and the ejection fraction from 70 +/- 3 to 89 +/- 2% (p less than .001). The systolic blood pressure rose initially from 121 +/- 6 to 143 +/- 5 mmHg (p less than .001). The diastolic blood pressure declined from 80 +/- 0 to 51 +/- 13 mmHg (p less than .01), and the estimated peripheral resistance to one-third of its preethanol level (p less than .001). These marked cardiovascular changes suggest that the ethanol-calcium carbimide interaction can be hazardous to alcoholics with ischaemic or other forms of myocardial diseases.

Acetaldehyde↗
PubMed1977

Ethanol-induced hypoglycaemia in man: its suppression by the alcohol dehydrogenase inhibitor 4-methylpyrazole.

Infusion of ethanol (0.6 g/kg body wt) caused marked hypoglycaemia in subjects fasted for 36 h. Previous administration of the alcohol dehydrogenase (ADH) inhibitor 4-methylpyrazole (4-MP, 7 mg/kg body wt i.v.) strongly suppressed the ethanol-induced hypoglycaemia. The rate of ethanol elimination was 84.6 mg/kg per hour. 4-MP at the dose used caused a 21% reduction of ethanol elimination, but had no significant effect on blood acetaldehyde levels. 4-MP also significantly suppressed the ethanol-induced elevation of blood lactate and almost completely prevented the increase in the 3-hydroxybutyrate/acetoacetate ratio, but had only a slight effect on the lactate/pyruvate ratio of venous blood. The results demonstrate that the hypoglycaemia and lactacidaemia produced by the oxidation of alcohol can be prevented by a dose of 4-MP that diminishes or prevents the ethanol-induced shift in the NAD-coupled redox state of the liver.

Acetaldehyde↗
PubMedDate not supplied

The effect of chronic ethanol ingestion on ethanol metabolizing enzymes in isolated periportal and perivenous rat hepatocytes.

Periportal (pp) and perivenous (pv) hepatocyte populations were separated using a two-directional closed perfusion technique with selective addition of collagenase either to direct or retrograde perfusions (Väänänen, H. et al., Liver 1983; 3:131). The activity of GPT in hepatocytes from the pp-area was 1.9 times higher than in cells from the pv-area (p less than 0.01). The distribution of glutamate dehydrogenase and pyruvate kinase activities was reversed; pp/pv ratios of 0.7 and 0.5, respectively, were observed (p less than 0.001, p less than 0.05). Chronic ethanol consumption for 12 weeks (mean daily ethanol intake 11.4 gm per body weight corresponding to 29% of total energy intake) did not cause histological changes but decreased GPT activity, increased glutamate dehydrogenase and pyruvate kinase activities and did not alter their pp/pv distribution. Alcohol dehydrogenase and aldehyde dehydrogenase activities were evenly distributed in pp- and pv-hepatocytes. Chronic ethanol treatment slightly decreased alcohol dehydrogenase activity (p less than 0.05) and increased the activity of low Km aldehyde dehydrogenase (p less than 0.001, p less than 0.05). The specific activity of NADPH-dependent microsomal ethanol oxidation was 50% higher in pv-hepatocytes (p less than 0.05). Chronic ethanol treatment did not increase the specific activity of microsomal ethanol oxidation but reduced the pp-pv activity difference. The results indicate that the enzymatic capacity to oxidize ethanol is evenly distributed in the acinus and that, after long-term moderate ethanol treatment, despite lack of parenchymal lesions, changes in the activity of enzymes involved in ethanol metabolism are observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMedDate not supplied

Elevated blood acetate as indicator of fast ethanol elimination in chronic alcoholics.

The concentration of acetate was determined in the hepatic and peripheral blood of 10 chronic alcoholics and six healthy non-alcoholic controls after a peroral dose of ethanol (0.8 g/kg b.wt.). The blood acetate concentration was significantly higher in the hepatic vein than peripherally and remained at a rather constant level both in alcoholics and controls during the course of ethanol elimination. However, the level of acetate was significantly (p less than 0.005) higher in alcoholics than in controls both in the hepatic vein (1.79 and 1.15 mM) and peripherally (0.91 and 0.52 mM) (alcoholics and controls respectively). The alcoholics also eliminated ethanol 54% faster than the controls (159 mg/kg b.wt./hr and 103 mg/kg b.wt./hr; alcoholics and controls respectively). Furthermore a highly significant correlation was found between the rate of ethanol elimination and blood acetate level both in the hepatic (r = 0.877, p less than 0.001) and in the peripheral vein (r = 0.799, p less than 0.001). Our results suggest that an increased level of blood acetate during ethanol oxidation may be used as an indicator of enhanced ethanol elimination.

Acetates↗
PubMedDate not supplied

L-carnitine alleviates alcohol-induced liver damage in rats: role of tumour necrosis factor-alpha.

AIMS: Excessive alcohol intake induces hepatic fatty infiltration, which has been suggested to sensitize the liver to further damage. To test this hypothesis, L-carnitine, a constitutional lipotropic compound, was administered to rats chronically treated with ethanol by liquid diet feeding for 10 weeks. RESULTS: Ethanol administration caused marked steatosis, mild inflammation and elevated plasma alanine aminotransferase and tumour necrosis factor alpha (TNF-alpha) concentrations. Dietary supplementation with L-carnitine significantly reduced all these parameters as well as the hepatic concentration of thiobarbituric acid reactive substances, an indicator of lipid peroxidation products. Pretreatment with L-carnitine also significantly blunted ethanol-induced stimulation of TNF-alpha release by isolated Kupffer cells. CONCLUSIONS: This study provides direct support for the notion that steatosis sensitizes the liver to further damage and suggests an involvement of TNF-alpha in this process.

Animals↗
PubMedDate not supplied

The nitrefazole-ethanol interaction in man: cardiovascular responses and the accumulation of acetaldehyde and catecholamines.

The cardiovascular effects of ethanol ingestion after pretreatment with a new antialcohol drug, nitrefazole (2-methyl-4-nitro-1-(4-nitro-phenyl)imidazole, Altimol) were studied. Left ventricular function was examined by echocardiography and systolic time intervals in six healthy Finnish male volunteers who ingested 0.15-0.25 g of ethanol/kg, 24 hr after an 800 or 1600-mg peroral dose of nitrefazole. After ethanol ingestion, accumulation of acetaldehyde in blood (25-150 microM) was accompanied by a 1.5-2-fold increase in plasma noradrenaline, a 3-10-fold increase in plasma adrenaline, and a 0.5-2.0 degrees C rise in skin temperature. Heart rate increased by 70% and cardiac output by 107%. Diastolic blood pressure decreased by 30% and peripheral vascular resistance by 54%. Ejection fraction and maximum circumferential fiber-shortening velocity increased by 26 and 71%, respectively; the pre-ejection period/ejection time ratio decreased by 46%. An apparent vasovagal collapse was noticed in two nitrefazole-treated subjects after ethanol ingestion, and a third subject experienced a fainting attack shortly after the experiment. Thus, in subjects pretreated with nitrefazole, ingestion of rather small amounts of ethanol results in marked accumulation of acetaldehyde apparently due to aldehyde dehydrogenase inhibition. This causes elevation of plasma catecholamines and intense enhancement of cardiac performance. The marked cardiovascular changes demonstrate the potency of nitrefazole, suggesting that, particularly with alcoholics with occult myocardial diseases, its interaction with ethanol may be even more hazardous than that produced by other antialcohol drugs.

Acetaldehyde↗