A Comparative Blinded Study in Miniature Swine of Whole Blood-, Hemoglobin-, Platelet-, Plasma-, and Lymphocyte-Associated Acetaldehyde as Markers for Ethanol Intake

Blood samples were obtained from miniature swine maintained on 0, 2, or 6 g/kg/24 hr ethanol for 8 months (N = 6 in each group). Samples from drinking pigs were taken after 8 hr of ethanol abstinence and all were coded and sent for "blinded" analysis. A fluorigenic high performance liquid chromatographic assay was used to quantify whole blood-associated acetaldehyde, hemoglobin-associated acetaldehyde, plasma-associated acetaldehyde, platelet-associated acetaldehyde, and lymphocyte-associated acetaldehyde. Detectable levels of acetaldehyde were found in each sample in both drinking and nondrinking pigs. Analysis of whole blood-associated acetaldehyde was most discriminatory in distinguishing nondrinking from drinking pigs (mean 21.4 +/- 1.0 microM for nondrinkers vs. 24.6 +/- 1.5 SD for the group consuming 2 g/kg ethanol, p = 0.001). Measurements of hemoglobin-associated acetaldehyde normalized to protein concentration (250 +/- 47 nmoles/g vs. 203 +/- 33 SD, p less than 0.05 drinking vs. nondrinking pigs) and platelet-associated acetaldehyde (0.46 0.34 vs. 0.15 +/- 0.16 nmoles/3 x 10(8) platelets, p = 0.05 drinking vs. nondrinking pigs) were also useful in discriminating drinking from nondrinking animals. Analysis of plasma-associated acetaldehyde and lymphocyte-associated acetaldehyde were not useful as markers of ethanol consumption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhancement of ethanol induced rectal mucosal hyper regeneration with age in F344 rats.

Experimental studies in rats have shown an independent stimulation of rectal cell turnover by either chronic ethanol consumption or age. In this study the combined effect of these two factors on colorectal cell regeneration has been investigated. Ninety male F344 rats aged 2, 12, and 22 months were pair fed nutritionally adequate liquid diets containing 36% of total energy either as ethanol or isoenergetic carbohydrates. After four weeks of feeding, colorectal crypt cell production rates were measured using a stathmokinetic technique with vincristine. While age by itself did not affect colorectal cell renewal, chronic ethanol consumption stimulated rectal, but not colonic crypt cell production rate in an age dependent manner. While no significant effect of ethanol was noted in young animals, cell proliferation was significantly enhanced in middle aged animals by 81% (4.1 (2.7-5.5) v 7.4 (6.0-8.7) cells/crypt/hour, p < 0.001) and in old animals by 138% (4.5 (3.3-5.6) v 10.7 (8.9-12.4) cells/crypt/hour, p < 0.001) after ethanol ingestion. Because acetaldehyde, the first and most toxic metabolite of ethanol, has been detected in the colorectal mucosa and may lead to tissue injury influencing cell regeneration, acetaldehyde concentrations have been measured in the colons of 15 male F344 rats of various ages after an acute intraperitoneal dose of ethanol (2.5 g/kg bodyweight). There was a significant positive correlation between crypt cell production rate and acetaldehyde concentrations measured in the distal and proximal colon after an acute dose of ethanol (r = 0.5955, p < 0.005). These data clearly show that the ethanol mediated stimulation of cell regeneration in the rectum is age dependent. As reported earlier, there was found indirect evidence that acetaldehyde participates in the pathogenesis of rectal hyperregeneration after chronic alcohol consumption. This hyperregeneration of the rectal mucosa after alcohol drinking could by itself favour carcinogenesis, which is especially relevant in old age.     

Chronic ethanol consumption selectively stimulates rectal cell proliferation in the rat.

Cell proliferation was examined in the gastrointestinal tract of 30 pair fed rats having received an isocaloric liquid diet containing 36% of total calories either as ethanol or carbohydrates for four weeks. Utilising the metaphase arrest technique with vincristine, cell proliferation was measured as crypt cell production rate. This was selectively increased in the rectal mucosa of ethanol fed rats (19.1 +/- 2.0 vs 9.1 +/- 1.8 cells/crypt/h; p less than 0.005). There was a concomitant increase in proliferative compartment size (48.1 +/- 5.6% vs 30.1 +/- 8.5% of crypt population size; p less than 0.001). Serum gastrin concentrations were also found to be significantly increased after ethanol feeding (172 +/- 51 vs 106 +/- 27 pmol/l; p less than 0.01). The ethanol dependent proliferative changes in the rectal mucosa are predictive of higher susceptibility of this site to carcinogenesis, supporting experimental and epidemiological data. Increased gastrin concentrations may partly explain the observed rectal hyperproliferation. Other possible causes cannot, however, be excluded.     

Studies of Whole Blood Associated Acetaldehyde as a Marker for Alcohol Intake in Mice

Thirty C57BI mice were randomized into two groups. Group 1 served as controls while Group 2 was given 10% V/V ethanol with the drinking water. Whole blood- associated acetaldehyde (WBAA) was measured on capillary blood samples using a fluorigenic high performance chromatographic assay. WBAA peaked at Day 2. A stable mean plateau of 263 +/- 71 SD with a range of 160-400 nmoles/g hemoglobin WBAA was found in the group consuming ethanol compared with 122 +/- 17 SD and a range of 88-150 nmoles/g hemoglobin for controls (p less than 0.001). When ethanol was discontinued, levels of WBAA declined and became similar to those of controls by 9 days following cessation of ethanol. The quantitative difference between ethanol-consuming and control animals and also the rapid rise of whole blood-associated acetaldehyde and the relatively slow decline following cessation of ethanol intake indicate that such a test might be a useful monitor of drinking behavior.     

Effects of acute and chronic ethanol administration on the gastrointestinal hormones gastrin, enteroglucagon, pancreatic glucagon and peptide YY in the rat

The effect of acute and chronic ethanol administration on the gastrointestinal hormones gastrin, enteroglucagon (EG), pancreatic glucagon (PG) and peptide YY (PYY) was studied in the rat alcohol model. Plasma levels of gastrin and PYY were not significantly changed under chronic and/or acute alcohol, while PG was stimulated by acute intraperitoneal ethanol injections in control animals as well as in chronically ethanol-fed rats (8 +/- 1 vs. 28 +/- 6 pmol/l, p less than or equal to 0.05, and 7 +/- 1 vs. 21 +/- 4 pmol/l, p less than or equal to 0.05). EG levels were significantly raised after chronic ethanol feeding (45 +/- 5 vs. 73 +/- 8 pmol/l, p less than or equal to 0.01) and even further elevated if an acute dose of alcohol was given to chronically ethanol-fed rats (73 +/- 8 vs. 168 +/- 29 pmol/l, p less than or equal to 0.05). The immunohistologically evaluated numbers of the respective hormone-producing cells were not significantly changed by alcohol feeding. The ethanol-dependent elevations of EG and PG may contribute, at least in part, to the intestinal hyper-regeneration, motility disturbances and altered glucose metabolism observed after alcohol consumption.     

Lactulose reduces intracolonic acetaldehyde concentration and ethanol elimination rate in rats

BACKGROUND: Normal colonic bacteria possessing alcohol dehydrogenase activity can oxidize ethanol to acetaldehyde. Acetaldehyde recently has been shown to be a local carcinogen in humans. The aim of the study was to examine the effect of lactulose feeding on fecal and cecal pH, intracolonic acetaldehyde concentration, and total ethanol elimination rate in rats. METHODS: Sixty Wistar rats were divided into four groups. Groups 2 and 4 received lactulose daily (11 g/kg body weight for 14 days). On days 7 and 14, groups 1 and 2 received ethanol (1.5 g/kg body weight) intraperitoneally, whereas groups 3 and 4 received saline. RESULTS: Fecal and cecal pH values decreased significantly after lactulose treatment compared with the controls. Lactulose feeding reduced the total ethanol elimination rate by 13.8% (257 +/- 0.008 mg/kg/hr vs. 298 +/- 0.003 mg/kg/hr, p < 0.001) and the intracecal acetaldehyde concentration by 66.2% after ethanol (49 +/- 29 microM vs. 145 +/- 47 microM, p = 0.03) compared with the controls. CONCLUSION: Lactulose feeding to rats significantly reduces ethanol elimination rate and intraluminal acetaldehyde concentration in the colon after ethanol administration. This prebiotic thus could be used as an effective agent to block the microbial production of carcinogenic acetaldehyde in the large intestine.     

Inhibition of alcohol-associated colonic hyperregeneration by alpha-tocopherol in the rat

BACKGROUND: Chronic alcohol consumption results in colorectal mucosal hyperregeneration, a condition associated with an increased risk for colorectal cancer. Possible mechanisms may involve the effects of acetaldehyde and/or free radicals generated during alcohol metabolism. Vitamin E is part of the antioxidative defense system, and its concentration is decreased or its metabolic utilization increased in various tissues after chronic alcohol consumption. We wondered whether alpha-tocopherol supplementation may prevent ethanol-induced colorectal cell cycle behavior and whether these changes were related to alterations in protein synthesis. METHODS: Five groups of male Wistar rats, each consisting of 14 animals, received liquid diets as follows: group 1, alcohol; group 2, alcohol + alpha-tocopherol; group 3, control (i.e., isocaloric glucose); group 4; control (i.e., isocaloric glucose) + alpha-tocopherol. Group 5 was fed a solid chow diet ad libitum. After 4 weeks of feeding, immunohistology was performed with anti-proliferating cell nuclear antigen (PCNA) or anti-BCL2 antibodies. Fractional (k(s)) and absolute (V(s)) rates of protein synthesis and rates of protein synthesis relative to RNA (k(RNA)) and DNA (k(DNA)) were measured with a flooding dose of L-[4-3H] phenylalanine with complementary analysis of protein and nucleic acid composition. RESULTS: The PCNA index was increased significantly in the colon after ethanol administration compared with controls (ethanol, 10.3 +/- 2.3 vs. control, 6.51 +/- 1.6% PCNA positive cells, p < 0.05), although neither the protein, RNA, and DNA concentrations nor k(s), k(RNA), k(DNA), and V(s) were affected. This increase in PCNA index was significantly diminished by coadministration of alpha-tocopherol (ethanol + alpha tocopherol, 7.86 +/- 1.71% PCNA positive cells, p < 0.05) without significant alterations in protein synthetic parameters. A similar result was obtained for the PCNA index in the rectal mucosa (ethanol, 14.6 +/- 4.4 vs. control, 12.1 +/- 4.2% PCNA positive cell), although this did not reach statistical significance. Neither ethanol nor alpha tocopherol feeding had any significant effect on BCL-2 expression in the colorectal mucosa. As with the colon, protein synthetic parameters in the mucosa were not affected by alcohol feeding at 4 weeks. These effects on colonic cell turnover without corresponding changes in protein synthesis thus represent a specific localized phenomenon rather than a general increase in anabolic processes in the tissue and reaffirm the hyperregenerative properties of chronic alcohol consumption. CONCLUSIONS: Alcohol-associated hyperproliferation could be prevented, at least in part, by supplementation with alpha-tocopherol. This may support the hypothesis that free radicals are involved in the pathogenesis of alcohol-associated colorectal hyperproliferation.     

Hepatic accumulation of lysosomes and defective transcytotic vesicular pathways in cirrhotic rat liver.

To investigate the potential role of lysosomes in cirrhosis, we analyzed the activity of lysosomal enzymes in rats exposed long-term to phenobarbital and carbon tetrachloride. The activity of lysosomal enzymes was markedly increased in the homogenate of cirrhotic livers (e.g., arylsulfatase 9 +/- S.D.2 vs. 16 +/- 6 nmoles.min-1.mg-1 in control rats and cirrhotic rats, respectively; p less than 0.001). The corresponding plasma levels were also increased (7 +/- 1 vs. 12 +/- 3 nmoles.min-1.mg-1; p less than 0.01), whereas biliary excretion was diminished (16 +/- 7 vs. 7 +/- 2 pmol.min-1.gm liver-1; p less than 0.05) in cirrhotic rats. Stereological quantification of lysosomes visualized cytochemically revealed an increase of pericanalicular lysosomes averaging 1.5 +/- 0.4 around a canaliculus in controls and 3.7 +/- 1.0 in cirrhotic rats (p less than 0.01). Because this suggested a defect in the transcellular vesicular pathway, we investigated the biliary excretion of horseradish peroxidase and epidermal growth factor in perfused livers. Bile flow and total horseradish peroxidase excretion were similar in control rats and cirrhotic rats. However, the early peak of biliary horseradish peroxidase excretion--usually taken as evidence of paracellular transport--was increased in cirrhotic rats (13 +/- 7 vs. 57 +/- 22%; p less than 0.01), whereas the second peak--reflecting the transcellular vesicular pathway(s)--was markedly reduced (87 +/- 7 vs. 43 +/- 22%; p less than 0.001). A similar reduction in the biliary excretion of intact epidermal growth factor and of its degradation products was found. These results demonstrate an increased number of lysosomes in hepatocytes of cirrhotic livers; this appears to be the result of accumulation rather than proliferation, in view of the reduced transcellular vesicular movement of different markers into bile.     

Demonstration of dissimilar acute haemodynamic effects of ethanol and acetaldehyde.

To determine whether the acute cardiac depressant effects of ethanol could be attributed to its metabolite (acetaldehyde), either ethanol or acetaldehyde was intravenously infused into pentobarbital anaesthetised, closed-chest dogs. At a venous blood ethanol level of 199 +/- 43 (SE) mg . dl-1, ejection fraction had decreased from 35 +/- 2 to 30 +/-2%, P less than 0.05, max dP/dt/end-diastolic volume from 14.0 +/- 2.1 to 8.6 +/- 1.1 kPa . s-1 . cm-3 (105 +/- 16 to 65 +/- 8 mmHg . s-1 . cm-3), P less than 0.02, whereas end-diastolic volume (P less than 0.005), myocardial oxygen consumption (P less than 0.05) and coronary blood flow (P less than 0.005) had increased. Higher ethanol levels exaggerated these changes when peak arterial acetaldehyde was 20.2 +/- mumol . litre-1. By contrast, infusion of acetaldehyde to a peak blood level comparable with that produced by ethanol increased cardiac output from 2.4 +/- 0.2 to 2.8 +/- 0.2 litre-1 . min-1 P less than 0.01), coronary sinus oxygen saturation from 46 +/- 4 to 55 +/- 3% (P less than 0.25) and reduced systemic resistance from 8.0 +/- 0.7 to 6.3 +/- 0.5 kPa . litre-1 . min-1 (60 +/- 5 to 47 +/- 4 mmHg . litre-1 . min-1) (P less than 0.001). High dosage of acetaldehyde to a level of 129 +/- 23 mumol . litre-1 produced elevation of cardiac output (P less than 0.001), ejection fraction (P less than 0.01), coronary blood flow (P less than 0.02), whereas systemic resistance (P less than 0.001), heart rate (P less than 0.05) and myocardial oxygen consumption (P less than 0.05) decreased. Discontinuation of acetaldehyde infusion significantly reversed these changes. Max dP/dt/left ventricular end-diastolic volume and left ventricular end-diastolic volume were not significantly altered by acetaldehyde. Thus, ethanol depresses cardiac performance and increases myocardial oxygen consumption. By contrast, acetaldehyde at levels produced by ethanol metabolism improves cardiac performance, consequent to afterload reduction, and reduces myocardial oxygen consumption.     

Liver triglyceride concentration and body protein metabolism in ethanol-treated rats: effect of energy and nutrient supplementation.

The objective of this study was to compare the metabolic effects of long-term ethanol consumption with oral (Lieber-DeCarli) and enteral feeding techniques. Enteral feeding allowed administration of greater amounts of energy and nutrients. After 21 days of treatment using the Lieber-DeCarli technique, the ethanol-treated rats had the following significant (P less than 0.05) differences from pair-fed controls: lower cumulative nitrogen balance (days 5-21; 2.8 +/- 0.1 g N vs. 3.5 +/- 0.1 g N), lower protein content of gastrocnemius muscle (289 +/- 17 mg vs. 358 +/- 11 mg) and intestinal mucosa (461 +/- 19 mg vs. 577 +/- 40 mg), higher plasma leucine concentration (147 +/- 8 mumol/L vs. 102 +/- 8 mumol/L), higher liver protein content (2222 +/- 122 mg vs. 1679 +/- 58 mg), and higher liver triglyceride concentration (38.4 +/- 2.8 mg/g vs. 8.7 +/- 1.0 mg/g). When rats received the same amount of nitrogen (1.5 g.kg-1.day-1) and ethanol (13 g.kg-1.day-1) but 16.3% more energy and nutrients by a surgically implanted gastric cannula (enterally fed), the effects of ethanol on nitrogen balance, tissue protein content, plasma leucine concentration, and liver triglyceride concentration were similar to those observed in the rats fed orally. It is concluded that the metabolic effects observed using the Lieber-DeCarli feeding technique are due to ethanol per se and not the synergism of ethanol and undernutrition as recently suggested.     

Effect of aging on in vivo and in vitro ethanol metabolism and its toxicity in F344 rats

To investigate the effect of aging on ethanol metabolism, 24 male and female F344 rats aged 2 and 12 mo that were fed a laboratory diet received ethanol (1.2 and 2.5 g/kg body wt) intraperitoneally. In male rats, in vivo ethanol elimination significantly decreased according to age both at high (436 +/- 38 vs. 294 +/- 27 mg/kg.h; p less than 0.01) and low (365 +/- 19 vs. 261 +/- 8 mg/kg.h; p less than 0.01) blood ethanol concentrations. Age did not influence the specific activity of hepatic or gastric alcohol dehydrogenase, whereas the activity was significantly decreased with age in the liver (p less than 0.05) and in the stomach (p less than 0.001) when related to body weight. In addition, the activity of the hepatic microsomal ethanol oxidizing system decreased significantly according to age (8.7 +/- 0.5 vs. 6.00 +/- 0.3 nmol/min.mg micr. protein; p less than 0.001). To study the response of ethanol-metabolizing enzymes to chronic ethanol ingestion, 2- and 19-mo-old male F344 rats were pair-fed nutritionally adequate liquid diets containing 36% of total calories either as ethanol or isocaloric carbohydrate for 3 wk. In this experiment specific alcohol dehydrogenase activity was not significantly affected by age, whereas the hepatic microsomal function estimated by the determination of cytochrome P450, microsomal ethanol oxidizing system, and aniline hydroxylation as well as hepatic mitochondrial low Km-acetaldehyde dehydrogenase activity was found to be markedly depressed with age (p less than 0.01). Chronic ethanol consumption increased microsomal enzyme activities in older rats to levels comparable to those observed in young animals prior to ethanol administration. Chronic ethanol feeding also resulted in an increased hepatic fat accumulation, which was significantly enhanced in older rats. In contrast to male rats, in vivo ethanol metabolism was practically identical for 2- and 12-mo-old female rats. These data demonstrate an enhanced toxicity of alcohol in older compared to younger male but not female rats associated with a delay in alcohol elimination both at high and low ethanol blood concentrations and a decrease in ethanol- and acetaldehyde-metabolizing enzyme activities.     

Opiate Antagonist Nalmefene Inhibits Ethanol-induced Flushing in Asians: A Preliminary Study

Ethanol-induced flushing (EIF) occurs in up to 80% of Asians and is characterized by facial flushing, tachycardia, and increased cardiac output. Since endogenous opiates and prostaglandins may be mediators of flushing syndromes, we attempted to block EIF in four Asian flushers with single doses of either the opiate antagonist nalmefene, or the prostaglandin synthesis inhibitor indomethacin. Nonflushers (2 Caucasian, 2 Asian) and four Asian flushers were given on separate days water, ethanol (0.4 g/kg p.o.), ethanol plus nalmefene (2 mg i.v.), or ethanol plus indomethacin (50 mg p.o.). Ethanol concentrations of flushers and nonflushers were similar. Mean (+/- SEM) plasma acetaldehyde concentrations of flushers (28.2 +/- 11.8 microM) were significantly greater than nonflushers (1.4 +/- 0.5 microM) following ethanol ingestion (p less than 0.001). Ethanol alone always induced a significant rise in facial skin temperature [mean area under the curve (AUC) = 5142 +/- 648 % delta T x min, p less than 0.01] and of pulse (mean AUC = 1622 +/- 120 bpm x min, p less than 0.001) in flushers compared to water ingestion. A single dose of nalmefene (2 mg i.v.) but not indomethacin (50 mg p.o.), reduced the mean (+/- SEM) ethanol-induced rise in facial skin temperature of flushers by 58 +/- 14% (p less than 0.05) without changing plasma acetaldehyde concentrations. These data are preliminary evidence that the opiate antagonist, nalmefene, blocks some of the vascular manifestations of EIF without altering the elevated plasma concentrations of acetaldehyde.     

Decreased uptake of taurocholate and ouabain by hepatocytes isolated from cirrhotic rat liver

To differentiate between the "intact" and "sick" cell hypothesis explaining decreased clearance of endo- and xenobiotics, we measured uptake of taurocholate and ouabain in hepatocytes isolated from cirrhotic rat liver. Cirrhosis was induced by chronic exposure of male Sprague-Dawley rats to phenobarbital and carbon tetrachloride. Uptake of [14C]taurocholate and [3H]ouabain was measured by a rapid filtration technique. Hepatocytes from cirrhotic liver were as viable as control hepatocytes--as judged by trypan blue exclusion and lactate dehydrogenase release--but consumed 28% less oxygen. Vmax of both taurocholate (3.16 +/- 0.95 vs. 0.40 +/- 0.35 nmoles X min-1 X 10(6) cells-1; p less than 0.001) and ouabain (2.16 +/- 0.78 vs. 0.83 +/- 0.26 nmoles X min-1 X 10(6) cells-1; p less than 0.005) was significantly reduced. These results are compatible with the "sick" cell hypothesis.     

Secretion and metabolic clearance rates of thyroxine and triiodothyronine in streptozotocin-diabetic rats

This study was undertaken to evaluate the effects of streptozotocin-induced diabetes on T4 and T3 production rate (PR) and metabolism in rats. [125I]T4 and [125I]T3 were injected iv and sequential blood samples were obtained. Plasma ethanol extracts were analyzed for [125I]T4 and [125I]T3 by thin layer chromatography. T4 and T3 production rates and kinetic parameters of T4 and T3 metabolism in control, diabetic and insulin-treated diabetic rats were assessed by applying kinetic analyses to measurements of disappearance of injected T4 and T3 radiotracer from plasma. The metabolic clearance rate (MCR) and the fractional disappearance rate (K) of T4 in diabetic rats (0.72 +/- SD, 0.02 ml/h X 100 g, and 0.034 +/- 0.006 h-1, respectively) were significantly lower (P less than 0.001) than in the control group (1.01 +/- 0.04 ml/h X 100 g and 0.056 +/- 0.004 h-1). Similarly, the MCR and K values of T3 were also significantly reduced (P less than 0.001) in the diabetic animals: 16.2 +/- 0.7 ml/h X 100 g and 0.088 +/- 0.007 h-1 in controls vs 13.0 +/- 1.2 ml/h X 100 g and 0.058 +/- 0.009 h-1 in diabetics, respectively. Insulin therapy significantly reversed these alterations. There was also a significant reduction (P less than 0.001) in plasma T4 (18 +/- 6 ng/ml) and T3 (0.20 +/- 0.05 ng/ml) concentrations in the diabetic rats compared to control values, whose T4 and T3 levels averaged 65 +/- 10 and 0.68 +/- 0.09 ng/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of Placental Amino Acid Uptake in Rats Following Acute and Chronic Ethanol Exposure

The effects of acute and chronic maternal ethanol consumption on in vitro placental uptake of alpha-aminoisobutyric acid (AIB), cycloleucine, L-alanine (Ala), L-leucine (Leu), and L-lysine (Lys) were determined. Ethanol (4 g/kg. po) administered 2 hr prior to sacrifice, reduced (p less than 0.05) placental villous net uptake of cycloleucine and Ala by 29%. Prior chronic ethanol consumption depressed (p less than 0.05) placental uptake of AIB (38%), cycloleucine (45%), Ala (35%), Leu (25%), and Lys (34%). In vitro exposure of previously untreated villous fragments for 2 hr to 2 mg/ml of ethanol reduced (p less than 0.05) the net uptake of AIB and cycloleucine by 24% and 31%, respectively, whereas the minimum concentration of acetaldehyde required to cause a significant inhibition was 310 microM for AIB and 465 microM for cycloleucine. Ethanol (3 mg/ml) had no effect on AIB or cycloleucine net uptake if sodium was omitted from the incubation media. The efflux of AIB (10(-6)M) and cycloleucine (10(-6)M) from villous tissue was unaffected (p less than 0.05) by either ethanol (3 mg/ml) or acetaldehyde (600 microM) and obeyed first order kinetics. It was concluded that acute, and especially chronic, maternal ethanol consumption can depress the placental uptake of a variety of amino acids in the rat and, in the acute setting, the effect was on a sodium-dependent system involved in amino acid influx into placental cells.     

In vivo interactions between H2-receptor antagonists and ethanol metabolism in man and in rats

The influence of a 7-day medication of either cimetidine (1,000 mg per day) or ranitidine (300 mg per day) on serum ethanol concentrations after a single oral dose of ethanol (0.8 gm per kg body weight) was investigated in a randomized placebo-controlled study in eight male volunteers. Compared with the placebo, cimetidine but not ranitidine produced a significant increase in both the peak serum ethanol concentration (85.9 +/- 3.5 vs. 73.0 +/- 3.2 mg dl-1, p less than 0.02) and in the area under the serum ethanol concentration time curve (350 +/- 19 vs. 304 +/- 25 mg dl-1 hr-1, p less than 0.05). However, the ethanol elimination rate was not affected by cimetidine. When ethanol (1.0 gm per kg body weight) was administered intravenously, cimetidine failed to induce a change in ethanol metabolism. Furthermore, the effect of H2-receptor antagonists was studied in animal experiments. Female Sprague-Dawley rats received a single dose of ethanol (7 or 3 gm per kg body weight) together with an intraperitoneal injection of either cimetidine (120 mg per kg body weight), ranitidine (120 mg per kg body weight) or isotonic saline. After alcohol absorption, ethanol elimination was significantly inhibited by both cimetidine (3.99 +/- 0.39 vs. 5.68 +/- 0.23 mmoles kg-1 hr-1, p less than 0.02) and ranitidine (4.21 +/- 0.14 vs. 5.68 +/- 0.23 mmoles kg-1 hr-1, p less than 0.02) at high ethanol concentrations (60 to 20 mM) but not at blood ethanol concentrations below 20 mM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunological and biochemical factors associated with spontaneous bacterial peritonitis

A prospective study (June 1988-December 1989) of all patients admitted with ascites due to cirrhosis was undertaken: Biochemical and immunological factors which may have significance in the development of spontaneous bacterial peritonitis were determined. Among 56 patients (44 males and 12 females) SBP developed in 16% of the group. No age differences were found and the etiology of the cirrhosis was mainly alcoholic. Patients with SBP had lower alpha-2 globulin concentrations: 0.43 +/- 0.12 vs. 0.60 +/- 0.18 g/dl (p less than 0.05) and a lower prothrombin time: 41 +/- 13% vs. 69.5 +/- 13 vs. 69.5 +/- 21% (p less than 0.001). Patients with SBP had also lower ascitic fluid total protein 0.99 +/- 0.4 vs. 1.64 +/- 1.1 g/dl (p less than 0.01) as well as lower alfa-2 globulin: 0.065 +/- 0.012 vs. 0.096 +/- 0.067 g/dl (p less than 0.05); beta globulin, 0.11 +/- 0.047 vs. 0.2 +/- 0.17 g/dl (p less than 0.05); gamma globulin, 0.32 +/- 0.1 vs. 0.52 +/- 0.4 g/dl (p less than 0.05); IgG, 275 +/- 157 vs. 477 +/- 335 g/dl (p less than 0.05); C3, 9.2 +/- 3.2 vs. 17 +/- 13 mg/dl (p less than 0.01) and C4, 2.83 +/- 1.5 vs. 4.66 +/- 3.9 mg/dl (p less than 0.05) than patients without this complication.     

Cardiac structure and function before and after acute and chronic verapamil administration in hypertensive patients.

The aim of this study has been to analyze the acute and chronic effects of oral verapamil on diastolic function indices, derived from Doppler echocardiography, and left-ventricular (LV) dimensions and mass, assessed by M-mode echocardiography, in hypertensive patients without LV hypertrophy. 12 patients with essential hypertension were studied in basal conditions and (1) after a single oral administration of verapamil 160 mg and placebo in a double-blind protocol and (2) over chronic treatment (12 months) with verapamil 240 mg/day. At baseline, the ratio between early and atrial-induced transmitral velocities (E/A ratio) was lower in patients than in 12 age-matched normal subjects (1.08 +/- 0.2 vs. 1.51 +/- 0.3, p less than 0.01). Acute verapamil administration significantly decreased arterial blood pressure (162 +/- 26/101 +/- 8 to 142 +/- 12/88 +/- 7 mm Hg, p less than 0.01 after 2 h) and increased the E/A ratio to 1.26 +/- 0.3 (p less than 0.05) after 3 h. No change in ventricular dimensions and heart rate was observed. After chronic therapy, we found a further increase in the E/A ratio in 10 responder patients (1.49 +/- 0.3, p less than 0.01). The LV mass index, that was higher than in normal subjects before the treatment (118 +/- 16 vs. 91 +/- 11 g/m2, p less than 0.01), was significantly reduced (100 +/- 17 g/m2, p less than 0.05 vs. basal, nonsignificant vs. normal subjects). Our results demonstrate that acute administration of verapamil only partially improves the abnormal indices of diastolic function in hypertensive patients, whereas chronic treatment, by reducing LV mass indices and blood pressure to normal values, can completely normalize the indices of LV diastolic filling.     

Effects of acute and chronic administration of verapamil on the anatomy and function of the left ventricle in essential hypertensive patients

The aim of this study was to analyze the acute and chronic effects of oral verapamil on diastolic function indices, derived from Doppler echocardiography and left ventricular (LV) dimensions and mass, assessed by M-mode echocardiography, in hypertensive patients (pts). Twelve essential hypertensive pts without LV hypertrophy were studied in basal conditions and 1) after a single oral administration of verapamil 160 mg and placebo, in double blind protocol and 2) over chronic treatment (six months) of verapamil 240 mg/day. At baseline the ratio between early and atrial-induced transmitral velocities (E/A ratio) was lower in pts than in 12 age-matched normal subjects (1.0 +/- 0.3 vs 1.5 +/- 0.3, p less than 0.01). Acute verapamil administration significantly decreased arterial blood pressure (162 +/- 26/101 +/- 15 to 142 +/- 12/88 +/- 7 mmHg, p less than 0.01) after two hours and increased the E/A ratio to 1.26 +/- 0.3 (p less than 0.05) after three hours. No change in ventricular dimensions or heart rate was observed. After chronic therapy we found a further increase in the E/A ratio (1.49 +/- 0.3, p less than 0.01) in 10 responder pts. The LV mass index, which was higher than in normal subjects before the treatment (118 +/- 16 vs 91 +/- 11 g/m2, p less than 0.01), was significantly reduced (100 +/- 17 g/m2, p less than 0.05 vs basal, ns vs normal subjects). Our results demonstrate that acute administration of verapamil only partially improves the abnormal indices of diastolic function in hypertensive pts, whereas chronic treatment, by reducing left ventricular mass indices and blood pressure to normal values, can completely normalize the indices of LV diastolic filling.     

Increased rectal cell proliferation following alcohol abuse

BACKGROUND: Epidemiological data indicate an increased risk for rectal cancer following chronic alcohol consumption. As chronic ethanol ingestion leads to rectal hyperregeneration in experimental animals, indicating a state of increased susceptibility to carcinogens, we studied cell proliferation in alcohol abusers. METHODS: Rectal biopsies were taken from 44 heavy drinkers and 26 controls. Cell proliferation, including proliferative compartment size, was measured by immunohistological staining for proliferative cell nuclear antigen (PCNA) and Ki67, and by in situ hybridisation for histone H3. Quantification of cell proliferation using PCNA staining was evaluated in 27 alcohol abusers and 12 controls. In addition, immunohistology was performed for cytokeratins and gene products of Rb1, bcl-2, and p53. RESULTS: Heavy drinking resulted in increased cell proliferation of the rectal mucosa, as shown by increased detection of different proliferation markers. However, cell differentiation regarding cytokeratin expression patterns was unchanged as well as regulatory factors involved in carcinogenesis and/or apoptosis. CONCLUSION: Chronic alcohol abuse leads to rectal mucosal hyperproliferation in humans, a condition associated with an increased cancer risk.