[Substance transport in the colon and its pharmacologic modification].
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Acid-Base Equilibrium↗
Biomedical subjects
W Gerok
Publications and source records attributed to W Gerok.
Localization and turnover of dipeptidylpeptidase IV in the domains of rat liver plasma membrane.
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Animals↗
Effect of 5-diazouracil on the catabolism of circulating pyrimidines in rat liver and kidneys.
The inhibitory effect of 5-diazouracil on the catabolism of circulating uracil and 5-fluorouracil was examined in the rat in vivo. Measurements of the activity of the entire enzymatic pathway of uracil catabolism in the cytosolic supernatant of different rat organs as well as the determination of the total amount of 5-fluorouracil catabolites, accumulated in these tissues, served to clarify their role in the complete systemic breakdown of uracil or 5-fluorouracil. The activity of the enzymatic pathway involved in uracil catabolism was estimated from the 14CO2 produced from [2-14C]uracil in the cytosolic supernatants. Complete degradation of uracil was detected only in the liver and, at a much lower rate, in the kidneys. Fifteen min after the i.p. injection of a tracer dose of 5-fluoro[6-14C]-uracil, more than 90% of the total radioactivity in blood plasma was associated with 5-fluorouracil catabolites. The relative amount of the major catabolite alpha-fluoro-beta-alanine and of dihydrofluorouracil in blood plasma was considerably suppressed after a pretreatment with 5-diazouracil inversely correlated with a 27-fold increase in the absolute amount of unchanged 5-fluorouracil. Control animals accumulated by far the highest amount of total acid-soluble radioactivity from 5-fluoro[6-14C]uracil in liver and kidneys. Total radioactivity in all other organs was much lower and was comparable to the amount of label in blood plasma. In liver and kidneys, the sum of total acid-soluble catabolites including dihydrofluorouracil, alpha-fluoro-beta-ureidopropionic acid, and alpha-fluoro-beta-alanine made up more than 98% of the label correlating with minimal salvage utilization of the base analogue in both organs. Injection of 5-diazouracil 2 h before a tracer dose of 5-fluoro[6-14C]uracil strongly inhibited the accumulation of labeled catabolites in liver and kidneys causing a fall in total acid-soluble radioactivity in both tissues by 75 and 66%, respectively. In blood plasma and all other organs, however, pretreatment with 5-diazouracil was followed by a 2-fold enhancement of the radioactivity contents, mostly due to the appearance of unchanged 5-fluorouracil. Under these conditions, there was a 2.6- to 4-fold increase in the relative proportion of cis-diol group-containing anabolites of 5-fluorouracil in liver and in kidneys. Within 2 h, 12.7% of the administered radioactivity from 5-fluorouracil was excreted into bile. 5-Diazouracil lowered the biliary excretion of radioactivity to 2% of the injected dose.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
[Value of increased urinary excretion of modified nucleosides as tumor markers in colon cancer].
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Adult↗
Role of plasma membrane transport in hepatic glutamine metabolism.
In livers of fed rats and in perfused livers supplied with a physiological portal glutamine concentration of 0.6 mM, the mitochondrial and cytosolic glutamine concentrations are 20 mM and 7 mM, respectively, thus, the mitochondrial/cytosolic glutamine concentration gradient is 2-3. Uptake and release of glutamine by periportal and perivenous hepatocytes occurs predominantly by an Na+-dependent transport system (so-called system 'N'). Histidine in near-physiological concentrations inhibits both glutamine uptake by periportal hepatocytes and its release by perivenous hepatocytes. This is not due to an inhibition of glutamine-metabolizing enzymes by histidine or its metabolites. With physiological portal glutamine concentrations (0.6 mM), stimulation of glutaminase flux or of glutamine transaminase flux is followed by a decrease of hepatic glutamine levels to about 80% or 30%, respectively, glutamine levels are further decreased to 50% or 20% in the presence of histidine. When glutamine is synthesized endogenously (no glutamine added), the histidine-induced inhibition of glutamine release is paralleled by a 210% increase of the hepatic tissue level of glutamine. In experiments with and without methionine sulfoximine and in the absence of added glutamine, the glutamine content in the small perivenous hepatocyte population containing glutamine synthetase is estimated to be about 3.5 mumol/g wet weight and that in the periportal hepatocytes as low as 0.1 mumol/g wet weight. In contrast to the prevailing view, it is concluded that glutamine transport across the plasma membrane of hepatocytes is a potential regulatory site in glutamine degradation and synthesis, especially under the influence of effectors like histidine.
Amino Acids↗
[Peritoneovenous shunt in ascites therapy. Complications and their treatment].
Complications occurred in 29 of 37 patients after ascites retransfusion (n = 16) or introduction of a peritoneovenous shunt (n = 21). Blood clotting disturbances, that could either be successfully treated with drugs or which led to interruption of the reinfusion, appeared in 38%. Estimation of plasminogen proved to be of reliable prognostic value thus enabling prophylactic measures to be taken. Post-operatively 14 patients had transient fever not requiring specific treatment. Local fibrinolysis or shunt revision was successful in three patients with shunt thromboses. According to our experience most complications can be avoided by prophylactic and therapeutic measures.
Adult↗
Hepatic urea synthesis and pH regulation. Role of CO2, HCO3-, pH and the activity of carbonic anhydrase.
In isolated perfused rat liver, urea synthesis from ammonium ions was dependent on extracellular HCO3- and CO2 concentrations when the HCO3-/CO2 ratio in the influent perfusate was constant (pH 7.4). Urea synthesis was half-maximal at HCO3- = 4 mM, CO2 = 0.19 mM and was maximal at HCO3- and CO2 concentrations above 20 mM and 0.96 mM, respectively. At physiological HCO3- (25 mM) and CO2 (1.2 mM) concentrations in the influent perfusate, acetazolamide, the inhibitor of carbonic anhydrase, inhibited urea synthesis from ammonium ions (1 mM) by 50-60% and led to a 70% decrease in citrulline tissue levels. Acetazolamide concentrations required for maximal inhibition of urea synthesis were 0.01-0.1 mM. At subphysiological HCO3- and CO2 concentrations, inhibition of urea synthesis by acetazolamide was increased up to 90%. Inhibition of urea synthesis by acetazolamide was fully overcome in the presence of unphysiologically high HCO3- and CO2 concentrations, indicating that the inhibitory effect of acetazolamide is due to an inhibition of carbonic-anhydrase-catalyzed HCO3- supply for carbamoyl-phosphate synthetase, which can be bypassed when the uncatalyzed intramitochondrial HCO3- formation from portal CO2 is stimulated in the presence of high portal CO2 concentrations. With respect to HCO3- supply of mitochondrial carbamoyl-phosphate synthetase, urea synthesis can be separated into a carbonic-anhydrase-dependent (sensitive to acetazolamide at 0.5 mM) and a carbonic-anhydrase-independent (insensitive to acetazolamide) portion. Carbonic-anhydrase-independent urea synthesis linearly increased with the portal 'total CO2 addition' (which was experimentally determined to be CO2 addition plus 0.036 HCO3- addition) and was independent of the perfusate pH. At a constant 'total CO2 addition', carbonic-anhydrase-dependent urea synthesis was strongly affected by perfusate pH and increased about threefold when the perfusate pH was raised from 6.9 to 7.8. It is concluded that the pH dependent regulation of urea synthesis is predominantly due to mitochondrial carbonic anhydrase-catalyzed HCO3- supply for carbamoyl phosphate synthesis, whereas there is no control of urea synthesis by pH at the level of the five enzymes of the urea cycle. Because HCO3- provision for carbamoyl phosphate synthetase increases with increasing portal CO2 concentrations even in the absence of carbonic anhydrase activity, susceptibility of ureogenesis to pH decreases with increasing portal CO2 concentrations. This may explain the different response of urea synthesis to chronic metabolic and chronic respiratory acidosis in vivo.
Acetazolamide↗
Murine interleukin 1 stimulates alpha 2-macroglobulin synthesis in rat hepatocyte primary cultures.
In rat hepatocyte primary cultures recombinant interleukin 1 was found to stimulate alpha 2-macroglobulin synthesis, whereas albumin synthesis was decreased. Although recent experiments gave evidence that a hepatocyte-stimulating factor distinct from interleukin 1 must exist, we conclude that interleukin 1 exerts a direct effect on hepatocytes by inducing acute-phase protein synthesis.
Albumins↗
Secretion of high-mannose-type alpha 1-proteinase inhibitor and alpha 1-acid glycoprotein by primary cultures of rat hepatocytes in the presence of the mannosidase I inhibitor 1-deoxymannojirimycin.
Two different forms of alpha 1-proteinase inhibitor and alpha 1-acid glycoprotein were found in primary cultures of rat hepatocytes. After a 2.5-h labeling period with [35S]methionine the high-mannose-type precursor of alpha 1-proteinase inhibitor (Mr 49000) and alpha 1-acid glycoprotein (Mr 39 000) and the mature-complex-type alpha 1-proteinase inhibitor (Mr 54 000) and alpha 1-acid glycoprotein (Mr 43 000-60 000) could be immunoprecipitated from the cells, but only the complex-type forms of the two glycoproteins were secreted into the hepatocyte media. When hepatocytes were incubated with the mannosidase I inhibitor 1-deoxymannojirimycin at a concentration of 4 mM, the 49 000-Mr form of alpha 1-proteinase inhibitor and the 39 000-Mr form of alpha 1-acid glycoprotein could be detected in the cells as well as in their media. Neither the secretion of alpha 1-proteinase inhibitor nor that of alpha 1-acid glycoprotein was impaired by 1-deoxymannojirimycin. While alpha 1-proteinase inhibitor and alpha 1-acid glycoprotein, secreted by control cells, were resistant to endoglucosaminidase H, alpha 1-proteinase inhibitor and alpha 1-acid glycoprotein, secreted by hepatocytes treated with 4 mM 1-deoxymannojirimycin, could be deglycosylated by endoglucosaminidase H. When the [3H]mannose-labeled oligosaccharides of alpha 1-proteinase inhibitor, secreted by 1-deoxymannojirimycin-treated hepatocytes, were cleaved off by endoglucosaminidase H and analyzed by Bio-Gel P-4 chromatography, they eluted at the position of Man9GlcNAc, indicating that mannosidase I had been efficiently inhibited. 1-Deoxymannojirimycin did not inhibit the synthesis or the cotranslational N-glycosylation of alpha 1-proteinase inhibitor or alpha 1-acid glycoprotein.
1-Deoxynojirimycin↗
Hepatic carbamoyl phosphate metabolism. Role of cytosolic and mitochondrial carbamoyl phosphate in de novo pyrimidine synthesis.
The interrelationship between the two carbamoyl phosphate pools in intact hepatocytes and intact liver was studied with respect to de novo pyrimidine synthesis by use of selective inhibitors of the mitochondrial and the cytosolic carbamoyl-phosphate synthetase. Inhibition of mitochondrial carbamoyl phosphate synthesis by 4-pentenoate was without effect on galactosamine-stimulated pyrimidine synthesis. Conditions favouring mitochondrial carbamoyl phosphate accumulation, like excess ammonium ions or L-norvaline, led to an increase in pyrimidine synthesis bypassing the feedback inhibition of cytosolic carbamoyl-phosphate synthetase by UTP. A stimulation of pyrimidine synthesis was not observed when the carbamoyl phosphate accumulation was due to aspartate deficiency in the presence of aminooxyacetate. The full response of pyrimidine synthesis to excess ammonium ions was restored, even in the presence of aminooxyacetate, when aspartate was substituted. This is explained by an inhibition of aspartate carbamoyltransferase flux [in view of the Km (aspartate = 0.7 mmol/l) of this enzyme] resulting from a 90% decrease in aspartate tissue levels. Acivicin, the inhibitor of cytosolic carbamoyl-phosphate synthetase, completely abolished the galactosamine-induced stimulation of pyrimidine synthesis, but was without effect on the stimulation of pyrimidine synthesis by ammonium ions and L-norvaline. It is concluded that experimental changes in mitochondrial carbamoyl phosphate content exert effects on de novo pyrimidine synthesis; however, it is considered unlikely that relevant amounts of mitochondrial carbamoyl phosphate are used for pyrimidine synthesis under physiological conditions. In addition the data point to a potential regulatory role of aspartate in hepatic pyrimidine synthesis.
Aminooxyacetic Acid↗
Uridine catabolism in Kupffer cells, endothelial cells, and hepatocytes.
Kupffer cells, endothelial cells, and hepatocytes were separated by centrifugal elutriation. The rate of uracil formation from [2-14C]uridine, the first step in uridine catabolism, was monitored in suspensions of the three different liver cell types. Kupffer cells demonstrated the highest rate of uridine phosphorolysis. 15 min after the addition of the nucleoside the label in uracil amounted to 51%, 13%, and 19% of total radioactivity in the medium of Kupffer cells, endothelial cells, and hepatocytes, respectively. If corrected for Kupffer cell contamination, hepatocyte suspensions demonstrated similar activities as endothelial cells. In contrast to non-parenchymal cells, hepatocytes continuously cleared uracil from the incubation medium. The lack of uracil consumption by Kupffer cells and endothelial cells points to uracil as the end-product of uridine catabolism in these cells. Kupffer cells and endothelial cells did not produce radioactive CO2 upon incubation in the presence of [2-14C]uridine. Hepatocytes, however, were able to degrade uridine into CO2, beta-alanine, and ammonia as demonstrated by active formation of volatile radioactivity from the labeled nucleoside. There was almost no detectable formation of thymine from thymidine or of cytosine, uracil, or uridine from cytidine by any of the different cell types tested. These results are in line with low thymidine phosphorolysis and cytidine deamination in rat liver. Our studies suggest a co-operation of Kupffer cells, endothelial cells, and hepatocytes in the breakdown of uridine from portal vein blood with uridine phosphorolysis predominantly occurring in Kupffer cells and with uracil catabolism restricted to parenchymal liver cells.
Animals↗
Mesocaval and distal splenorenal shunts: effect on hepatic function, hepatic hemodynamics, and portal systemic encephalopathy.
The effect of the mesocaval interposition shunt (n = 12) and the distal splenorenal shunt (n = 9) on the wedged hepatic venous pressure, the estimated hepatic blood flow, quantitative hepatic function, and the rate of portal systemic encephalopathy was evaluated in 21 patients who had bled from esophageal varices. After mesocaval shunt the wedged hepatic venous pressure was significantly reduced by 42% (from 26 +/- 3 mm Hg to 15 +/- 5 mm Hg, P less than 0.001) compared to 16% only (from 25 +/- 3 mm Hg to 21 +/- 2 mm Hg, P less than 0.005) after distal splenorenal shunt. The estimated hepatic blood flow also decreased significantly after mesocaval shunt by 61% (from 1.45 +/- 0.46 l/min to 0.56 +/- 0.25 l/min, P less than 0.001) compared to 29% (from 1.29 +/- 0.32 l/min to 0.91 +/- 0.39 l/min, P less than 0.05) after distal splenorenal shunt. Despite significantly different influences of both types of shunt operations on wedged hepatic venous pressure and estimated hepatic blood flow (P less than 0.001), postoperative changes of hepatic function were comparable in both groups of patients. The galactose elimination capacity, the initial plasma disappearance rate of Bromsulphalein, and the plasma ratio of valine, leucine, and isoleucine to phenylalanine and tyrosine were reduced by 13%, 26%, and 29%, respectively, after mesocaval shunt, compared to 12%, 25%, and 17% after distal splenorenal shunt. Only two patients of the mesocaval shunt group with the largest decrease in estimated hepatic blood flow developed portal systemic encephalopathy postoperatively, and the distal splenorenal shunt patients with their minor hemodynamic sequelae remained free of portal systemic encephalopathy.
Adult↗
De novo pyrimidine biosynthesis in isolated rat hepatocytes. Quantitative aspects of the regulation by UTP.
Quantitative aspects of de novo pyrimidine biosynthesis in rat hepatocytes were monitored. A reduction of intracellular UTP contents by different concentrations of D-galactosamine led to a dose-dependent increase of 14CO2 incorporation into the sum of all acid-soluble uracil nucleotides. In controls the rate of de novo synthesis which was calculated from the incorporation rate of 14CO2 into the sum of all acid-soluble uracil nucleotides was 0.014 mumol X h-1 X g-1 compared to 0.056 mumol X h-1 X g-1 wet weight of liver in situations of a maximally stimulated de novo synthesis. Incubation of hepatocytes with uridine led to a dose-dependent reduction of 14CO2 incorporation to less than 25% of the amount incorporated in the controls. Alterations of the CTP content had no influence on the 14CO2 incorporation. In the presence of high D-galactosamine concentrations the increase of the total amount of acid-soluble uracil nucleotides exceeded the rate of the de novo synthesis derived from the incorporation of 14CO2 into the sum of the acid-soluble uracil nucleotide pool. It was also greater than the increase of the total amount of intra- and extracellular orotate after acidic hydrolysis--even in the presence of 6-azauridine, which stimulated de novo pyrimidine biosynthesis by itself.
Adenosine Triphosphate↗
[Ascites. Current aspects of diagnosis and therapy].
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Ascites↗
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↗
Reaction mechanism of the calcium-transport ATPase in endoplasmic reticulum of rat liver. Demonstration of different reactive forms of the phosphorylated intermediate.
A calcium-transport ATPase is inserted into the endoplasmic reticulum of rat liver. Catalysis of calcium translocation involves transient covalent binding of the terminal phosphate residue of ATP by the enzyme, resulting in the formation of an alkali- and hydroxylamine-labile phosphorylprotein intermediate. Both MgATP as well as CaATP can be utilized in the phosphorylation reaction which requires calcium as a cofactor. Magnesium accelerates the turnover of the phosphorylprotein intermediate. An ADP-reactive and ADP-unreactive state of the phosphoenzyme could be distinguished. In the ADP-reactive state with tightly bound calcium, the phosphoenzyme can transphosphorylate its phosphate residue to ADP, giving rise to synthesis of ATP. The ADP-reactive phosphoenzyme can be converted into an ADP-unreactive state by prolonged incubation with excess EGTA (ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid). It is suggested that this conversion is brought about by the removal of tightly bound calcium from the phosphoenzyme. A strong homology of the sequential reaction steps during calcium translocation by the calcium-transport ATPases in endoplasmic reticulum from rat liver and sarcoplasmic reticulum from skeletal muscle is suggested.
Adenosine Diphosphate↗
Unglycosylated rat alpha 1-proteinase inhibitor has a six-fold shorter plasma half-life than the mature glycoprotein.
The plasma half-lives of glycosylated and unglycosylated alpha 1-proteinase inhibitor-radioactively labeled with [35S]methionine in rat hepatocyte primary cultures - were determined in the rat. Unglycosylated alpha 1-proteinase inhibitor was synthesized by hepatocytes in the presence of tunicamycin. Media from hepatocytes containing 35S-labeled glycosylated or unglycosylated alpha 1-proteinase inhibitor were injected into the tail veins of rats. At different times after injection alpha 1-proteinase inhibitor was isolated from plasma by affinity chromatography with anti-alpha 1-proteinase inhibitor Sepharose. Radioactivity measurements revealed a plasma half-life of 170 min for glycosylated alpha 1-proteinase inhibitor and of 30 min for the unglycosylated form of the inhibitor.
Animals↗
Determination of rheogenic ion transport in rat proximal colon in vivo.
A direct clamping technique is demonstrated, which allows monitoring of rapid changes of the short-circuit current (Isc) and the specific transepithelial resistance (Rm) as well as measurement of ion fluxes under short-circuit conditions in vivo. Due to the cylindrical symmetry of the colon the intraluminal electrode was devised as a centrally fixed silver rod, by which radial current injection was achieved. The geometrical arrangement of the electrodes guaranteed zero potential difference (PD) along the whole axis of the colon segment. The Isc was determined to 3.3 +/- 0.7 mueq h-1 cm-2 and Rm equal to 121 +/- 5 omega cm2. These data obtained by direct short-circuiting agree well with our earlier Rm and Isc data based on cable analysis, where the Isc was calculated from the open-circuit PD and Rm. This is considered as evidence for the reliability of the two independent in vivo techniques. Their validity was confirmed by the expected effects of drugs acting on rheogenic ion transport. Both the indirect (via Rm) as well as the direct Isc determination may be used alternatively as required; one may serve to match the other. For larger tubular structures like the rat colon the direct clamping should be preferred as the standard procedure for the Isc determination in vivo.
Alprostadil↗