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Biomedical subjects

W Gerok

Publications and source records attributed to W Gerok.

At least 199 records · Page 11Linked to original sources
PubMed1987

Actions of extracellular UTP and ATP in perfused rat liver. A comparative study.

1. In perfused rat liver infusion of UTP and ATP in micromolar concentrations increased the portal pressure, with UTP being three times more effective than ATP at concentrations below 50 microM. Whereas ATP (up to 100 microM) increased oxygen consumption, there was a dose-dependent inhibition of oxygen uptake by UTP. 2. Both nucleotides stimulated hepatic glucose output; however, the time-courses were different. Withdrawal of UTP, but not of ATP (up to 100 microM) caused a further transient, but substantial stimulation of glucose output. 3. ATP led to a transient net K+ uptake by the liver being followed by a K+-release phase. Similar changes were observed with UTP; however, the initial K+ uptake was prolonged compared to ATP (1.9 min versus 3.5 min) and withdrawal of UTP, but not of ATP, stimulated hepatic K+ release markedly. 4. Metabolic and hemodynamic effects comparable to those induced by ATP were obtained with beta- and gamma-thio substituted ATP, whereas beta,gamma-methylene-substituted ATP was much less effective. The characteristic effects of UTP on glucose output, portal pressure and K+ fluxes were preserved during constant infusion of ATP or its beta,gamma-methylene derivative, pointing to additive effects. 5. ATP (20 microM) led to a net Ca2+ release (50-60 nmol/g liver) within 2-3 min. When the extracellular Ca2+ concentration was lowered from 1.25 mM to 0.3 mM, this Ca2+ release was increased to about 110 nmol/g liver whereby its time course remained largely unchanged. With 1.25 mM Ca2+, UTP induced Ca2+ movements only near the detection level (i.e. below 10-20 nmol/g liver); however, with 0.3 mM Ca2+ in influent perfusate, there was a slow Ca2+ release (not completed within 5-6 min). The maximal rates of Ca2+ efflux following ATP and UTP (20 microM each) were 70 nmol and 30 nmol g-1 min-1. Withdrawal of UTP led to a short Ca2+ release superimposing a phase of net Ca2+ uptake. 6. The data show that extracellular UTP is a potential and effective regulator of hepatic metabolism, ion fluxes across the hepatocyte membrane and hemodynamics. Compared to ATP, UTP seems to be more effective and the responses to both nucleotides are different. The data suggest that the action of UTP could involve a receptor distinct from the purinergic P2 receptor, whereas the ATP action involves predominantly the P2Y purinoceptor subtype.

Adenosine Triphosphate↗
PubMed1987

Proteases and antiproteases related to the coagulation system in plasma and ascites--an approach to differentiate between malignant and cirrhotic ascites.

The concentrations of several proteases and antiproteases known to be present in ascites were tested in plasma and ascitic fluid with regard to their ability to separate ascites according to malignant or nonmalignant disease. Seventeen patients with proven malignant ascites and 37 with ascites due to liver cirrhosis were included. Activities of plasminogen, alpha 2-antiplasmin, antithrombin-III, and factor V, and the concentration of alpha 1-protease inhibitor were significantly higher in the plasma of patients with malignant ascites than in cirrhotic patients. Fibronectin, plasminogen, alpha 2-macroglobulin, alpha 1-protease inhibitor, antithrombin-III, and albumin revealed higher concentrations or activities in malignant ascites than in cirrhotic ascites. Due to a wide variation of most parameters, only fibronectin, antithrombin III, and alpha 1-protease inhibitor in ascites had a sensitivity and specificity higher than 90% for malignant ascites. When the specific protein/albumin ratio was used, only the accuracy of fibronectin was increased reaching a sensitivity and specificity of 100%. The plasma/ascites gradients of the proteins assessed differed significantly, that of fibronectin being much higher (22 +/- 7) than that of all other proteins. In malignant ascites fibronectin concentration was only correlated with alpha 1-protease inhibitor concentration but not with the concentration or activity of all other proteins, while in cirrhotic ascites most proteins revealed a positive correlation. The determination of the fibronectin concentration or the fibronectin/albumin ratio in ascites can differentiate malignant and nonmalignant ascites. All other proteases and antiproteases assessed are of lesser value for this purpose, although most are significantly increased in ascites and plasma of patients with malignant disorders.

Antithrombin III↗
PubMed1987

Proteases and antiproteases related to the coagulation system in plasma and ascites--influence of dexamethasone.

Fibrinolysis induced by the infusion of plasminogen activators into the circulation has been shown to cause coagulation disorders in ascites retransfusion. Dexamethasone is known to inhibit the synthesis of plasminogen activators by peritoneal macrophages. We therefore assessed its potential in preventing the occurrence of fibrinolysis by injecting 16 mg dexamethasone intraperitoneally in 10 patients 24 h before ascites retransfusion was performed. In addition, the effect of dexamethasone upon the activity or concentration of several proteases and antiproteases related to coagulation in plasma and ascites was analyzed on 15 occasions. An increase of the activity of plasminogen, alpha 2-antiplasmin, and antithrombin III, and in the concentration of alpha 1-protease inhibitor in ascites was induced by the dexamethasone injection. However, the reaction was not identical in all patients. Those patients having an increase of plasminogen activities of 0.6 CTA U/ml or more did not show signs of fibrinolysis during retransfusion. The results obtained indicate that intraperitoneal injection of dexamethasone decreases the concentration of plasminogen activators in ascites and thereby reduces the risk of coagulation disorders during retransfusion procedures. Since the effect is variable and not sustained, assessment of preoperative plasminogen concentrations is mandatory in order to prevent complications.

Antithrombin III↗
PubMed1987

Ca2+-activated ATPase in microsomes from human liver.

Human liver microsomal fractions exhibit ATP-supported Ca2+ uptake which is half-maximal at 7 X 10(-7) M free Ca2+ in the presence of oxalate. Ca2+ uptake is coupled to a Ca2+-stimulated ATPase activity, which is half-maximal at 4 X 10(-7) M free Ca2+. Catalysis involves formation of an Mr = 116,000 phosphoprotein with stability characteristics of an acylphosphate compound suggested to represent a phosphoryl protein intermediate of the Ca2+-ATPase. Phosphorylation is half-maximal at about 10(-6) M free Ca2+. The Mr = 116,000 protein is highly susceptible to proteolysis with trypsin. The phosphorylated active site was localized in an Mr = 58,000 primary tryptic fragment and in an Mr = 34,000 subfragment. Analyses on the mechanism of the Ca2+-ATPase suggest the following reaction sequence: formation of an ADP-reactive phosphoenzyme (Mr = 116,000) with bound Ca2+, which can transphosphorylate its Pi to ADP, giving rise to synthesis of ATP; reversible transformation of the ADP-reactive phosphoenzyme into an isomer without bound Ca2+, which cannot further react with ADP; hydrolytical cleavage, probably catalyzed by Mg2+, of the ADP-unreactive phosphoenzyme with liberation of Pi. Comparison with the Ca2+-transport ATPase in sarcoplasmic reticulum of skeletal muscle led us to suggest that the Mr = 116,000 Ca2+-ATPase belongs to the class of E1P . E2P-ATPases and might be operative as a Ca2+-transport ATPase at the level of the endoplasmic reticulum in human liver.

Calcium↗
PubMed1987

Perivascular nerve stimulation and phenylephrine responses in rat liver. Metabolic effects, Ca2+ and K+ fluxes.

Electrical stimulation of perivascular nerves (20 Hz/2 ms/20 V) in perfused rat liver led to a transient increase of 14CO2 production from [1-14C]glutamate, glutathione and thiol efflux, an increase in the lactate/pyruvate and the 3-hydroxybutyrate/acetoacetate ratio, glucose release and of portal pressure. These metabolic effects were accompanied by a Ca2+ release from the liver within the initial 2 min, being followed by Ca2+ reuptake, which lasted about 3 min. The initial Ca2+ release was 67 nmol/g liver and was smaller than that observed after phenylephrine (5 microM) addition (156 nmol/g liver). Hepatic Ca2+ release following nerve stimulation or phenylephrine was not significantly affected when the hemodynamic changes were largely prevented by sodium nitroprusside (10 microM). Although the amounts of Ca2+ released were different, the glycogenolytic responses, but not the other metabolic effects, were quantitatively similar with nerve stimulation and phenylephrine. Within the first 3 min of nerve stimulation there was a K+ uptake by the liver being followed by a K+ release over the next 5-6 min and a subsequent slow K+ uptake phase. These changes resembled those observed with phenylephrine. Phentolamine, an alpha-adrenergic antagonist, abolished the Ca2+ and K+ movements following nerve stimulation as well as glucose release and the hemodynamic changes. During continuous infusion of phenylephrine, nerve stimulation led still to an increase of portal pressure; however, the effects of nerve stimulation on Ca2+ and K+ fluxes and glucose release were largely suppressed. It is concluded that the metabolic effects of electrical nerve stimulation are mediated by a redistribution of cellular Ca2+ following alpha-receptor activation. Nerve stimulation involves Ca2+ and K+ fluxes across the plasma membrane. The metabolic effects are qualitatively similar to those induced by phenylephrine. The quantitative difference between nerve stimulation and phenylephrine is explained by a differential subacinar response, with fewer cells being reached by nerve stimulation than cells containing alpha-receptors. The hemodynamic changes of nerve stimulation point to the existence of sphincters near the inflow of the sinusoidal bed.

Animals↗
PubMed1987

The role of N-glycosylation for the plasma clearance of rat liver secretory glycoproteins.

The clearance of total rat liver secretory glycoproteins and of alpha 1-acid glycoprotein carrying no or different types of oligosaccharide side chains was studied in vivo and in the isolated perfused rat liver. In order to obtain unglycosylated or differently glycosylated forms of secreted glycoproteins, rat hepatocyte primary cultures were incubated with various inhibitors of N-glycosylation. Tunicamycin was used for the synthesis of unglycosylated (glyco)proteins, the mannosidase I inhibitor 1-deoxymannojirimycin for the synthesis of high-mannose type and the mannosidase II inhibitor swainsonine for the synthesis of hybrid-type glycoproteins. Glycoproteins carrying carbohydrate side chains of the complex type were synthesized by control hepatocytes. In vivo and in the perfused rat liver, high-mannose-type glycoproteins were cleared at the highest rate, followed by unglycosylated and hybrid-type glycoproteins. The lowest clearance rate was found for the glycoproteins with carbohydrate side chains of the complex type. For the highly glycosylated alpha 1-acid glycoprotein the differences in clearance rates were more pronounced. The following plasma half-lives were determined in vivo: complex type, 100 min; hybrid type, 15 min; unglycosylated form, 5 min; and high-mannose type less than 1 min. In the recirculating perfused liver 28% of complex-type alpha 1-acid glycoprotein, 40% of hybrid type, 47% of unglycosylated and 93% of high-mannose-type alpha 1-acid glycoprotein were removed from the perfusate within 2 h. It is concluded that N-glycosylation and processing to complex-type oligosaccharides seems to be of great importance for the circulatory life time of plasma glycoproteins.

Animals↗
PubMed1987

Hepatocellular carcinoma and hepatitis B virus infection: molecular evidence for monoclonal origin and expansion of malignantly transformed hepatocytes.

The clonality of tumor cells was studied in a patient with metastasizing hepatocellular carcinoma (HCC). Using hepatitis B virus (HBV) DNA as a genetic marker, the pattern of integration of viral DNA into the tumor cell genome was determined by Southern blot analyses of DNAs extracted from different HCC lesions in the liver and both lungs. All tumor tissues examined were found to have viral DNA integrated into the same site(s) of the cellular genome. This finding provides direct molecular evidence for a monoclonal origin and expansion of malignantly transformed hepatocytes during tumor growth and metastasis. This characteristic is similar to other human cancers associated with viral infections, such as adult T-cell leukemia, Burkitt's lymphoma, or cervical cancer, and is important for our understanding of viral oncogenesis in man.

Aged↗
PubMed1987

Pharmacokinetics of amiloride in renal and hepatic disease.

The pharmacokinetics of the antikaliuretic amiloride has been studied in healthy controls and in patients with chronic renal failure or hepatitis. It was 40% bound to protein. In healthy volunteers 49% of an oral dose was recovered unchanged in the urine. The renal clearance of amiloride was about 3 times the creatinine clearance, which means that it was predominantly excreted via tubular secretion. Renal impairment reduced the clearance of amiloride, causing a prolongation of the t1/2 and drug accumulation in plasma. In hepatitis the t1/2 of amiloride was prolonged and the AUC increased. Urinary recovery (Ae) of amiloride was greater in hepatitis patients than in controls.

Adult↗
PubMed1987

Bioavailability of zinc from zinc-histidine complexes. I. Comparison with zinc sulfate in healthy men.

Zinc supplementation is beneficial in some clinical conditions. Histidine has been shown to improve zinc absorption in animals. To test its influence on zinc absorption in humans, we studied the bioavailability of zinc from zinc-histidine complexes as compared to zinc sulfate in 10 healthy volunteers. Ingestion of zinc complexed with histidine at a ratio of 1:2 or 1:12 increased serum-zinc concentration 25% more than ingestion of zinc sulfate. Calculated uptake was 30-40% increased with zinc histidine over zinc sulfate. Urinary excretion was not different with any preparation. Application of 15 mg zinc as zinc histidine 1:2 gave an identical serum-zinc response as 45 mg zinc taken as zinc sulfate. Zinc histidine complexes are better absorbed than zinc sulfate in humans.

Adult↗
PubMed1987

Bioavailability of zinc from zinc-histidine complexes. II. Studies on patients with liver cirrhosis and the influence of the time of application.

Supplementation may benefit patients with liver cirrhosis. Zinc uptake from zinc-histidine complex 1:2 was assessed in eight patients with liver cirrhosis. Influence of the time of application was also studied. Compared with healthy controls, patients showed a 40% lower uptake of zinc after 20 mg zinc from zinc histidine. Bioavailability was identical when zinc was taken 6 h or 1 h before a meal but an order of magnitude greater than with or 1 h after a meal. No significant increase of serum zinc was found when zinc was given with a meal or 1 h after. Lower doses of zinc-histidine complexes than of zinc sulfate may be used to supplement patients with liver cirrhosis. Time of application is of great importance if this substitution is to be successful.

Adult↗
PubMed1987

Alpha 2-macroglobulin synthesis in an astrocyte subpopulation.

The proteinase inhibitor alpha 2-macroglobulin (alpha 2-M) is an acute phase protein in the adult rat. During inflammatory events, it is synthesized in the liver and secreted into the bloodstream to remove proteases that are released on injury. Recently, its occurrence in fetal rat brain has been reported. Its cellular origin and biological function in the developing brain, however, remained obscure. In this article, it is shown that astroglial cells cultured from newborn rat brain synthesize and secrete alpha 2-M. Its synthesis markedly increases with time in culture. Immunocytochemical studies reveal that only a subpopulation of astrocytes is alpha 2-M positive, alpha 2-M synthesis in the developing brain by neuroectoderm-derived cells asks for a broader definition of its function in the body. Since interactions of proteases and protease inhibitors appear to play a crucial role in cell migration and neurite outgrowth, alpha 2-M expression in astrocytes is discussed not only in relation to its potential role in the acute phase response to injury in the adult brain but also in regard to its possible involvement in brain development.

Animals↗
PubMed1987

Role of membrane glycoproteins in mediating trophic responses.

During growth and differentiation the plasma membrane has a key role not only in the reception and transmission of extracellular signals such as hormones and growth factors, but also in communicating cellular response to the cellular microenvironment. Cellular response to trophic stimuli includes alterations of cell shape and cell surface antigenicity, of cell-cell recognition and cellular adhesion, of cell matrix binding and the adaptation of cell surface receptors. The plasma membrane is therefore regarded as a 'central agency' for the integration of a single cell into the complex system of a tissue or of an organism. The numerous functions of the plasma membrane are mainly mediated by membrane integrated glycoproteins or glycolipids both sharing the common feature of covalently bound oligosaccharide side chains. Specific alterations of oligosaccharide structure and metabolism associated with growth, differentiation and various pathologic conditions suggest a specific role for the oligosaccharide moieties in the regulation of cell surface functions (Table 1). This review intends to focus on the role of plasma membrane glycoproteins describing briefly principles of glycoprotein structure and function, and characteristics of their biosynthesis and degradation.

Animals↗
PubMed1987

Identification of different transport systems for bile salts in sinusoidal and canalicular membranes of hepatocytes.

The preservation of the functional polarity of hepatocytes in liver snips (1 x 2 x 4 mm) was demonstrated by fluorescent microscopic studies using the sodium salt of (N-[7-(4-nitrobenzo-2-oxa-1,3-diazol)]-3 beta-amino-7 alpha,12 alpha- dihydroxy-5 beta-cholan-24-oyl)-2-aminoethanesulfonic acid. This fluorescent bile salt derivative is not only taken up by hepatocytes of several cell layers at the surface of the snips but also secreted into bile canaliculi. The intact hepatobiliary transport of bile salts by hepatocytes of liver snips demonstrates that they are a useful system for the investigation of those transcellular transport processes which require the integrity of hepatic structure. Photoaffinity labelling of liver snips with the sodium salt of (7,7-azo-3 alpha,12 alpha-dihydroxy-5 beta-[3 beta-3H]cholan- 24-oyl)-2-aminoethanesulfonic acid revealed that the bile-salt-binding membrane polypeptides with apparent Mr values of 54,000 and 48,000 are exclusively located in the sinusoidal membrane, whereas a single bile-salt-binding polypeptide with an apparent Mr of 100,000 is located in the bile-canalicular membrane. Photoaffinity labelling of liver snips at 4 degrees C, when transcellular bile-salt transport is insignificant, resulted in the labelling of the two sinusoidal membrane polypeptides and practically no labelling of the polypeptide with an apparent Mr of 100,000. This latter polypeptide was also not labelled when Ca2 deprivation abolished bile secretion completely. These results indicate that the directed hepatobiliary transport of bile salts in hepatocytes is accomplished by transport systems which are different for sinusoidal uptake and canalicular secretion.

Animals↗
PubMed1987

Prostaglandin responses in isolated perfused rat liver: Ca2+ and K+ fluxes, hemodynamic and metabolic effects.

Addition of prostaglandin F2 alpha and prostaglandin E2 to isolated perfused rat liver led to a dose-dependent, transient net Ca2+ release, which was completed within 3 min. Withdrawal of the prostaglandins resulted in a Ca2+ re-uptake over a period of about 10 min. Simultaneously, these prostaglandins induced an increase of portal pressure, stimulated hepatic glucose output and 14CO2 production from [1-14C]glutamate and led to K+ movements across the hepatocyte plasma membrane similar to those observed with other Ca2+-mobilizing agents. With prostaglandin F2 alpha there was a close correlation between the net Ca2+ release and the maximal rate of initial net K+ uptake by the liver (linear regression coefficient r = 0.902; n = 20). Prostaglandin F2 alpha was more effective than prostaglandin E2 or D2. Because prostaglandins are known to be produced by hepatic non-parenchymal cells during stimulation by phagocytosis or by addition of extracellular ATP or UTP, these data suggest an interaction between non-parenchymal and parenchymal liver cells and point to a modulating role of prostaglandins in hepatic metabolism and microcirculation, which is mediated by Ca2+-mobilizing mechanisms.

Animals↗
PubMed1987

Renal and hepatic nitrogen metabolism in systemic acid base regulation.

Renal and hepatic nitrogen metabolism are linked by an interorgan glutamine flux, coupling both renal ammoniagenesis and hepatic urea production to systemic acid-base regulation. Reconsideration of established pathways and recent observations led to a conceptional change with a movement from a two-organ concept (lungs and kidney) of acid-base balance to a three-or-more organ concept (lungs, kidney, liver). This development implies new regulatory sites of systemic pH control and consequently a new pathophysiological understanding of derangements of acid-base homeostasis. In this new concept the urea cycle regulates the removal of metabolically generated bicarbonate during a protein load in a pH- and bicarbonate-dependent manner. This is related to a switch of hepatic ammonium detoxication from urea to glutamine synthesis in metabolic acidosis, and vice versa in alkalosis. An adaptive increase in the renal capacity for glutamine deamidation and deamination and for ammonium excretion leads to a proportional decrease in renal urea excretion at the expense of ammonium in acidotic conditions. The present review summarizes experimental data and clinical implications resulting from this new concept, which was also the subject of a recent Conference of the German Society for Clinical Chemistry "Mechanisms and Control of pH Homeostasis".

Acid-Base Equilibrium↗
PubMed1987

[Hepatic encephalopathies].

The functional disturbances of the central nervous system in hepatic encephalopathy are due to several coexisting pathogenetic factors: Endogenous neurotoxins, imbalance of amino acids in blood plasma and alterations of the blood-brain barrier. These factors, in turn, effect alterations of neurotransmitters and their receptors. Therapeutic interventions are aimed at the inhibition of ammonia production by protein restriction, lactulose or antibiotics. A new therapeutic concept is the application of branched chain amino acids. Their effect is based on the stimulation of protein synthesis in muscle, enhanced urea synthesis in the liver and increased ammonia detoxification by glutamine synthesis in the brain.

Ammonia↗