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At least 109 records · Page 6Linked to original sources
PubMed1991

Portacaval anastomosis disrupts circadian locomotor activity and pineal melatonin rhythms in rats.

To determine whether hepatic encephalopathy may be associated with a disruption of circadian function, the circadian rhythms of locomotor activity and pineal melatonin content were examined in an animal model of complete portal-systemic shunting, rats with a portacaval anastomosis (PCA). The locomotor activity rhythm of all sham-operated animals entrained normally to a light/dark cycle and exhibited a normal free-running period during exposure to constant light. In contrast, PCA led to a dampening of the locomotor activity rhythm in all animals and the abolishment of a circadian periodicity in the activity rhythm of approximately 50% of rats during exposure to either a light/dark cycle or constant light. While normal diurnal variations of pineal melatonin content were seen in sham-operated rats, the amplitude of this variation appeared to be decreased in PCA animals. The similar effects of PCA on both a behavioral and an endocrine circadian rhythm, known to be regulated by a common neural pacemaker, coupled with studies indicating that a variety of other circadian rhythms may be disrupted in both animals and humans with hepatic dysfunction, suggests that this circadian disturbance originates within the pacemaker or on one of its afferent/efferent pathways.

Animals↗
PubMed1990

Selective loss of N-methyl-D-aspartate-sensitive L-[3H]glutamate binding sites in rat brain following portacaval anastomosis.

Excitatory amino acids have been implicated in the pathogenesis of hepatic encephalopathy. In the present study, kainate, quisqualate and N-methyl-D-aspartate (NMDA) subclasses of L-glutamate receptors were measured in adult rat brain by quantitative receptor autoradiography following surgical construction of an end-to-side portacaval anastomosis (PCA). PCA resulted in sustained hyperammonemia and decreased binding of L-glutamate to the NMDA receptor when compared to sham-operated controls. Decreases in binding ranged from 17 to 39% in several regions of cerebral cortex, hippocampus, striatum, and thalamus. Binding to quisqualate and kainate receptor subtypes was not altered. PCA leads to astrocytic changes in brain but does not result in any measurable loss of neuronal integrity. It is therefore proposed that decreased glutamate binding to the NMDA receptor following PCA results from increased extracellular glutamate caused by decreased reuptake into perineuronal astrocytes and a compensatory down-regulation of these receptors. Such changes could be of pathophysiological significance in hepatic encephalopathy.

Ammonia↗
PubMed1986

Estradiol regulation of the secretory immune system in the female reproductive tract: IgA in uterine and vaginal secretions of rats following portacaval anastomosis.

The uterine immune system is under the control of estradiol which acts to increase the levels of both IgA and secretory component (SC) in uterine secretions. The objective of the present study was to determine whether serum is the primary source of the IgA which enters uterine secretions in response to estradiol. To examine this, serum IgA levels in rats were surgically elevated by portacaval anastomosis which prevents hepatic clearance of IgA. Under these conditions, IgA levels in serum were 2- to 4-fold higher than those of intact or sham-operated animals. Levels of IgA in uterine secretions of portacaval animals, however, were significantly lower than those measured in controls when animals were ovariectomized and treated with estradiol. IgA in vaginal secretions of portacaval animals was greater than that in sham-operated or intact rats. To determine whether IgA had leaked from the uterus into vaginal secretions, a second group of animals had their uteri ligated at the utero-cervical junction prior to hormone treatment. Following estradiol stimulation, uterine IgA levels in portacaval animals were the same as those measured in intact and sham-operated animals. When free SC was measured in uterine secretions of ligated rats, levels were the same in all three groups. These studies indicate that elevated levels of serum IgA did not lead to a rise in uterine IgA. Further, since SC, which is thought to be a receptor for transporting IgA into mucosal secretions, remained unchanged, it appears unlikely that IgA movement into the uterine lumen was transport limited. These studies suggest that the presence of IgA in uterine and vaginal secretions is not due exclusively to serum contributions but may involve local synthesis of IgA.

Animals↗
PubMed1999

Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis.

Two mechanisms may account for brain edema in fulminant hepatic failure: the osmotic effects of brain glutamine, a product of ammonia detoxification, and a change of cerebral blood flow (CBF). We have shown brain edema, a marked increase in brain glutamine, and a selective rise in CBF in rats after portacaval anastomosis receiving an ammonia infusion. In this study, we inhibited the activity of glutamine synthetase with methionine-sulfoximine (MSO) and examined ammonia levels, brain water and CBF. Four groups received either a continuous ammonium acetate or control infusion; half of the animals had been pretreated with MSO or vehicle. The ammonia group exhibited brain edema (79.97 +/- 0.04 vs. 81.11 +/- 0. 13% water), an increase in cerebrospinal fluid (CSF) glutamine (1.29 +/- 0.21 vs. 2.84 +/- 0.39 mmol/L) and CBF (63 +/- 11 vs. 266 +/- 45 mL/min/100 g brain). When MSO was added to the ammonia infusion, ammonia levels rose further (928 +/- 51 vs. 1,293 +/- 145 mmol/L, P <.05) but CSF glutamine decreased (2.84 +/- 0.39 vs. 1.61 +/- 0.2 mmol/L, P <.01). Brain edema (80.48 +/- 0.11%) and cerebral hyperemia (140 +/- 25 mL/min/100 g brain) were significantly ameliorated in the ammonia plus MSO group. Brain output of circulating nitric oxide (NO(x)) was increased in the ammonia-infused group but normalized in the ammonia plus MSO group. In this model, the rise of CBF reflects intracranial events that occur after glutamine synthesis. Activation of nitric oxide synthase in the brain could account for these findings.

Ammonia↗
PubMed1985

The sinusoidal barrier in rats with portacaval anastomosis: a morphometric study.

Shunting of portal blood in the rat leads to liver atrophy and to an increase in arterial blood flow with microcirculatory disturbances. The aim of this study was to investigate the effects of these disturbances on the liver sinusoidal barrier (endothelial and perisinusoidal cells) using morphometric techniques. Rats with portacaval anastomosis (PCA) and sham operated pair-fed controls were studied 3 months after the shunt. Sinusoidal volume density in PCA increased but not significantly and the volume density (Vv) of total endothelial (EC) and perisinusoidal cells (PSC) increased by 104.54% compared to sham operated pair-fed rats. The increase of EC Vv was not associated with an increase in surface density (Sv) suggesting a fall in the number of small fenestrations and an increase in cell thickness. This interpretation supports the morphological observations. The increase of PSC Vv was mainly related to the increase in their subendothelial processes Vv and not to that of the cell body Vv. Lipids Vv and RER Sv expressed per sinusoidal cells remained unchanged suggesting that the balance between the 2 hypothetical functions of the PSC, namely fibrogenesis and storage of vitamin A, was maintained. In conclusion, changes of EC and PSC after PCA result mainly in thickening of the sinusoidal barrier. This increase may impair exchanges between the sinusoidal lumen and Disse space and contribute to functional abnormalities.

Animals↗
PubMed1972

The effect of portacaval anastomosis on oral carbohydrate tolerance and on plasma insulin levels.

In patients with portal hypertension, plasma insulin levels were raised both fasting and after oral glucose or intravenous tolbutamide. This supports previous suggestions that resistance to endogenous insulin plays a major role in producing the impaired glucose tolerance found in chronic hepatic dysfunction. The operation of portacaval anastomosis was followed by impaired oral fructose tolerance, but did not significantly change oral glucose tolerance. Plasma insulin levels were unchanged by the operation, either fasting or following the stimulus of an oral glucose load or intravenous tolbutamide. The insulin response after operation was only higher after intensive pancreatic beta cell stimulation by a combination of glucose, tolbutamide, and glucagon. These results indicate that, in patients with hepatic dysfunction, little insulin is being removed by the liver from the portal blood except when the insulin secretory rate is unusually high.

Fasting↗
PubMed1989

[Chronic hepatic encephalopathy in cirrhotic patients and spontaneous portacaval anastomosis. Portal angiographic and manometric study].

Portal angiographic and manometric studies were prospectively carried out in 9 cirrhotic patients with spontaneous chronic portal-systemic encephalopathy. Hepatic encephalopathy presented as coma in 8 patients, and was the first manifestation of chronic liver disease in 6 cases. Hemodynamic studies showed a) a large single spontaneous portacaval anastomosis (gastrorenal, splenorenal, gradient (mean +/- SD = 16.3 +/- 5.4 mm Hg); c) a wedge hepatic venous pressure higher than portal pressure in 8 cases (difference: 1-11 mm Hg).

Blood Pressure Determination↗
PubMed1999

Mild hypothermia modifies ammonia-induced brain edema in rats after portacaval anastomosis.

BACKGROUND & AIMS: The pathogenesis of brain edema in fulminant hepatic failure is still unresolved. Mild hypothermia (33 degrees-35 degreesC) can ameliorate brain edema after traumatic brain injury. We evaluated mild hypothermia in a model of ammonia-induced brain edema in which accumulation of brain glutamine has been proposed as a key pathogenic factor. METHODS: After portacaval anastomosis, anesthetized rats were infused with ammonium acetate at 33 degrees, 35 degrees, and 37 degreesC or vehicle at 37 degreesC. Water and glutamine levels in the brain, cardiac output, and regional and cerebral hemodynamics were measured when intracranial pressure increased 3-4-fold (ammonia infusion at 37 degrees) and matched times (other groups). RESULTS: Mild hypothermia reduced ammonia-induced brain swelling and increased intracranial pressure. Brain glutamine level was not decreased by hypothermia. Brain edema was accompanied by a specific increase in cerebral blood flow and oxygen consumption, which were normal in both hypothermic groups. When the ammonia infusion was continued in hypothermic rats, plasma ammonia levels continued to increase and brain swelling eventually developed. CONCLUSIONS: Mild hypothermia delays ammonia-induced brain edema. In this model, an increase in cerebral perfusion is required for brain edema to become manifest. Mild hypothermia could be tested for treatment of intracranial hypertension in fulminant hepatic failure.

Acetates↗
PubMed1993

Cerebral blood flow and the hyperdynamic circulation of rats after portacaval anastomosis.

Both increased and decreased values of cerebral blood flow have been reported in liver disease. Furthermore, the relation between the cerebral circulation and the generalized hemodynamic disturbance seen in chronic liver disease with portal-systemic shunting has not been fully characterized. We studied this problem in a well defined model of the hyperdynamic circulation, the rat after portacaval anastomosis (PCA). Using the radioactive microsphere technique, cardiac output and regional blood flows were measured; regional vascular resistances were then calculated. While the fraction of cardiac output perfusing the splanchnic bed was significantly increased, the corresponding brain fraction was reduced. Blood flow to the cerebral hemispheres and midbrain was significantly decreased. Arterial vasodilatation was demonstrated by the fall in arterial pressure, systemic vascular resistance as well as splanchnic and renal resistances; cerebrovascular resistance, however, was unchanged. No relation between values of arterial pressure and cerebral blood flow was seen, making a failure of cerebrovascular autoregulation unlikely. The decrease in hemispheric and midbrain perfusion without changes in vascular resistance suggests that a drop in blood flow is appropriately coupled to a reduction in brain metabolism. The cerebral circulation does not participate in the hyperdynamic state that is seen in this model.

Animals↗
PubMed2004

Tacrolimus ameliorates cerebral vasodilatation and intracranial hypertension in the rat with portacaval anastomosis and hyperammonemia.

Arterial hyperammonemia and cerebral vasodilatation correlate with cerebral herniation in patients with fulminant hepatic failure (FHF). Tacrolimus is a calcineurin inhibitor that passes the blood-brain barrier and may increase cerebrovascular tone and restrict cerebral ammonia influx. In this study, we determined if tacrolimus prevents cerebral vasodilatation and high intracranial pressure (ICP) in the rat with portacaval anastomosis (PCA) challenged to high arterial ammonia (NH4+) concentration. Seven groups of mechanically ventilated rats, with 6-9 rats in each group, were investigated within 48 hours after construction of a PCA (4 groups) or after sham operation (3 groups). Three groups of the rats received infusion of NH4+ and 4 groups received saline for approximately 180 minutes. Two groups of the PCA rats receiving either NH4+ or saline had an i.v. injection of tacrolimus (0.4 mg/kg) or vehicle before start of NH4+ or saline infusion. Cerebral blood flow (CBF) was monitored by a laser Doppler probe in brain cortex. ICP was monitored by placement of a catheter in the cerebrospinal fluid. CBF and ICP increased in PCA rats receiving NH4+ infusion compared to PCA controls and to all groups of sham-operated animals (P <.05). In the group of PCA rats pre-treated with tacrolimus before receiving ammonia infusion, the increase in ICP was ameliorated compared to the ammonia infused group receiving vehicle (P <.03). Tacrolimus also prevented an increase in CBF in the PCA group receiving NH4+ (P <.05) compared to the control groups. In conclusion, Tacrolimus prevents cerebral vasodilatation and ameliorates intracranial hypertension in PCA rats receiving NH4+ infusion. These findings indicate that tacrolimus could be of clinical value in the prevention of cerebral hyperemia, high ICP, and serious brain damage in patients with FHF.

Anastomosis, Surgical↗
PubMed1999

Portacaval anastomosis causes selective alterations of peripheral-type benzodiazepine receptor expression in rat brain and peripheral tissues.

There is a growing body of evidence to suggest that peripheral-type benzodiazepine receptors (PTBRs) and their endogenous ligands are implicated in the pathogenesis of end-organ failure in chronic liver disease. Portal-systemic encephalopathy, a major neuropsychiatric complication associated with chronic liver disease, results in activation of brain PTBR and probably in peripheral organs. In order to address these issues, PTBR mRNA was measured using semi-quantitative RT-PCR in extracts of cerebral cortex, kidney and testis of rats four weeks after end-to-side portacaval anastomosis and sham-operation (controls). Densities of PTBR sites were measured concomitantly by in vitro receptor binding using the selective PTBR ligand [3H]PK11195. Portacaval shunting resulted in a 2 to 3-fold increase in expression of PTBR in brain and kidney and a 37% reduction in expression in testis. Densities of [3H]PK11195 sites changed in parallel with the alterations of gene expression. These findings suggest that selective alterations of PTBR expression are implicated in the pathogenesis of peripheral tissue hypertrophy (kidney) and/or atrophy (testis) which accompanies portal-systemic shunting in chronic liver failure. In brain, activation of PTBR could result in an increase in the production of neurosteroids with potent inhibitory action in the CNS, which could contribute to the pathogenesis of portal-systemic encephalopathy.

Animals↗
PubMed2001

Assessment of bioaccumulation and neurotoxicity in rats with portacaval anastomosis and exposed to manganese phosphate: a pilot study.

The use of the additive methylcyclopentadienyl manganese tricarbonyl in unleaded gasoline has resulted in increased attention to the potential toxic effects of manganese (Mn). Hypothetically, people with chronic liver disease may be more sensitive to the adverse neurotoxic effects of Mn. In this work, bioaccumulation of Mn, as well as histopathology and neurobehavioral damage, in end-to-side portacaval anastomosis (PCA) rats exposed to Mn phosphate via inhalation was investigated. During the week before the PCA operation, 4 wk after the PCA operation, and at the end of exposure, the rats were subjected to a locomotor evaluation (day-night activities) using a computerized autotrack system. Then a group of 6 PCA rats (EXP) was exposed to 3050 microg m(-3) (Mn phosphate) for 8 h/day, 5 days/wk for 4 consecutive weeks and compared to a control group (CON), 7 PCA rats exposed to 0.03 microg m(-3). After exposure, the rats were euthanized and Mn content in tissues and organs was determined by neutron activation analysis. The manganese concentrations in blood (0.05 microg/g vs. 0.02 microg/g), lung (1.32 microg/g vs. 0.24 microg/g), cerebellum (0.85 microg/g vs. 0.64 microg/g), frontal cortex (0.87 microg/g vs. 0.61 microg/g), and globus pallidus (3.56 microg/g vs. 1.33 microg/g) were significantly higher in the exposed group compared to the control group (p <.05). No difference was observed in liver, kidney, testes, and caudate putamen between the two groups. Neuronal cell loss was assessed by neuronal cell counts. The loss of cells in globus pallidus and caudate putamen as well as in frontal cortex was significantly higher (p <.05) for the EXP group. Assessment of the locomotor activities did not reveal any significant difference. This study constitutes a first step toward our understanding of the potential adverse effects of Mn in sensitive populations.

Administration, Inhalation↗
PubMed2001

Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis.

Patients with fulminant hepatic failure (FHF) die with brain edema, exhibiting an increased cerebral blood flow (CBF) at the time of cerebral swelling. Mild hypothermia prevents brain edema in experimental models and in humans with FHF, an effect associated with normalization of CBF. To study the effects of alterations of CBF on the development of brain edema, we administered intravenous (IV) indomethacin to rats receiving an ammonia infusion after portacaval anastomosis. This model predictably develops brain edema and a marked increase in CBF at 3 hours of infusion. Brain water was measured with the gravimetry technique; CBF was monitored with both laser Doppler flowmetry and radioactive microspheres, whereas intracranial pressure (ICP) was monitored with a cisterna magna catheter. Coadministration of indomethacin prevented the increase in CBF seen with ammonia alone (110 +/- 19% vs. -2 +/- 9%) as well as the increase in brain water (80.86 +/- 0.12% vs. 80.18 +/- 0.06%) and the increase in ICP. Plasma ammonia and brain glutamine levels were markedly elevated in the ammonia-infused group and unaffected by indomethacin. However, ammonia uptake by the brain was significantly reduced by indomethacin. Levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, were reduced in the cerebrospinal fluid (CSF) of indomethacin-treated animals. As with mild hypothermia, avoiding cerebral vasodilatation with indomethacin will prevent the development of brain edema in this hyperammonemic model. Cerebral vasoconstriction reduces cerebral ammonia uptake and, if selective to the brain, may be of benefit in FHF.

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Monitoring of brain water by chemical shift imaging during ammonia-induced brain swelling in rats after portacaval anastomosis.

Brain edema is a leading cause of death in acute liver failure (ALF). In experimental models of ALF, an increase in the content of brain water has been inferred indirectly by measuring intracranial pressure or determined directly via analysis of brain tissue postmortem. In this study, noninvasive proton two-dimensional chemical shift imaging (2-D CSI) was used to follow the time course of the development of brain edema in a well characterized model, namely ammonium acetate infusion into rats 48 to 72 h after portacaval anastomosis (PCA). Clear differences between control and experimental rat brains were observed, with an increase of brain water signal only in the parietal cortex of the PCA + ammonia group. Selective swelling of the cerebral cortex points to a cytotoxic mechanism in the evolution of brain edema in this model. CSI signal enhancement was much greater than the gravimetrically determined water content increase. The significantly greater signal change observed with 2-D CSI may reflect enhanced proton density that results from increased water content as well as edema-related alterations in water relaxation times.

Ammonia↗
PubMed2001

Time-dependent modifications of splanchnic circulation in female pigs submitted to end-to-side portacaval anastomosis.

Fractional systemic bioavailability of orally administered drugs was found to be unexpectedly low in liver cirrhosis, even after surgical portal-systemic shunting. Fecal loss or intestinal first-pass elimination were assumed to explain the finding. In this paper we evaluated alternative pathophysiological interpretations relating low bioavailability to adaptive circulatory modifications. D-Sorbitol was used because its hepatic extraction is very high and hepatic removal follows a flow-dependent clearance regimen. D-Sorbitol bioavailability was measured at steady state in pigs submitted to end-to-side portacaval anastomosis, immediately after surgery and four weeks later. Intestinal first-pass elimination dependent on fecal loss and intraluminal degradation was excluded by administering D-sorbitol into the superior mesenteric artery. Almost complete bioavailability was observed immediately after surgery (N = 6, 0.96+/-0.08); four weeks later the bioavailability dropped (-36.8+/-18.7%; P < 0.001) while hepatic clearance significantly increased (+83.6+/-47.9%; P < 0.01). Experimental data support the hypothesis that adaptive circulatory changes spontaneously occur after some time, leading to a lower than expected portal bioavailability.

Animals↗