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W Hilgier

Publications and source records attributed to W Hilgier.

At least 19 recordsLinked to original sources
PubMed1994

Increase of the brain uptake index for L-ornithine in rats with hepatic encephalopathy.

We measured the brain uptake index (BUI) for radiolabelled L-ornithine (ORN) in rats with acute hepatic encephalopathy (HE) induced by two (onset stage) or three (comatous stage) administrations of a hepatotoxin-thioacetamide (TAA). In the comatose group, an increase of the BUI to 275% of control was measured at 24 h post-treatment. In the onset group, the BUI for ORN increased gradually with time: it reached 220% of control at 7 days post-treatment and 442% of control at 21 days post-treatment. HE did not raise the BUI for a blood-brain barrier (BBB) non-penetrable amino acid L-aspartate (ASP), indicating that HE activates ORN transport but does not produce BBB leakage. ORN transport through BBB was not increased in rats with hyperammonemia comparable to that accompanying HE, but was induced without liver damage. Considering recent evidence that ORN acting intracerebrally ameliorates pathophysiological symptoms of HE, increased transport ORN across BBB should facilitate HE therapy based on systemic administration of this amino acid.

Acetates↗
PubMed1994

Similarities of the in vivo and in vitro effects of mercuric chloride on [3H]ouabain binding and potassium activation of Na+/K(+)-ATPase in isolated rat cerebral microvessels.

A previous study revealed that a single i.p. administration of 6 mg/kg body wt. of mercuric chloride (MC) durably inhibits the rat cerebral microvascular Na+/K(+)-ATPase activity [1]. In this study, cerebral microvessels isolated 18 h after MC treatment were compared to those obtained from control rats and subsequently treated or not treated with MC in vitro, with regard to: (a) [3H]ouabain binding to, and (b) K(+)-activation kinetics of, the Na+/K(+)-ATPase. Microvessels from MC-treated rats showed a decrease of [3H]ouabain binding down to 62% of the control binding, and the same degree of inhibition was attained in microvessels treated in vitro with 5 microM MC. Analysis of the K(+)-activation kinetics of Na+/K(+)-ATPase revealed a decrease of Vmax from the control value of 13.1 to 7.67 mumol/mg/h in microvessels from MC-treated rats and 6.07 mumol/mg/h in microvessels treated in vitro with 5 microM MC, with no change in Km in either case. The similarity of the effects of in vivo and in vitro treatments suggests that the inhibition of the cerebromicrovascular Na+/K(+)-ATPase following in vivo administration of MC results from a direct interaction of Hg2+ with the enzyme.

Animals↗
PubMed1994

Ammonia added in vitro, but not moderate hyperammonemia in vivo, stimulates glutamate uptake and H(+)-ATPase activity in synaptic vesicles of the rat brain.

The uptake of radiolabelled neurotransmitters: glutamate (GLU), GABA, and dopamine (DA) and the activity of the vacuolar type H(+)-pumping ATPase (H(+)-ATPase), were measured in crude synaptic vesicles treated in vitro with a neurotoxic (3 mM) dose of NH4+ (acetate or chloride), or isolated from rats with a moderate increase of brain ammonia (to approximately 0.6 mM) induced by i.p. administration of ammonium acetate (HA rats) or a hepatotoxin-thioacetamide (HE rats). In vitro treatment with ammonium salts increased the sodium-independent, chloride-dependent uptake of GLU but did not stimulate the uptake of GABA or DA. The in vitro treatment also stimulated the H(+)-ATPase activity. Since H(+)-ATPase generates the electrochemical gradient driving synaptic vesicular neurotransmitter transport, its stimulation by ammonia may have facilitated GLU uptake. However the GLU specificity of the effect must be related to other factors differentially affecting GLU uptake and the uptake of other neurotransmitters. Enhanced GLU accumulation in the synaptic vesicles may contribute to the increase of synaptic GLU exocytosis previously reported to accompany acute increases of brain ammonia to toxic levels. However, GLU uptake and H(+)-ATPase activity, but also the uptake of GABA and DA, were unchanged in synaptic vesicles prepared from rats with HA or HE. This indicates that changes in GLU and/or GABA release reported for moderate hyperammonemic conditions must be elicited by factors unrelated to the synaptic vesicular transport of the amino acids.

Ammonia↗
PubMed1994

Brain ion and amino acid contents during edema development in hepatic encephalopathy.

Brain edema in hepatic encephalopathy has been associated with circulating ammonia that is metabolized to glutamine. We measured alterations in blood chemistry and brain regional specific gravity and ion and amino acid contents in models of simple hyperammonemia and liver failure induced by daily administrations of ammonium acetate (AAc) or thioacetamide (TAA), respectively. Serum and brain ammonia increased to similar levels (200 and 170% of control, respectively) in both experimental groups. Serum transaminase activities increased 10-fold in animals injected with TAA but were unchanged in animals given AAc injections. In both experimental groups glutamine was elevated in cerebral white matter, cerebral gray matter, and basal ganglia, whereas brain tissue specific gravity decreased in all brain regions, indicating edema formation. In the AAc group, we observed a decrease in glutamate and taurine contents concomitant with the development of brain edema. In these animals, cerebral gray matter specific gravity and taurine contents returned to control levels 24 h after the third AAc injection. TAA-injected animals demonstrated similar decreases in brain tissue specific gravity, whereas glutamine, glutamate, and taurine contents were all elevated. During hepatic encephalopathy, ammonia-induced changes in brain amino acid content may contribute to brain edema development.

Acetates↗
PubMed1992

The effect of ammonia and pH on brain gamma-glutamyl transpeptidase in young rats.

Acute hyperammonemia, induced by two consecutive injections of ammonium acetate (550 and 450 mg per kg b.wt.), decreased the activity of gamma-glutamyl transpeptidase (GGT) in most brain regions of 18- and 30-day-old rats. This decrease in the brain GGT activity was more pronounced in younger than in older rats. After the addition of NH4Cl to the incubation medium, the inhibitory action of NH4+ on this enzyme activity was also demonstrated in crude synaptosomal membranes at pH 7.4, but in a range of NH4+ concentrations many-times higher than those found in the plasma or brains of young hyperammonemic rats. Because similar concentrations of NH4+ stimulated the activity of the purified enzyme from rat kidney (mainly at pH 9.0), the inhibition of GGT activity in the young rat brain is probably mediated indirectly and not by a direct interaction of ammonia with the enzyme molecules.

Acetates↗
PubMed1992

Characteristics of large neutral amino acid-induced release of preloaded L-glutamine from rat cerebral capillaries in vitro: effects of ammonia, hepatic encephalopathy, and gamma-glutamyl transpeptidase inhibitors.

The release of newly loaded L-[14C]glutamine (L-Gln) from rat cerebral cortical capillaries was stimulated by L-transport system substrates: tryptophan (TRY), leucine (leu), and nonlabeled L-Gln, respectively, by 32, 50, and 40% above the basal release resulting from superfusion with standard Krebs-Henseliet buffer. However, no stimulation was observed upon treatment with D-Gln or L-glutamate (L-Glu), which are not the L-system substrates, or with ammonium chloride. The stimulatory effect of TRY was temperature dependent but sodium independent, and was abolished in the presence of a sulfhydryl reagent N-ethylmaleimide (NEM). The results support the view that the L-Gln-stimulated uptake of large neutral amino acids (LNAA) across the blood-brain barrier involves the L-system mediated Gln-LNAA exchange. The TRY-stimulated Gln release was enhanced in vitro by simultaneous addition of ammonium chloride, and in capillaries derived from rats with acute hepatic encephalopathy (HE). These results confirm the role of Gln-LNAA exchange in the excessive accumulation of LNAA in brain observed in a variety of hyperammonemic conditions. Superfusion of L-Gln-loaded capillaries in a buffer containing gamma-glutamyl transpeptidase (GGT) inhibitors, serine borate (SB) or 6-diazo-5-oxo-L-norleucine (DON), increased the basal L-Gln release and made it irresponsive to subsequent treatment with TRY. However, the basal release was also increased by superfusion with serine alone or Leu, and this treatment abolished the subsequent effect of TRY as well. Moreover, DON stimulated L-Gln release from capillaries superfused in a standard way, and the effects of DON and TRY were additive. Hence, in the present conditions, SB and DON acted as L-system substrates rather than as GGT inhibitors. Taken together, the results do not support the concept that GGT mediates the Gln-LNAA exchange.

Amino Acids↗
PubMed1991

Decreased potassium-stimulated release of [3H]D-aspartate from hippocampal slices distinguishes encephalopathy related to acute liver failure from that induced by simple hyperammonemia.

The calcium-dependent, high (65 mM) potassium-evoked release of the L-glutamate analogue [3H]D-aspartate (D-Asp) was measured in hippocampal slices derived from rats with (a) hepatic encephalopathy (HE) induced with a hepatotoxin, thioacetamide, (b) hyperammonemia produced by i.p. administration of ammonium acetate, and (c) in normal slices preincubated for 30 min with 1 mM ammonium acetate. HE (variant a) inhibited the release by about 30%, which was interpreted to indicate depressed exocytosis of synaptic glutamate. This phenomenon is likely to lead to a decrease of glutamate-mediated neural excitation, which in turn could contribute to the neural inhibition typical of HE. By contrast, and in agreement with earlier reports, hyperammonemia (variant b) did not affect D-Asp release, whereas in vitro treatment of the slices with ammonium acetate (variant c) resulted in a 60% increase of the release. Hence, impairment of synaptic glutamate exocytosis is the phenomenon that distinguishes HE related to toxic liver failure from simple hyperammonemia. This result emphasizes the role of other factors than ammonia in the pathophysiological mechanism of HE.

Acetates↗
PubMed1991

Decreased glucose utilization in discrete brain regions of rat in thioacetamide-induced hepatic encephalopathy as measured with [3H]-deoxyglucose.

To evaluate the possible contribution of bioenergetic failure in the particular brain regions to the pathomechanism of hepatic encephalopathy (HE), local cerebral metabolic rate for glucose (LCMRglue) was evaluated from [3H]-deoxyglucose uptake in frontal, visual and auditory cortex, striatum, cerebellum and medulla oblongata of rats with acute HE induced with a hepatotoxin--thioacetamide (TAA). HE caused a decrease of LCMRglue in all the regions studied. The strongest decrease (about 65%) was noted in hippocampus and cerebral cortex--the two regions rich in glutamatergic neurons. The results indicate a possible link between decreased energy metabolism and impaired excitatory, glutamatergic neurotransmission--the two factors whose contribution to HE has so far been implicated separately.

Animals↗
PubMed1990

Activation of arginine metabolism to glutamate in rat brain synaptosomes in thioacetamide-induced hepatic encephalopathy: an adaptative response?

Crude (P2) synaptosomes derived from rats with acute hepatic encephalopathy (HE) induced with thioacetamide showed a slightly increased uptake of radiolabeled arginine (ARG) and a 2.5-fold enhanced conversion of newly taken-up ARG to both glutamate (GLU) and gamma-aminobutyric acid (GABA) as compared with control synaptosomes. Pulse treatment of the preloaded synaptosomes with a high potassium medium decreased their radioactive GLU and GABA content without affecting the content of the precursor ARG. This result, which was identical with control or HE preparations, appears to indicate that ARG contributes at least, in part, to the synthesis of neurotransmitter GLU or GABA. As measured in purified synaptosomal preparations, HE increased by about 50% the activities of arginase and ornithine-delta-aminotransferase--the two enzymes of the ARG to GLU shunt. It is postulated that increased conversion of ARG to GLU may compensate for excessive utilization of the latter amino acid as an ammonia trap during HE and, as such, may be considered as an adaptative response of the synaptic compartment to this pathological condition.

Acetamides↗
PubMed1989

Rapid decrease of high affinity ouabain binding sites in hippocampal CA1 region following short-term global cerebral ischemia in rat.

High affinity [3H]ouabain binding was examined in the hippocampal CA1 region and frontal cortex of rats subjected to 5 min complete cerebral ischemia in a clinical death model, and to subsequent resuscitation. A decrease of Bmax directly after ischemia and its further gradual decrease during 120 min of reperfusion were noted in the ischemia-vulnerable CA1 region, whereas no change of Bmax was observed in frontal cortex. The apparent Kd constant showed insignificant fluctuations in either of the two brain regions. Since ouabain binds with high affinity to the neuronal (alpha +)-form of Na+/K+-ATPase, the results indicate a rapid enzyme loss in CA1 neurons. The high affinity ouabain binding test proved to be a sensitive detector of premorphological changes in nerve cell membranes in ischemia.

Animals↗
PubMed1988

Changes in the activity of gamma-glutamyl transpeptidase in brain microvessels, astroglial cells and synaptosomes derived from rats with hepatic encephalopathy.

Prolonged thioacetamide treatment increased gamma-glutamyl transpeptidase (GGT) activity in the rat liver and induced neurological symptoms of hepatic encephalopathy (HE). The enzyme activity measured without an amino acid or peptide acceptor was increased in cortical capillaries and synaptosomes, but remained unchanged in astroglia isolated from the brains of hyperammonemic rats. In the presence of L-glutamine the activity of GGT was stimulated by about 60% in astroglial cells while in the capillaries and synaptosomes the amino acid stimulation was less pronounced. Glycylglycine also stimulated the GGT activity in the astroglia more (4-fold) than in cortical capillaries or synaptosomes (3-fold). Similar stimulatory effects of these gamma-glutamyl moiety acceptors on the GGT activity were observed in capillaries, glial cells and synaptosomes derived from the brains of rats with HE. These results indicate that GGT may be involved in the excessive accumulation of large neutral amino acids (and some peptides) in the brain of rats with HE.

Animals↗
PubMed1986

Arginine in thioacetamide-induced hepatogenic encephalopathy in rats: activation of enzymes of arginine metabolism to glutamate.

Two subsequent phases of hepatogenic encephalopathy (HE), the metabolic and precomatous phase, were produced in rats by thioacetamide treatment. Plasma and brain levels of arginine and its metabolites in the arginine-glutamate pathway, and activities of 2 brain enzymes of this pathway: arginase (L-arginine amidohydrolase, EC3521) and ornithine amino-transferase (OAT, ornithine-oxo-acid aminotransferase, EC26113) were measured in these rats. Plasma arginine sharply decreased in the metabolic phase and rose above control level in the precomatous phase, whereas ornithine and glutamate increased and urea decreased in both phases. Brain amino acids levels remained unchanged throughout, confirming earlier report of their insensitivity to external manipulation. Both brain enzymes showed a similar stepwise increase in their activities up to 150% the control level. The results are indicative of increased involvement of arginine as a precursor of amino acid neurotransmitters glutamate and GABA, with possible implication for the course of HE.

Animals↗
PubMed1985

The brain octopamine and phenylethanolamine content in rats in thioacetamide-induced hepatogenic encephalopathy.

The brain octopamine (OA) and phenylethanolamine (PhEA) content was determined in rats subjected to repeated intraperitoneal administrations of thioacetamide (TAA) known to produce different stages of hepatogenic encephalopathy (HE). A more than 2.5-fold increase of OA and a 2-fold increase of PhEA was observed after prolonged (3 times) administration of TAA, coinciding with impaired ammonia detoxication in brain and with the onset of pathophysiological changes typical for HE. Only insignificant changes in the content of the amines were observed in the early stages of the experiment as well as in the recovery period. The results are consistent with the "false neurotransmitter" hypothesis of Fischer and Baldessarini, assuming the participation of OA and PhEA in the pathogenesis of HE.

2-Hydroxyphenethylamine↗
PubMed1984

Brain carbonic anhydrase activity in rats in experimental hepatogenic encephalopathy.

Carbonic anhydrase (CA) activity was measured in the brains of rats subjected to repeated administration of thioacetamide (TAA), known to produce symptoms of hepatogenic encephalopathy (HE). In the early phase of the experiment, an increase of the enzyme activity was observed, which correlated well with elevated blood ammonia, while the brain ammonia remained unchanged. Prolonged TAA treatment resulted in the cessation of the activation of CA coinciding with the increase of brain ammonia above control levels. The results, in addition to supporting the idea that CA participates in ammonia detoxication in brain, may also indicate that the enhancement of the enzyme activity represents an adaptation mechanism to the increased ammonia load during HE.

Ammonia↗