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Biomedical subjects

U Baumgartner

Publications and source records attributed to U Baumgartner.

At least 37 records · Page 2Linked to original sources
PubMed1993

Carvedilol stereopharmacokinetics in rats: affinities to blood constituents and tissues.

Carvedilol, a lipophilic beta-adrenoceptor antagonist with vasodilating activities, is characterized by a high as well as stereoselective metabolic clearance and distribution volume. Tissue distribution of carvedilol enantiomers and their conjugates were determined under steady-state conditions in rats (p.o., 10 mg/kg, repetitive dosage; n = 5) and after single i.v. administration in control rats and rats with surgical portacaval shunt (pcs) (10 mg/kg; n = 3 each group). In addition, in vitro plasma protein binding was evaluated. The plasma protein binding of carvedilol in rats is > 98% for total plasma (tp) and > 96% for rat serum albumin (rsa) solution (4%), with enantioselectivity ratios of 1.53 (tp) and 1.27 (rsa). Significantly higher unbound fractions were observed in pcs rats, in part due to reduced protein concentrations. In contrast to plasma, where a preponderance of the R-enantiomer with an S/R ratio of 0.6 was found, S-carvedilol was predominant in all tissues (heart, liver, kidneys, lung, spleen, muscle, and adipose tissue), with S/R ratios of 1.3-1.4 in most of these tissues and 2.3 in liver. This preferential tissue partitioning of S-carvedilol was in accordance with its higher unbound fraction in plasma. Carvedilol accumulated predominantly in the highly perfused and/or eliminating organs liver, kidneys, and lung (tissue/plasma ratios; lung: S 76, R 34; liver: S 21, R 5; kidney: S 8, R 3). A similarly enantioselective distribution into the heart of control as well as pcs rats was observed, where the S-enantiomer concentrations exceeded the plasma concentrations 7-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1993

Rats with portacaval shunt as a potential experimental pharmacokinetic model for liver cirrhosis: application to carvedilol stereopharmacokinetics.

As an experimental model for reduced liver function rats with surgical portacaval shunts (pcs) may be used. Carvedilol, a nonselective beta-adrenoceptor antagonist with vasodilating activity, is extensively metabolised by phase I as well as phase II pathways. In order to study the stereoselective pharmacokinetics of carvedilol in liver disease, pcs and control rats were given rac-carvedilol intravenously and p.o. The carvedilol enantiomers and their conjugates were assayed in plasma, urine, and bile. Carvedilol was highly bound to plasma proteins; binding was reduced by pcs. In all groups, the plasma concentrations of (R)-carvedilol exceeded those of (S)-carvedilol significantly. In comparison to the control group the plasma concentrations of both enantiomers increased after pcs, while the difference between the stereoisomers decreased. The total clearance decreased proportionally to the decrease in liver weight (30%). Both the apparent oral clearance, as well as its stereoselectivity were reduced, by up to 90 and 43%, respectively. The biliary clearance of the parent drug after i.v. dosage increased in rats with pcs due to the reduced hepatic metabolism.

Adrenergic beta-Antagonists↗
PubMed1993

[The value of colon contrast enema in ileus diagnosis].

In 115 patients with clinical and radiological signs of small and/or large bowel obstruction the contrast enema of the colon was evaluated prospectively to localize the site of occlusion in the colon. Contrast enema was performed in 76 patients with Gastrografin and in 39 with barium. In 22 of 24 patients with large bowel obstruction, in 7 of 11 with combined small and large bowel obstruction, in 4 of 14 with small bowel obstruction and in 19 of 66 with partial obstruction the site of obstruction was identified in the colon. In 107 of 115 patients the site of intestinal obstruction in the colon was either confirmed or excluded (sensitivity 89.2%, specificity 96.6%). In 6 patients the contrast enema failed due to incontinence, missing cooperation or insufficient preparation. In two cases with coprostasis the occlusion was missinterpreted as a carcinoma. Electrolytes and serum fluid concentration before and after the enema were not significantly influenced using the different contrast media. Contrast enema is indicated in patients with intestinal obstruction of unknown site, malignancies, after radiation therapy and recurrent partial obstruction.

Adolescent↗
PubMed1992

Cholestasis, metabolism and biliary lipid secretion during perfusion of rat liver with different bile salts.

The biological effects of bile acids depend largely upon their molecular structure. When bile acid uptake exceeds the maximal biliary secretory rate (SRm) cholestasis occurs. In order to characterize the influence of bile acid structure on its cholestatic potency we systematically studied SRm, maximal bile flow, maximal and cumulative phospholipid and cholesterol secretion with different taurine-conjugated tri-, di- and keto bile acids (Table I) in the isolated perfused rat liver. Bile acids with a high critical micellar concentration (CMC) promoted the greatest bile flow; a positive non-linear correlation between CMC and maximal bile flow was found. 3 alpha-Hydroxylated bile acids with a hydroxyl group in 6 alpha and/or 7 beta position and lacking a 12 alpha hydroxy group had a high SRm. SRm was not related to CMC or maximal bile flow, respectively. Phospholipids and cholesterol were secreted in a nearly fixed ratio of 12:1; a strong linear relationship could be observed. Cumulative phospholipid secretion over 48 min was significantly lower for non and poor micelle forming bile acids (TDHC and TUC) than for those with comparatively low CMC values (TUDC, TC, THC, THDC, TCDC) (70-140 vs. 210-450 nmol/g liver). At SRm all bile acids with good micelle forming properties showed a similar cumulative biliary lipid output. However, when biliary lipid output was related to 1 mumol bile acid secreted bile acids with a low SRm induced the highest lipid secretion (TCDC, TC). These data (1) demonstrate that a 6 alpha and/or a 7 beta hydroxy group on the steroid nucleus reduce cholestatic potency if the 12 alpha hydroxy group is absent, (2) suggest that in the case of micelle forming bile acids the total amount of phospholipids secreted in bile (depletion of cellular phospholipids) is associated with the occurrence of cholestasis whereby bile acids with a low SRm deplete the cellular phospholipid content at much lower bile acid concentrations than those with a higher SRm and (3) imply that bile acids with non and poor micelle forming properties (TDHC, TUC) presumably do not cause cholestasis (solely) by depletion of cellular phospholipids.

Animals↗
PubMed1991

Loss of zonal heterogeneity and cell polarity in rat liver with respect to bile acid secretion after bile drainage.

Functional liver heterogeneity depends on the current perihepatic environment. The effect of chronic bile drainage on hepatic secretion of bile acids in periportal and pericentral rat liver cells was studied. After 4 days of biliary drainage, rat livers were perfused in vitro in either forward (through the portal vein) or backward direction (through the vena cava) in single-pass arrangement with taurodeoxycholate (32 nmol.min-1.g liver-1). Tritium-labeled taurodeoxycholate (0.5 muCi) was injected as a pulse to determine uptake, biotransformation, and hepatic secretion. During bile drainage, bile flow fell from 1.8 microL.min-1.g liver-1 to approximately 0.6 microL.min-1.g liver-1. Bile acid secretion rate dropped from initially 50 nmol.min-1.g liver-1 to approximately 5 nmol.min-1.g liver-1 within 24 hours and remained at this level for the next 3 days. After bile drainage, liver histology was well preserved and was indistinguishable from controls. During liver perfusion of controls in both directions, bile flow exceeded 1 microL.min-1.g liver-1, whereas bile-drained animals demonstrated a bile flow between 0.4 and 0.6 microL.min-1.g liver-1. In contrast to controls, the drained-animal liver did not excrete label exclusively in bile but simultaneously excreted about one third back to the perfusate medium (regurgitation). Biliary bile acid recovery within the first 10 minutes after 3H-taurodeoxycholate bolus injection was 90% (of label taken up) in forward-perfused controls but only 40% in forward-perfused drained animals. Backward-perfused control and drained animals. Backward-perfused control and drained animals excreted about 20% in this time interval and did not differ significantly. T50, the time to excrete 50% of label taken up in bile or both bile and effluent, increased from 4.3 +/- 0.36 minutes (SD) in forward-perfused controls to 13.2 +/- 2.28 minutes in forward-perfused, drained animals. T50 of backward-perfused controls and backward-perfused drained animals did not differ significantly (17.8 +/- 1.75 minutes vs. 21.0 +/- 3.95 minutes). In conclusion, chronic bile drainage reduces liver heterogeneity with respect to velocity of bile acid excretion and cell polarity is lost with respect to hepatocellular translocation of bile acids.

Anastomosis, Surgical↗
PubMed1991

Altered biosynthesis of gangliosides in developing biliary cirrhosis in the rat.

The biosynthesis of gangliosides was studied in developing biliary cirrhosis in rats 14, 28, and 42 days after bile duct obstruction. The total content and patterns of gangliosides in livers and sera, and the activity of six hepatic ganglioside synthases in a cell-free system were determined. Up to 7-fold increased synthase activities were strictly correlated in time and extent with increased total contents of gangliosides in liver and serum. In addition, altered patterns of serum gangliosides were observed. The results clearly demonstrate that the liver is the main source of elevated serum gangliosides in biliary cirrhosis in the rat. Increased hepatic biosynthesis and the secretion of gangliosides into the serum appear to be an important pathogenetic event. Alterations of hepatic enzyme activities indicate that GL2 and GM3 synthase regulate total hepatic ganglioside content. However, certain abnormalities in ganglioside patterns which were observed in the liver and sera of cirrhotic animals can not be explained by changes in hepatic enzyme activity. They indicate additional pathobiochemical mechanisms to be involved, e.g., altered hepatocellular processing and/or impaired secretion into bile.

Animals↗
PubMed1991

Portacaval shunt as an experimental model of impaired hepatic release of vitamin A in liver disease.

Vitamin A concentrations in serum and liver were studied in rats with a portacaval shunt for 48 days after shunt surgery. In addition, serum and tissue concentrations of zinc were analyzed. Following portacaval shunting serum vitamin A concentration decreased to 25% of the level in sham-operated controls, whereas serum zinc concentration decreased to 80%. The mean urinary excretion rate of zinc increased in shunted rats [18.7 +/- 2.1 micrograms/day (0.28 +/- 0.03 mumol/day)] compared with controls [13.8 +/- 1.7 micrograms/day (0.21 +/- 0.03 mumol/day)] (P less than 0.01). The concentration of retinol and total retinoids in liver tissue increased 2-3-fold in rats with a portacaval shunt, and the ratio of retinol to retinoids was slightly increased. The differences were reduced when the total organ content was calculated, because of the reduced liver weight in the shunted rats. The concentration of zinc in liver tissue decreased in rats with portacaval shunts [30.8 +/- 4.9 micrograms/g wet wt (0.47 +/- 0.07 mumol/g) vs. 35.6 +/- 3.7 micrograms/g wet wt (0.54 +/- 0.06 mumol/g) in controls; P less than 0.01]. The concentration of zinc was inversely correlated with retinol (r = -0.52, P less than 0.05) and total retinoid levels (r = -0.70, P less than 0.05) in rats with portacaval shunts but not in controls. The data are consistent with the hypothesis of an impaired release of vitamin A from the liver in rats with portacaval shunts, an impairment that could be due to liver zinc deficiency.

Animals↗
PubMed1990

Hepatic passage of bile acids increases oxygen uptake by perfused rat liver.

It has been claimed that the hepatic passage of conjugated bile acids does not increase oxygen uptake by the isolated perfused rat liver. We studied a variety of bile acids in the single-pass perfused rat liver. All bile acids studied except taurocholate and tauro-beta-muricholate induced an increase in oxygen uptake of 2.1%-11.2% (baseline 2.54 +/- 0.57 mumoles/min per g liver). Raised values for oxygen uptake were not specifically associated with the critical micellar concentration of the bile acid, with bile acid uptake, or with bile acid secretion. It is postulated that bile acid toxicity may have an intracellular effect on hepatic oxygen uptake.

Animals↗
PubMed1990

Taurohyocholate, taurocholate, and tauroursodeoxycholate but not tauroursocholate and taurodehydrocholate counteract effects of taurolithocholate in rat liver.

The infusion of taurolithocholate (TLC) in vivo or in the isolated perfused liver of the rat causes cholestasis and cellular necrosis. In order to analyze the protective effect of bile salts differing in number and steric position of their hydroxy groups against TLC-induced cholestasis, isolated rat livers were perfused with taurocholate (TC), taurohyocholate (THC), tauroursocholate (TUC), taurodehydrocholate (TDHC), and tauroursodeoxycholate (TUDC) (16 and 32 mumol/l) with or without TLC (8 and 16 mumol/l). Bile flow, bile salt secretion, and the hydroxylation pattern of the bile salts secreted were analyzed. TLC caused complete cholestasis after 15 min of perfusion. All bile salts studied had a protective effect. THC, TC, and TUDC completely abolished the cholestasis induced by TLC while TUC did so only for the first 10 min. TDHC was protective only as long as it was biotransformed into hydroxyoxo bile salts. Coinfusion of bile salts did not influence uptake of TLC (greater than or equal to 93% of dose). Differences were found regarding the amount of TLC biotransformed (% of uptake): TC 50%; THC 32%; TUDC 36%; TUC 20%. Light microscopy revealed cellular necrosis, and dilated canaliculi were found in livers perfused with TLC only or in combination with TUC or TDHC, while the other bile salts prevented these changes. We conclude that bile salts with low micelle-forming capacity have little protective effect against TLC-induced cholestasis. These bile salts induce less biotransformation of TLC than TC, THC, and TUDC. The protective effect is not dependent on the hydrocholeretic effect of the added bile salt and is not due to an uptake inhibition.

Animals↗
PubMed1990

Tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and toxicity in rat liver.

Ursodeoxycholate has been advocated for the treatment of cholestatic liver diseases. The coinfusion of tauroursodeoxycholate with taurolithocholate in the perfused rat liver completely prevented the decrease of bile flow and the increase of oxygen uptake found with taurolithocholate only. Bile flow and bile salt secretion were increased with the coinfusion of both bile acids as compared with the infusion of tauroursodeoxycholate only (+4.30 microliters/g liver per 30 min) with 16 and 32 mumol/l tauroursodeoxycholate (+1.55 microliters/g liver per 30 min with 80 and 160 mumol/l). Morphological examination revealed a 50% decrease of the number of necrotic cells in the periportal area. Tauroursodeoxycholate did not inhibit the uptake of taurolithocholate, but increased its transcellular passage and biotransformation. Thus, tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and liver cell toxicity probably by an intracellular mechanism.

Animals↗
PubMed1990

The influence of portocaval shunting on inner ear structures.

In rats with a portocaval shunt the cells of the inner ear were examined in an ultrastructural study. In 15 rats a porto-caval shunt (PCS) was constructed. Control rats underwent identical procedures but no anastomosis was produced (SOP). The control rats were pair-feeded. PCS rats developed an increased urinary zinc excretion associated with weight loss, alopecia, lethargy and atrophy of the testes. The serum zinc concentration in PCS rats was significantly reduced. In the inner ear we found ultrastructurally an increasing number of lysosomes and a severe damage of the myelin sheath of the granular ganglion cells. The myelin sheath was split and filled with great myelin figures. In the outer hair cells resulted in an increasing number of lysosomes. In the stria vascularis and in Reissner's membrane a vacuolization of the tissue appeared. The results of this study show that rats with a porto-caval anastomosis serve as a pathophysiological model of zinc impoverishment like porto-caval shunting in patients with liver cirrhosis.

Animals↗
PubMed1987

Modulation of hepatic biotransformation and biliary excretion of bile acid by age and sinusoidal bile acid load.

Pericentral hepatocytes excrete bile acids more slowly and biotransform them more than periportal cells. This may reflect adaptation to low pericentral bile acid concentration or may be intrinsic. We studied two models in which pericentral bile acid concentrations are high: the 72-h choledocho-caval shunt (CCS) rat and the 3- to 4-wk-old rat. Livers were perfused forward or backward to assess periportal or pericentral hepatocyte function. Taurodeoxycholate (TDC) was infused at 32 nmol X min-1 X g liver-1, and a bolus of [3H]TDC was given to assess metabolism and excretion of bile acids. In CCS livers perfused backward, pericentral cells resembled periportal cells of controls in that time to excrete 50% of administered [3H]TDC (t50) was reduced by two-thirds and [3H]TDC biotransformation was reduced by about half. In young livers t50 was half that of adult livers when perfused backward. Biotransformation, however, was not reduced. Young livers biotransformed more than adult controls for any given residence time of bile acid in the liver. We conclude that the difference between pericentral and periportal cells as regards bile acid processing is adaptive. Livers from young rats biotransform more bile acid than those from controls under similar conditions.

Aging↗
PubMed1987

Detection of antibodies in serum of patients with idiopathic pulmonary fibrosis against isolated rat alveolar type II cells.

The serum of 2 patients suffering from idiopathic pulmonary fibrosis (IPF) repeatedly demonstrated a positive antibody reaction against rat alveolar type II cells isolated by the use of a combination of elastase and trypsin for disaggregation and a Percoll density gradient for purification. Neither of the other 8 IPF patients examined nor any of the controls showed a positive reaction. Because the 2 patients with serum antibodies against alveolar type II cells did not show any antinuclear antibodies, it is concluded that the antibodies against the surface of rat alveolar type II cells found in the serum of IPF patients may be autoantibodies involved in the pathogenesis of IPF.

Animals↗
PubMed1987

Reduced cholestatic potency of taurolithocholate during backward perfusion of the rat liver.

Rat livers perfused backward are less susceptible to taurolithocholate (TLC) cholestasis than livers perfused forward. To understand this phenomenon, the uptake, metabolism, and excretion of TLC were studied in rat livers perfused forward and backward with TLC. Bolus injections of [3H]TLC were administered 20 minutes after the onset of unlabeled TLC infusion. Biliary bile acids were measured enzymatically and bile acid species were separated and quantified by thin-layer chromatography. Determination of radioactivity in each spot yielded the percentage distribution of various biliary bile acid metabolites. After perfusion, livers were examined by light and transmission electron microscopy. TLC infusion at 32 nmoles/minute/gm of liver reduced bile flow by 80% or more within 30 minutes of forward perfusion but not at all during backward perfusion. TLC uptake was over 95% regardless of perfusion direction. Although the distribution of biliary metabolites of TLC was the same during forward and backward perfusion, maximal rate of total biliary bile acid excretion was four-fold higher and total recovery of radioactivity in bile was six-fold higher during backward perfusion. Less than 6% of excreted radioactivity was in the form of unmetabolized TLC. Severe cholestasis induced by forward TLC perfusion was associated with extensive structural distortion of bile canalicular membranes almost exclusively in the periportal zone but with little hepatocellular necrosis. Livers perfused backward manifested no cholestasis. They showed cell necrosis in the pericentral zone which became extensive (10%) by 60 minutes, but the canalicular changes occurred only in a small proportion of canaliculi in the pericentral region. Bile canalicular membrane changes developed extensively only when very high doses of TLC were perfused backward. Even then, bile flow fell only 60%. We conclude: the lesser susceptibility to TLC cholestasis of livers perfused backward is in part related to the greater biotransformation and consequent excretion of TLC by pericentral hepatocytes. TLC-induced cholestasis is associated more closely with bile canalicular membrane changes than with extent of hepatocellular necrosis. The greater reduction of bile flow with periportal than with pericentral canalicular change is compatible with current concepts of biliary microanatomy which postulate a flow of bile from pericentral through periportal regions of the lobule into the bile ductules.

Animals↗
PubMed1986

Greater taurodeoxycholate biotransformation during backward perfusion of rat liver.

Differing patterns of taurodeoxycholate (TDC) metabolism and biliary excretion were studied with a forward-and-backward perfusion model of the isolated rat liver. Livers were perfused with 8 microM TDC via either the portal vein (forward) or the hepatic vein (backward). Bile was collected, total bile acids measured enzymatically, and bile composition determined by high-pressure liquid chromatography and thin-layer chromatography. During backward perfusion 48% of infused TDC was metabolized to taurocholate (TC) and 22.0% to other minor TDC metabolites. During forward perfusion, however, only 16% of administered TDC was metabolized to TC and 6.5% to minor metabolites. Total bile acid output was similar for both forward and backward perfusions. The kinetics of biliary bile acid excretion also differed between forward and backward perfusion. The time necessary for 50% excretion of labeled TDC and its metabolites was 3.5 +/- 0.45 min during forward and 18 +/- 3.50 min during backward perfusion, a time difference of 14.5 min. The greater biotransformation of TDC during backward perfusion could be explained by its longer intracellular residence. The reason for the delayed excretion of TDC during backward perfusion is unknown.

Animals↗
PubMed1985

Loss of glucagon control of gluconeogenesis in liver cells from rats with bile duct obstruction.

Bile acids induce membrane alterations including reduced response to peptide hormones in vitro. Isolated liver cells from rats with bile duct obstruction were studied regarding gluconeogenesis and its hormonal control. While cells from shamoperated animals showed an 63% increase of glucose release in the presence of glucagon (1 microM), cells from cholestatic livers did not response regardless of the duration of obstruction. Cholestatic cells also showed other signs of membrane alterations, such as an increased enzyme leakage while redoxstatus and other metabolic responses were unchanged. These results suggest that a loss of hormonal control in the liver could contribute to disturbations of glucose homeostasis in cholestatic conditions.

Animals↗
PubMed1978

A stereological study of adrenocortical cells in spontaneously hypertensive rats (shr).

The ultrastructure of SHR (Spontaneously Hypertensive Rats) fasciculata cells was compared descriptively and quantitatively with that of nonstimulated fasciculata cells of Wistar rats using sterological methods. The volume and surface densities are expressed per cm3 of cytoplasm. The smooth endoplasmic reticulum in the SHR was significantly increased compared to the control animals (surface density : 28%, volume density: 35%). Mitochondria volume remained unchanged although the inner mitochondrial membranes were significantly reduced (37%). An attempt was made to draw up a relation between sterological and biochemical data of steroid synthesis within the fasciculata cell. A genetically determined enzymatic defect in the early steps of the transformation of cholesterol to pregnenolone may exist at the level of the inner mitochondrial membrane. Whether this altered steroid metabolism is important to the etiology of hypertension in the SHR requires further investigation.

Adrenal Cortex↗