Portacaval Shunted Rats Research Articles

Central Vs. Peripheral Spontaneous Behavioral Abnormalities in Experimental Hepatic Encephalopathy

Apelqvist, G., B. Hindfelt, G. andErsson and F. Bengtsson. Central vs. peripheral spontaneous behavioral abnormalities in experimental hepatic encephalopathy. Physiol Behav 61(6) 851–856, 1997.—The most common behavioral disturbance reported in experimental chronic hepatic encephalopathy (HE) refers to changes in spontaneous activities in an open field in the portacaval-shunted (PCS) rat. A major problem at present is that not all of these findings of abnormal PCS behavior are in agreement. We, therefore, investigated the total, central, and peripheral locomotor and rearing activities in an open field 2 and 6 months after PCS surgery. The results revealed that, 2 months after surgery, locomotor and rearing activities were lower in PCS rats compared to controls. At 6 months, a partial remission of the behaviors had occurred. Clearly though, as pointed out by the peripheral behavioral recordings, the hypoactivity persisted and, interestingly, central locomotor activity as higher in PCS rats than in controls. This novel finding may be attributed to the special study of central vs. peripheral components of the spontaneous open-field behavior in experimental chronic HE. Our observations may also help explain some of the seemingly discrepant results available in the literature.

Effects of Simulated Upper Gastrointestinal Hemorrhage on Ammonia and Related Amino Acids in Blood and Brain of Chronic Portacaval-shunted Rats

Effects of Simulated Upper Gastrointestinal Hemorrhage on Ammonia and Related Amino Acids in Blood and Brain of Chronic Portacaval-shunted Rats

Elevated brain 5-hydroxytryptophol levels in experimental portal-systemic encephalopathy.

Brain tissue levels of the two serotonin metabolites 5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured in porta-caval shunted rats, an in vivo model of portal-systemic encephalopathy. An intraperitoneal challenge of L-tryptophan (280 mg/kg body weight) to sham-operated rats was also instituted to increase the brain serotonin metabolism in these rats. The results revealed significant increases in 5-hydroxytryptophol (by 31% and 5-HIAA (by 87%) brain levels in porta-caval shunted rats as compared to sham-operated controls. The brain 5-hydroxytryptophol-to-5-HIAA ratio was lower in the porta-caval shunted rats. The 5-hydroxytryptophol levels in sham rats after the L-tryptophan challenge were intermediate between the porta-caval shunted and sham rats but not statistically significant for either group. These results suggest that increased brain 5-hydroxytryptophol levels might be associated with the pathogenesis of portal-systemic encephalopathy. Further, the elevated brain 5-hydroxytryptophol levels in experimental portal-systemic encephalopathy are probably a result of the increased brain serotonin metabolism prevailing in this condition rather than changes in the brain redox potential.

The portacaval-shunted rat: a new model for the study of the mechanisms controlling voluntary ethanol consumption and ethanol preference?

Portacaval anastomosis (PCA) is a surgical procedure whereby blood from the portal vein is shunted into the inferior vena cava. PCA in the rat results in a significant increase (from 0.77 +/- 0.26 to 3.51 +/- 0.37 g of ethanol/kg/day) in voluntary ethanol consumption in a free-choice paradigm between water and 5% ethanol solution. After PCA surgery, increased voluntary ethanol consumption starts abruptly at 6 to 7 days and is maintained for > 28 weeks. Voluntary ethanol consumption in rats after PCA results in blood ethanol levels up to 158 mg%. After PCA, the ethanol preference ratio (defined as the percentage of total fluid intake constituted by ethanol) increased from 19 +/- 2% to 78 +/- 2% (P < 0.001). Administration of the nonselective opioid receptor antagonist naloxone (5 mg/kg, sc) resulted in a significant 6-fold attenuation of voluntary ethanol consumption by rats with PCA, an effect that was not mediated by an effect on locomotor activity. These findings, together with previous reports of widespread alterations of the mu- and delta-opioid receptors in the brain after PCA, suggest that increased voluntary ethanol consumption and ethanol preference in PCA rats may result from activation of the endogenous opioid system. Preliminary studies suggest that rats with PCA manifest behavioral signs consistent with the development of dependence. The portacaval-shunted rat may provide a useful preparation for the study of mechanisms, in particular those involving the liver, implicated in the development of increased voluntary ethanol consumption and ethanol preference.

Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats.

The aim of this study was to investigate the possible role of N-methyl-D-aspartate (NMDA)-receptor overactivity in two different experimental rat models of encephalopathy: subacute encephalopathy caused by severe hyperammonemia in portacaval-shunted rats (AI-PCS rats) and acute hepatic encephalopathy caused by complete liver ischemia (LIS rats). The effect of the noncompetitive NMDA-receptor antagonist memantine (intraperitoneal [i.p.] 10-20 mg/kg bw or intravenous [i.v.] 5 mg/kg bw) was studied on the severity of encephalopathy by assessment of clinical grading and electroencephalogram (EEG) spectral analysis, on plasma ammonia concentrations, amino acid concentrations in cerebrospinal fluid (CSF), intracranial pressure (ICP), and brain water content. Both rat models developed encephalopathy within 3 to 6 hours, associated with increased CSF glutamate and aspartate concentrations and increased ICP and brain water content. Memantine administration in AI-PCS and LIS rats resulted in a significant improvement in clinical grading and less slowing of EEG activity (P < .05), and smaller increases in CSF glutamate (P < .05) concentrations. Moreover, ICP and brain water content were significantly lower in memantine-treated AI-PCS rats than in untreated AI-PCS rats (P < .05). Memantine had no significant effect on ICP and brain water content in LIS rats, and on ammonia concentrations in both models. These results indicate that NMDA-receptor activation might be involved in the pathogenesis of hyperammonemia-induced encephalopathy and of acute hepatic encephalopathy caused by LIS.

Protective effect of L-carnitine in ammonia-precipitated encephalopathy in the portacaval shunted rat.

L-carnitine administration prevents the neurological symptoms of acute ammonia toxicity. To further evaluate its efficacy in the prevention of hepatic encephalopathy in hyperammonemic conditions, L-carnitine (16 mmol/kg, intraperitoneally [i.p.] was administered 1 hour before ammonium acetate (NH4OAc) (8.5 mmol/kg, subcutaneously) to portacaval shunted (PCS) rats. Cerebrospinal fluid (CSF) ammonia, lactate, and amino acid levels were measured in relation to deteriorating neurological status in these animals. None of 35 L-carnitine-treated animals showed neurological deterioration after NH4OAC administration compared with saline-treated controls; the latter manifested severe encephalopathy progressing through loss of righting reflex to coma. Survival rate was 100% in the L-carnitine-treated group compared with 5% in saline-treated controls. Following NH4OAC administration to PCS rats, CSF ammonia increased to 0.93 +/- 0.15 mmol/L and 1.24 +/- 0.15 mmol/L at precoma and coma stages of encephalopathy (P < .01) respectively. Treatment with L-carnitine reduced CSF ammonia at both precoma and coma stages; the time-course of this protective effect paralleled blood and CSF L-carnitine accumulation. CSF alanine and lactate increases following NH4OAC administration to PCS rats were significantly attenuated following L-carnitine treatment. However, L-carnitine treatment did not lead to significant reductions in plasma ammonia nor CSF or brain glutamine in these animals. These findings show the therapeutic efficacy of L-carnitine in ammonia-precipitated coma in PCS rats and suggest that this protective effect is centrally mediated involving improved mitochondrial respiration. L-carnitine could be of therapeutic benefit in the prevention of hepatic encephalopathy precipitated by ammoniagenic conditions in humans with chronic liver disease.

Gender and diurnal effects on specific open-field behavioral patterns in the portacaval shunted rat.

Hepatic encephalopathy (HE) is a frequently observed neuropsychiatric syndrome with unknown pathogenesis in patients suffering from chronic liver failure. The portacaval shunted (PCS) rat has been extensively used as an experimental model for HE and for studying the effects of portal-systemic shunting. Previous behavioral studies on PCS rats have shown a number of abnormalities but there is no consensus about which abnormalities are characteristic. We therefore made a thorough descriptive study of 100 male and female PCS rats and sham-operated controls four to six weeks after the shunting procedure in an open field. The frequency, duration and average time sequence of various kinds of defined spontaneous behavioral patterns were investigated during both night and day in order to assess behavioral differences between PCS rats and sham-operated controls. The results indicate differences especially regarding motor exploratory behaviors such as forward locomotion and rearing. There were also differences in eating and sniffing behaviors. Our results show that the overall behavioral alteration seen in PCS rats compared to sham-operated controls is that of hypoactivity.

Increased expression of cholecystokinin-A receptor mRNA in pancreas and cholecystokinin-B receptor mRNA in oxyntic mucosa after porta-caval shunting in rats.

Porta-caval shunting enhances the trophic effects of cholecystokinin (CCK)-A receptor activation on the pancreas and of CCK-B receptor activation on the ECL cells in the oxyntic mucosa of the rat. The aim of the present study was to study the expression of CCK-A and CCK-B receptor mRNA after porta-caval shunting. Different doses of sulfated CCK-8 (CCK-8s) were administered to porta-caval shunting rats and sham-operated rats, 4 weeks after the operations. The pancreatic wet weight and DNA content were measured and the ECL cells in the oxyntic mucosa were counted after four days of continuous subcutaneous infusion. Total RNA was isolated from pancreas and oxyntic mucosa for Northern blot analysis of CCK-A and CCK-B receptor mRNA. Porta-caval shunting per se did not affect plasma CCK level nor the weight or DNA content of the pancreas, but resulted in increased number of ECL cells despite the fact that the serum gastrin concentration was reduced. The trophic response of the pancreas to low doses of CCK-8s was greater in porta-caval shunted rats than in sham-operated rats. Porta-caval shunted rats displayed an increased CCK-A receptor mRNA concentration in the pancreas (after stimulation with CCK-8s) and an increased CCK-B receptor mRNA concentration in the oxyntic mucosa. In conclusion, the porta-caval shunting-evoked enhancement of the trophic effect of CCK-A receptor activation on the pancreas and of CCK-B receptor activation on the ECL cells is associated with enhanced expression of CCK-A receptor mRNA in the pancreas and of CCK-B receptor mRNA in the oxyntic mucosa.

Precipitation of overt encephalopathy in the portacaval shunted rat: towards the development of an adequate model of chronic portal systemic encephalopathy.

To assess the feasibility of developing a model of overt portal-systemic encephalopathy (PSE) in rats with a surgically constructed portacaval anastomosis (PCA). The ability of increasing the load of nitrogenous substances in the gastrointestinal tract and/or further decreasing hepatocellular function to induce overt encephalopathy in rats with a PCA was determined. The load of nitrogenous substances in the gastrointestinal tract was increased by feeding a pure horse-meat diet or by gavaging with blood. Partial hepatectomy and the induction of cirrhosis were used to decrease hepatocellular function further. The severity of encephalopathy was assessed using a neurobehavioural scale. Overt encephalopathy was not induced in rats by a PCA alone, by a PCA plus a horse-meat diet, by a PCA plus induction of cirrhosis, or by a PCA plus a 50% hepatectomy. Predominantly mild, but overt, encephalopathy was induced in rats with a PCA alone by gavaging with blood and a higher incidence of more severe overt encephalopathy was induced in rats with a PCA combined with either cirrhosis or partial hepatectomy by gavaging with blood. Although these models of PSE were associated in some instances with plasma ammonia concentrations about 25 times higher than normal, no seizures were observed. A syndrome that resembles overt PSE in humans can be induced in the rat with a PCA by further reducing hepatocellular function and also gavaging with blood. Although the rat with a PCA has been. extensively used as a model in studies relating to the pathogenesis of PSE, a syndrome resembling overt PSE in humans cannot readily be induced in rats with a PCA.

Decreased plasma and tissue isoleucine levels after simulated gastrointestinal bleeding by blood gavages in chronic portacaval shunted rats.

Previously, arterial concentrations of the essential branched chain amino acid isoleucine (Ile) were found to have decreased by more than 50% after gastrointestinal haemorrhage in patients and after intragastric blood administration in healthy humans and pigs. Hypothetically, this induced hypoisoleucinaemia could deplete tissue Ile pools. To study the effect of repeated blood gavages on arterial and tissue Ile levels during normal and impaired liver function. Male Wistar rats. 14 days after portacaval shunting or sham surgery, rats received 3 ml bovine erythrocytes or saline at 0, 1, 2, and 3 hours via a gastrostomy catheter in the duodenum. At 0, 2, 4, 6 and 8 hours arterial blood and at 8 hours intestine, liver, muscle, and cerebral cortex were sampled for determination of ammonia and amino acid concentrations. In both groups repeated blood administration resulted in a marked decrease in plasma Ile (40-60%). This was accompanied by decreased tissue Ile concentrations in liver (50%), muscle (40-60%), and cerebral cortex (40-50%), but unaltered intestinal Ile levels. In contrast, the arterial and tissue concentrations of ammonia, urea, and of most amino acids increased, most strikingly of the other two branched chain amino acids, valine and leucine. Simulated gastrointestinal bleeding by blood gavages in rats with and without impaired liver function leads to hypoisoleucinaemia and decreased tissue Ile pools.

Biliary Excretion of 400– to 1,000–D Polyethylene Glycol Will Influence the Calculation of Small Intestinal Absorption in Portacaval–Shunted Rats

HepatologyVolume 25, Issue 2 p. 500-500 CorrespondenceFree Access Biliary excretion of 400- to 1,000-d polyethylene glycol will influence the calculation of small intestinal absorption in portacaval-shunted rats S Friman, S FrimanSearch for more papers by this authorJ Svanvik, J SvanvikSearch for more papers by this author S Friman, S FrimanSearch for more papers by this authorJ Svanvik, J SvanvikSearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1002/hep.510250243Citations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Panzar N, Bergqvist P, Bugge M, Olaison G, Lundin S, Jeppsson B, Weström B, et al. Small intestine absorption of polyetethylene glycol 400 to 1,000 in the portacaval shunted rat. Hepatology 1995; 21: 1167– 1173. 2 Friman S, Leanderson P, Tagesson C, Svanvik J. Biliary excretion of different sized polyethylene glycols in the cat. J Hepatol 1990; 11: 215– 220. 3 Friman S, Egestad B, Sjövall J, Svanvik J. Hepatic excretion and metabolism of polyethylene glycols and mannitol in the cat. J Hepatol 1993; 17: 48– 55. 4 Lake JR, Licko V, van Dyke RN, Scharschmidt BF. Biliary secretion of fluid–markers by the isolated perfused rat liver. J Clin Invest 1985; 76: 676– 684. 5 Friman S, Rådberg G, Svanvik J. Hepatic clearance of polyethylene glycol 900 and mannitol in the pig. Digestion 1988; 29: 172– 180. 6 Friman S, Persson H, Karlberg I, Svanvik J. The bile acid independent flow is reduced in the transplanted liver. Transplant Int 1992; 5: S163– S167. Citing Literature Volume25, Issue2February 1997Pages 500-500 ReferencesRelatedInformation

The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy

Background/Aims: The pathogenetic factors contributing to encephalopathy in portracaval shunted rats with hyperammonaemia were studied. Methods: Hyperammonaemia was induced by ammonium-acetate infusions in portacaval shunted rats (2.8 mmol·kg bw −1·h −1; AI-portacaval shunted rats) and in sham-portacaval shunted rats (6.5 mmol·kg bw −1; AI-NORM rats). Severity of encephalopathy was qualified by clinical grading and EEG spectral analysis. Changes in brain metabolites were assessed by amino acid analysis of brain cortex homogenates, whereas changes in amino acids with neurotransmitter activity were assessed in cerebrospinal fluid; brain water content was measured by subtracting dry from wet brain weights and intracranial pressure was measured by a pressure transducer connected to a cisterna magna cannula. Results: Although similar increased blood and brain ammonia concentrations were obtained in both experimental groups, only AI-portacaval shunted rats developed encephalopathy, associated with a significant increase in intracranial pressure. Other significant differences were: higher concentrations of brain glutamine and aromatic amino acids, higher concentrations of cerebrospinal fluid glutamine, aromatic amino acids, glutamate and aspartate in AI-portacaval shunted rats than in AI-NORM rats. Conclusions: These results indicate that hyperammonaemia alone does not induce encephalopathy, whereas portal-systemic shunting adds an essential contribution to the pathogenesis of encephalopathy. It is hypothesised that the larger increase in brain glutamine in AI-portacaval shunted rats than in AI-NORM rats is responsible for increased brain concentrations of aromatic amino acids, for cell swelling and for extracellular release of glutamate and aspartate. This might promote encephalopathy. If cell swelling is not restricted, intracranial hypertension will develop

Biliary excretion of 400- to 1,000-d polyethylene glycol will influence the calculation of small intestinal absorption in portacaval-shunted rats

Biliary excretion of 400- to 1,000-d polyethylene glycol will influence the calculation of small intestinal absorption in portacaval-shunted rats

L-Ornithine vs. L-ornithine-L-aspartate as a treatment for hyperammonemia-induced encephalopathy in rats

Background/Aims: The effect of L-ornithine (ORN) and L-ornithine-L aspartate (OA) therapy on “extracerebral” nitrogen metabolism, brain metabolism and neutrotransmission has been investigated in portacaval shunted rats with hyperamonemia-induced encephalopathy. Methods: One day before ammonium-acetate influsion, a portacaval shunt was performed in three experimental groups: 1 - control rats, 2 - ORN-treated rats and 3 - OA-treated rats. Ammonium-acetate was given as an intravenous bolus injection (0.4 mmol·kg bw −1 followed by a constant infusion (1.9 mmol·kg bw −1·h −1) so that steady-state blood ammonia concentrations (500–800 μM) were obtained in the course of 5 h. After 1 h, ammonium-acetate infusion, either L-ornithine or L-ornithine-L-aspartate, was infused for the next 4 h (3.0 mmol·kg bw −1·h −1) in the treated groups. The following parameters were measured: clinical grade of encephalopathy, EEG activity ( n=10–20/group), amino acids in plasma ( n=10–20/group) and brain dialysate ( n=5–9/group), and brain metabolites obtained by in vivo cerebral 1H-MRS ( n=4–6/group). Results: ORN and OA treatment resulted in significantly lower blood (34% and 39%) ad brain (42% and 22%) ammonia concentrations, significantly higher urea production (39% and 86%) and significantly smaller increases in brain glutamine and lactate concentrations than in controls. The changes were associated with a significantly smaller increase in clinical grade of encephalopathy in ORN- and OA-treated rats, and a significant improvement in EEG activity in ORN-treated rats. OA-treated rats showed a significant increase in aspartate and glutamate concentrations in brain dialysate. Conclusions: The beneficial effects of both treatments on the manifestations of hyperammonemia-induced encephalopathy can be explained by a reduction in blood and brain ammonia concentrations. It is suggested that when OA is administered, the effect of ornithine is partly counteracted by aspartate, inducing high brain extracellular concentrations of the two excitatory amino acids glutamate and aspartate, and perhaps causing overstimulation of NMDA receptors.

In vitro ammonia utilization and urea synthesis by rat liver after portacaval shunt.

The objective of this study was to study in vitro ammonia utilization and urea synthesis by the rat liver after portacaval shunt (PCS) in comparison to controls. This study is part of a series of experiments to investigate metabolic derangements in the liver following PCS. Sixteen male Wistar rats weighing 150-230 g were used. PCS was performed on 8 and the rest served as sham-operated controls. The experiments were performed 4 weeks postoperatively. The usually monitored postoperative parameters after PCS like body weight, rise in ammonia levels in the peripheral blood, atrophy of mesenteric fat, atrophy of the liver, etc., were comparable to other PCS series. Liver slices (1 x 2 x 1 mm) were prepared from each rat liver and incubated in Krebs-Henseleit buffer. After incubation, ammonia utilization in the controls was 162.88+/-20.12 micromol/g dry weight/h while in PCS rats it was 81.35+/-2.64 micromol/g dry weight/h (p < 0.0001). The rate of urea synthesis in controls was 122.54+/-12.93 micromol/g dry weight/h whereas in the PCS group it was 14.99+/-2.21 micromol/g dry weight/h (p < 0.0001). These results indicate a significant decline in the capacity of the liver for ammonia utilization as well as urea synthesis after PCS.

Portacaval shunting and hyperammonemia stimulate the uptake of L-[3H] arginine but not of L-[3H]nitroarginine into rat brain synaptosomes.

Elevated activities of nitric oxide synthase (NOS) have been reported previously in the brains of portacaval-shunted (PCS) rats, a model of chronic hepatic encephalopathy (HE). As L-arginine availability for nitric oxide synthesis depends on a specific uptake mechanism in neurons, we studied the kinetics of L-[3H]-arginine uptake into synaptosomes prepared from the brains of PCS rats. Results demonstrate that L-arginine uptake is significantly increased in cerebellum (60%; p < 0.01), cerebral cortex (42%; p < 0.01), hippocampus (56%; p < 0.01), and striatum (51%; p < 0.01) of PCS rats compared with sham-operated controls. Hyperammonemia in the absence of portacaval shunting also stimulated the transport of L-[3H]arginine; kinetic analysis revealed that the elevated uptake was due to increased uptake capacity (Vmax) without any change in affinity (Km). Incubation of cerebellar synaptosomes with ammonium acetate for 10 min caused a dose-dependent stimulation of L-[3H]arginine uptake. Neither portacaval shunting nor hyperammonemia had any significant effect on the synaptosomal uptake of NG-nitro-L-[3H]arginine. These studies demonstrate that increased NOS activity observed in experimental HE may result from increased availability of L-arginine resulting from a direct stimulatory effect of ammonia on L-arginine transport.

Long-term changes in glial fibrillary acidic protein and glutamine synthetase immunoreactivities in the supraoptic nucleus of portacaval shunted rats.

The present study was undertaken to ascertain whether, and to what extent, glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) expressions in the supraoptic nucleus (SON) could be modulated after one month and six months of portacaval shunting (PCS) in rats. GFAP and GS immunoreactivities were significantly higher in PCS rats than in control rats at one and six months. The increased GFAP and GS immunoreactivities observed in the SON astrocytes were directly related to the duration of PCS. In PCS rats, the number and length of both GFAP and GS immunopositive astroglial processes increased not only in the hypothalamic nucleus but in the perinuclear zone, where glutamatergic pathways have been described, whereas GFAP and GS expressions decreased in the ventral glial lamina. Since GS is one of the glutamate metabolizing enzymes and the SON is one of the areas of glutamatergic activity, our results show that astrocytes respond differentially to glutamate toxicity. This suggests that overexpression of GFAP and GS immunoreactivities could be associated with glutamatergic neurotransmission disorders.

Reversal of portacaval shunting normalizes brain energy consumption in most brain structures.

The cerebral metabolic rate of glucose consumption (CMRGlc) was measured throughout brains of rats with 1) portacaval shunts created for 2 wk, followed by restoration of normal blood circulation for 2 wk; 2) portacaval shunts created for 2 wk, followed by a sham operation and 2 wk of recovery; 3) two sham operations, each with 2 wk of recovery times. Portacaval-shunted rats had diminished CMRGlc (decreases of 7-23%) throughout the brain in agreement with previous studies. After restoration of normal liver blood flow, the CMRGlc of most structures returned to near-normal values, although a few structures, notably the hippocampus, remained 11-13% lower. These data suggest that the consequences of portacaval shunting to brain energy metabolism can be markedly improved, if not completely reversed, by restoring the normal pattern of blood flow to an otherwise healthy liver. Other metabolic and physical data collected (liver weight, liver-to-body weight, plasma ammonia) returned to normal except plasma glucose concentrations, which remained lower by 11%, suggesting a persistent, albeit mild, defect in glucose homeostasis.

Ammonium acetate challenge in experimental chronic hepatic encephalopathy induces a transient increase of brain 5-HT release in vivo

Ammonia has been shown to cause release of neurotransmitters such as serotonin (5-hydroxytryptamine; 5-HT) from synaptosomal preparations in vitro. In the present study, frontal neocortical extracellular levels of 5-HT and its major metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), were determined in vivo by the use of microdialysis in portacaval shunted (PCS) rats, an experimental model of chronic hepatic encephalopathy (HE), prior to and after an acute coma-inducing administration of ammonium acetate (NH 4Ac; 5.2 mmol/kg, i.p.). PCS rats displayed elevated ( P<0.01) 5-HIAA but unaltered 5-HT extracellular levels compared with controls, supporting the contention of an increased neocortical 5-HT metabolism but unaltered neuronal 5-HT output in chronic HE. However, a transient elevation of extracellular 5-HT levels was observed when PCS-NH 4 Ac rats were in coma. Increased brain ammonia may thus augment neuronal 5-HT release in chronic HE, which in turn could be a causative factor for precipitation of more severe stages of HE.

Brain extracellular quinolinic acid in chronic experimental hepatic encephalopathy as assessed by in vivo microdialysis: Acute effects of L-tryptophan

Increased brain quinolinic acid (QUIN) levels have been suggested to play a role in hepatic encephalopathy (HE). Previous brain tissue studies have been unable to confirm this hypothesis. Because QUIn is a potent NMDA-receptor agonist, it also is relevant to determine brain extracellular QUIN levels in HE. For this purpose, we assessed frontal neocortical extracellular QUIN levels by in vivo microdialysis in rats subjected to a portacaval shunt (PCS). We also evaluated the acute effects of altered L-tryptophan (L-TRP) availability on brain extracellular QUIN levels. The basal extracellular L-TRP levels were significantly (p < .001) higher in the PCS rats than in the sham-operated controls. However, the QUIN level (p < .05) and the QUIN to L-TRP ratio (p < .01) were significantly lower in the PCS rats. Elevated L-TRP availability increased the QUIN levels to a similar degree in both sham and PCS rats. This study, in conjunction with our previous results, does thereby not support a major involvement of QUIN in the pathogenesis of HE.