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Biomedical subjects

Y Israel

Publications and source records attributed to Y Israel.

At least 73 records · Page 4Linked to original sources
PubMed1989

Effects of propylthiouracil and methimazole on splanchnic hemodynamics in awake and unrestrained rats.

The treatment of alcoholic liver disease with propylthiouracil is based on its effect of suppressing the ethanol-induced increase in hepatic oxygen consumption. It has been postulated that liver necrosis ensues when the increase in oxygen demand by the liver exceeds oxygen delivery to this organ. Data are now presented which show that propylthiouracil also increases portal blood flow in awake, unrestrained rats. Liver blood flow was determined using the labeled microsphere technique in rats at various intervals (0.25, 0.5, 1.0, 3.0, 6.0 and 24 hr) after oral propylthiouracil (50 mg per kg). Administration of propylthiouracil (dose range: 6.25 to 100.0 mg per kg) produced a dose-dependent increase in portal blood flow when given either orally or intraarterially. Maximal flows were obtained with 50 mg per kg (controls = 37.8 +/- 1.5, oral propylthiouracil = 50.7 +/- 2.2 ml.kg-1.min-1). This increase in portal blood flow was accompanied by a decrease in preportal vascular resistance (controls = 2.61 +/- 0.16; propylthiouracil, 50 mg per kg = 1.79 +/- 0.09 mmHg per ml.kg-1.min-1). These effects were correlated with the plasma concentrations of propylthiouracil (r = 0.67, n = 68, p less than or equal to 0.001). The effect of oral propylthiouracil (50 mg per kg) on portal blood flow started at 0.5 hr and lasted for 6 hr after administration, whereas total liver blood flow was increased for 3 hr. Oral propylthiouracil (50 mg per kg) for 5 days resulted in a 53% increase in thyroid weight, an 85% reduction in 125I thyroid uptake and a 74% decrease in serum thyroxine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The gamma-glutamyltransferase/glutamine synthetase activity ratio. A powerful marker for the acinar origin of hepatocytes.

The activity of glutamine synthetase (GS) in hepatocytes isolated by digitonin-collagenase perfusion from the perivenous region was more than 10-times higher than in cells isolated from the periportal region. This distribution was confirmed by immunohistochemical staining for GS of cells separated from either region. In contrast, in periportal hepatocytes, the activity of gamma-glutamyltransferase (GGT) was 3-4 times as high as in perivenous hepatocytes. This acinar distribution was also confirmed histochemically. The striking reciprocal acinar distribution of these two enzymes, now observed by direct biochemical analysis of selectively isolated hepatocytes, confirms the earlier qualitative differences observed by histochemistry and immunohistochemistry. The GGT/GS ratio seems to serve as a powerful marker of the acinar origin of isolated hepatocyte populations. Preliminary data describing glutamine synthetase activity in plasma of some subjects with suspected liver dysfunction suggests this enzyme as a marker for pericentral damage.

Animals↗
PubMed1988

Depletion of hepatic glutathione by ethanol occurs independently of ethanol metabolism.

The mechanism of ethanol-induced depletion of hepatic glutathione (GSH) was studied in vivo and in isolated hepatocytes. Neither inhibition of ethanol metabolism with 4-methylpyrazole, nor a 10-fold elevation of acetaldehyde levels by inhibition of aldehyde dehydrogenase with cyanamide or disulfiram, affected the magnitude of the GSH depletion observed in vivo. The rate of intracellular GSH accumulation by isolated hepatocytes incubated with cysteine or methionine was not inhibited by the addition of 80 mM ethanol. A significantly decreased rate of GSH accumulation was, however, found in hepatocytes isolated from ethanol-intoxicated animals. Neither the in vivo pretreatment with ethanol nor its in vitro addition to isolated hepatocytes affected the rate of GSH efflux. The results suggest that ethanol itself, rather than its metabolic products, causes depletion of liver GSH, and that events occurring in vivo are required for such an effect to be exerted.

Acetaldehyde↗
PubMed1988

Noninvasive estimation of blood alcohol concentrations: ethanol vapor above the eye.

The present study describes, in animals, a novel approach to the in vivo, noninvasive determination of alcohol in the body. The concentration of ethanol in vapor above the lacrimal fluid in the eye was analyzed in situ by the use of a fast (1-min) gas sensor method developed previously for biological liquids. After an oral dose of 1 g/kg to 11 animals, eye vapor measurements and blood samples were obtained over 4 hr. The correlation of 61 blood ethanol concentrations obtained by the two methods yielded a correlation coefficient of 0.92 and a slope of 0.99. The metabolic rates of ethanol determined by gas chromatographic analysis of blood and by ethanol eye vapor analysis are virtually identical. The data suggest that ethanol eye vapor analysis may be an attractive, noninvasive method for the determination of ethanol in animals. The method is not subject to false high readings due to alcohol in the buccal cavity and thus might constitute an alternative to breath analysis in the human. In a separate series, ethanol was determined by head space gas chromatography in samples of blood and lacrimal fluid while the animals were under ketamine anesthesia. The correlation of ethanol concentrations in blood and lacrimal fluid (r = 0.99) shows that ethanol is distributed in lacrimal fluid which comprises part of total body water.

Animals↗
PubMed1988

New insights on the mechanism of the alcohol-induced increase in portal blood flow.

Acute administration of ethanol increases portal blood flow by 40-60%. This increase in blood flow compensates for the increase in O2 consumption that follows alcohol intake and may play a protective role against hypoxic hepatocellular necrosis. We have investigated the mechanism of this hemodynamic effect of ethanol in the rat using the labeled microsphere technique. We ruled out a direct role of systemic glucagon and of acetaldehyde in mediating the increase in portal flow. However, the increase in flow is maximal at a blood ethanol concentration of 3.5 mM, corresponding to that required to achieve the Vmax of alcohol dehydrogenase, and is suppressed by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. Alcohol ingestion results in zonal liver hypoxia and in increases in acetate, both of which have been shown to increase the levels of adenosine, a potent vasodilator, in blood and tissues. Ethanol produces a 400% increase in arterial adenosine. Adenosine infusion leads to a dose-dependent increase in portal blood flow of up to 100%, an effect that is suppressed by administration of 8-phenyltheophylline, an antagonist of adenosine at A1 and A2 receptors. Similarly, the ethanol-induced increase in portal blood flow is fully suppressed by 8-phenyltheophylline. In conclusion, adenosine appears to play an important role in the mechanism by which ethanol increases portal blood flow.

Adenosine↗
PubMed1988

Ethanol-induced increase in portal blood flow: role of adenosine.

The mechanism by which ethanol induces an increase in portal vein blood flow was studied in rats using radiolabeled microspheres. Ethanol (2 g/kg) by gavage resulted in an increase of 50-70% in portal vein blood flow. The ethanol-induced increase in portal blood flow was suppressed by the adenosine receptor blocker 8-phenyltheophylline [ethanol, 61.8 +/- 4.1 ml.kg-1.min-1; ethanol + 8-phenyltheophylline (0.2 mg.kg-1.min-1), 44.2 +/- 2.0 ml.kg-1.min-1; P less than 0.05]. By itself, 8-phenyltheophylline (0.2 mg.kg-1.min-1) was without effect on cardiac output or portal blood flow. Adenosine infusion resulted in a dose-dependent increase in portal blood flow with a maximal effect at a dose of 0.17 mg.kg-1.min-1 (control, 41.3 +/- 2.3; adenosine, 81.7 +/- 8.0 ml.kg-1.min-1; P less than 0.05). This adenosine-induced increase in portal blood flow was inhibited by 8-phenyltheophylline in a dose-dependent manner [adenosine, 81.7 +/- 8.0 ml.kg-1.min-1; adenosine + 8-phenyltheophylline (0.2 mg.kg-1.min-1), 49.8 +/- 6.6 ml.kg-1.min; P less than 0.05]. Both alcohol and adenosine significantly reduced preportal vascular resistance by 40% (P less than 0.02) and 60% (P less than 0.01), respectively. These effects were fully suppressed by 8-phenyltheophylline. It is concluded that adenosine is a likely candidate to mediate the ethanol-induced increase in portal vein blood flow. It is suggested that an increase in circulating acetate and liver hypoxia may mediate the effects of alcohol by increasing tissue and interstitial adenosine levels.

Adenosine↗
PubMed1988

Ethanol-induced increase in portal blood flow: role of acetate and A1- and A2-adenosine receptors.

The increase in portal blood flow induced by ethanol appears to be adenosine mediated. Acetate, which is released by the liver during ethanol metabolism, is known to increase adenosine levels in tissues and in blood. The effects of acetate on portal blood flow were investigated in rats using the microsphere technique. The intravenous infusion of acetate (7-250 mumol.kg-1.min-1) resulted in vasodilation of the preportal vasculature and in a dose-dependent increase in portal blood flow [control, 39.1 +/- 2.6 ml.kg-1.min-1; acetate (250 mumol.kg-1. min-1), 68.7 +/- 4.0 ml.kg-1.min-1]. This acetate-induced increase in portal blood flow was suppressed by the adenosine receptor blocker, 8-phenyltheophylline. Using the A1-adenosine receptor agonist N-6-cyclohexyl adenosine and the A2-agonist 5'-N-ethylcarboxamido adenosine, we demonstrate that the effect of adenosine on the preportal vasculature is mediated by the A2-subtype of adenosine receptors. In conclusion, these data support the hypothesis that the increase in portal blood flow after ethanol administration results from a preportal vasodilatory effect of adenosine formed from acetate metabolism in extrahepatic tissues.

Acetates↗
PubMed1988

Induction of an allergic reaction to alcohol metabolites by immunization.

Acetaldehyde, a product of alcohol metabolism, is known to bind covalently to plasma and red cell proteins, yielding stable adducts which have recently shown are recognized as foreign by the immune system. The present study demonstrates that immunization of mice with protein-acetaldehyde adducts in aluminum hydroxide gel results in the production of reaginic antibodies that recognize the adducts and trigger an allergic-anaphylactic reaction. These findings may lead to new approaches in the treatment of excessive alcohol consumption in humans.

Acetaldehyde↗
PubMed1987

Long-term treatment of alcoholic liver disease with propylthiouracil.

Propylthiouracil has been shown experimentally to protect against alcohol-induced hepatocellular necrosis in hypoxic conditions. An earlier, short-term study of patients with alcoholism and liver disease indicated clinical improvement with propylthiouracil, but the effect on mortality could not be assessed. In the present study, we investigated the effect of propylthiouracil on mortality in patients with alcoholic liver disease in a long-term, double-blind, randomized clinical trial involving 310 compliant patients who received propylthiouracil (n = 157) or placebo (n = 153) for a maximum of two years. There were no differences between the two groups in demographic and clinical characteristics and biopsy-confirmed diagnoses at randomization, or in daily urinary alcohol levels during the study. The cumulative dropout rate over two years was not significantly different (propylthiouracil group, 0.68; placebo group, 0.60). The group receiving propylthiouracil (300 mg per day) had a cumulative mortality rate half that in the group receiving placebo (0.13 vs. 0.25 [P less than 0.05] in the total sample, and 0.25 vs. 0.55 [P less than 0.03] in a subgroup of severely ill patients [propylthiouracil group, n = 56; placebo group, n = 41]). Proportional-hazards stepwise regression analyses indicated that only propylthiouracil treatment, prothrombin time, hemoglobin levels, and mean daily urinary alcohol levels significantly affected mortality. The hazards ratio for the complete group indicated that mortality in the propylthiouracil group was 0.38 (95 percent confidence interval, 0.20 to 0.83) that of the placebo group. Protection by propylthiouracil was not observed in patients with high morning urinary alcohol levels. No clinically important side effects of propylthiouracil were observed at the dose used. We conclude that the administration of propylthiouracil can reduce mortality due to alcoholic liver disease.

Alcohol Drinking↗
PubMed1987

Blood acetaldehyde and the ethanol-induced increase in splanchnic circulation.

Acute oral administration of ethanol significantly increases (50-60%) portal blood flow to the liver. As earlier studies have indicated that this effect is maximal at concentrations of ethanol that saturate the alcohol dehydrogenase (ADH) system and is blocked by the ADH inhibitor 4-methylpyrazol, we investigated the possible role of acetaldehyde, a product in the ADH reaction, as a mediator of this effect. In the first series of experiments it was shown that, contrary to expectations, cyanamide administration prior to alcohol suppressed fully the effect of ethanol on portal blood flow without altering it in the absence of ethanol [ethanol = 69.5 +/- 5.6; ethanol + cyanamide 42.9 +/- 2.4; control = 43.0 +/- 3.0; cyanamide = 55.1 +/- 3.7 ml X min-1 X (kg body wt)-1]. Arterial blood concentrations of acetaldehyde were elevated from 3.6 +/- 0.3 microM in the presence of ethanol to 293 +/- 48 microM in the presence of ethanol + cyanamide. Infusion of acetaldehyde either into the left ventricle, resulting in arterial blood acetaldehyde levels of 227 +/- 77 microM, or into the portal circulation, resulting in arterial blood levels of 198 +/- 40 microM, did not modify portal blood flow or splanchnic hemodynamics, nor the effect of ethanol per se. The combination of cyanamide + ethanol significantly reduced total peripheral resistance (from 28 +/- 3 to 19 +/- 2 dyne X cm X sec-5), while neither ethanol or cyanamide per se, nor acetaldehyde affected total peripheral resistance. Data suggest that acetaldehyde is not involved in the ethanol-mediated increase in portal vein flow. Further studies indicate that the effects of cyanamide in suppressing the ethanol-induced increase in portal blood flow and increasing total peripheral resistance appear to be related to an ethanol-cyanamide interaction which is independent of the acetaldehyde levels in the circulation.

Acetaldehyde↗
PubMed1987

Ethanol vapor above skin: determination by a gas sensor instrument and relationship with plasma concentration.

Studies with a new instrument show that blood ethanol concentrations in rats and humans can be estimated by measurement of ethanol vapor above the skin. After intravenous bolus administration of ethanol (1 g/kg) to rats a novel device based on the Figaro sensor was placed above the animal's abdomen. Plasma and skin vapor ethanol concentrations, analyzed by gas chromatography and sensor, respectively, declined in parallel (r = 0.96). In healthy human subjects, plasma and skin vapor concentrations, measured on the palm, also declined in parallel after intravenous ethanol infusion (1 hr, 0.5 g/kg), r = 0.99. In 10 alcoholic liver disease outpatients attending clinic in whom plasma ethanol concentrations ranged from 32-304 mg/dl, the correlation of plasma ethanol determined directly by gas chromatography and indirectly by skin vapor analysis was slope = 0.93, intercept = 1.8, r = 0.94. In controlled studies, skin vapor measurements are comparable with breathalyzer determinations; they may be performed in situations where breathalyzer measurements are inconvenient or where continuous monitoring is desirable.

Adult↗