Inhibition of Rat Brain Na+,K+−ATPase Activity by Serum from Patients with Fulminant Hepatic Failure†

Seda, H.; Hughes, Robin D.; Gove, Christopher D.; Williams, Roger

doi:10.1002/hep.1840040113

Cited by 51 publications

(9 citation statements)

References 24 publications

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“…The accumulation of two distinct intracellular osmoles has been proposed to account for the initial brain swelling in FLF. An increase of intracellular Na+ would occur as a result of circulating factors that inhibit the activity of Na+-K' ATPase (11). Consistent with this view, the measured digoxin-like immunoreactivity present in the serum of these patients was thought to reflect this inhibitory activity (12).…”

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confidence: 63%

Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis

et al. 1994

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Brain edema, leading to intracranial hypertension and brain herniation, is a major cause of death in fulminant liver failure. Astrocyte swelling is a prominent neuropathological feature in experimental fulminant liver failure. It has been postulated that the osmotic effects of glutamine, generated in astrocytes from ammonia and glutamate in a reaction catalyzed by glutamine synthetase, could mediate brain swelling. Normal rats and rats that received a portacaval anastomosis were infused with ammonium acetate or a sodium acetate control; brain water in cerebral cortex was measured with the gravimetry method, intracranial pressure by means of a cisterna magna catheter and cortical amino acids using high-performance liquid chromatography. Although brain edema was detected in both groups receiving ammonia, it was of a greater magnitude in portacaval anastomosis rats (80.94% + 0.17% vs. 80.24% + 0.09%, p < 0.01), resulting in the development of intracranial hypertension. When portacaval anastomosis rats were infused with ammonium acetate and pretreated with 150 mg/kg methionine-sulfoximine, an inhibitor of glutamine synthetase activity, brain edema was ameliorated and intracranial pressure did not rise. A dose-dependent reduction in brain glutamine levels was seen with increasing doses of methionine-sulfoximine; however, brain edema did not decrease beyond the 150 mg/kg dose, suggesting that the increase in brain water was not solely a result of glutamine accumulation. We conclude that brain edema of a magnitude that results in intracranial hypertension is more likely to develop in rats after portacaval anastomosis receiving a continuous ammonia infusion. The osmotic effects of glutamine appear to mediate, but only in part, the increase in brain water seen in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

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confidence: 63%

Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis

et al. 1994

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“…These samples were applied to a Sephadex G25 column (Pharmacia Ltd., Milton Keynes, UK; column length = 80 cm; internal diameter = 2.5 cm) eluted downward with ammonium bicarbonate solution (0.1 mole per liter, pH 7.9). Fractions were collected from the main peaks, which were numbered 1 to 8 as used in our previous studies (22,23) in 25 ml aliquots and freeze-dried twice to remove the volatile ammonium ions. The individual peaks were reconstituted in 1 ml distilled water immediately before assay for DLIS.…”

Section: Methodsmentioning

confidence: 99%

Digoxin-like immunoreactive substances in severe acute liver disease due to viral hepatitis and paracetamol overdose

1988

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The levels of endogenous serum digoxin-like immunoreactive substances were investigated during development of encephalopathy in patients with fulminant hepatic failure. The 67 patients studied had varying degrees of hepatic failure as a result of viral hepatitis or paracetamol overdose. Serum levels of digoxin-like immunoreactive substances were significantly increased in both viral hepatitis and paracetamol overdose, with mean values of 0.42 +/- S.D. 0.25 ng per ml (n = 36) and 0.53 +/- 0.19 ng per ml (n = 31), respectively, as compared to normal control subjects with mean values of 0.01 +/- 0.02 ng per ml (n = 21, p less than 0.001). A statistically significant correlation was found between serum digoxin-like immunoreactive substances and the degree of encephalopathy in the viral hepatitis patients and with the serum creatinine in the paracetamol overdose patients where renal failure was more severe. No correlation was found with liver damage as assessed by the prolongation of the prothrombin time, serum AST or bilirubin values. Experiments with ultrafiltration and heating showed that both free nonprotein-bound digoxin-like immunoreactive substances and the total digoxin-like immunoreactive substances measured were increased. Column chromatography of ultrafiltrates of fulminant hepatic failure serum on Sephadex G-25 demonstrated at least two peaks with digoxin-like immunoreactive activity. Reduced renal function is an important factor in the increased serum level of digoxin-like digoxin-like immunoreactive substances, but their presence due to liver failure, where there is increased permeability of the blood-brain barrier, could be relevant to the development of hepatic encephalopathy.

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“…Other studies from our group have provided evidence for cytotoxic edema in fulminant hepatic failure as a result of inhibition of cellular sodium transport. Patients' sera contain substances that inhibit Na+,K+-ATPase enzyme activity in brains of normal rats in uitro (26); also, inhibition of brain Na+,K+-ATPase was observed in rats with galactosamineinduced liver failure (27). Cytotoxic substances could affect the function of both astrocytes and endothelial cells and thus be involved in the ultrastructural abnormalities observed.…”

Section: Figmentioning

confidence: 99%

Electron Microscopic Study of Brain Capillaries in Cerebral Edema From Fulminant Hepatic Failure

et al. 1992

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Cerebral edema is a serious complication of the encephalopathy in fulminant hepatic failure. It is a major cause of death. The mechanisms responsible for its formation are unclear, and the aim of this study was to investigate the ultrastructural appearance of brain capillaries by scanning electron microscopy. Samples of cerebral cortex were obtained immediately after death from nine patients with fulminant hepatic failure (seven cases due to acetaminophen overdose, one caused by hepatitis B and one caused by non-A, non-B hepatitis) by needle biopsy at the site of insertion of an extradural pressure transducer to monitor intracranial pressure. The intercellular tight junctions between capillary endothelial cells were intact. The endothelial cells were swollen, with increased numbers of vesicles and vacuoles. The basement membranes were enlarged and vacuolized and the pericytes had increased numbers of vesicles and vacuoles, indicative of passage of fluid by this route. Marked intracellular swelling of the perivascular astroglial foot processes was present. Thus mainly cytotoxic mechanisms, with cellular swelling, and to a lesser extent vasogenic mechanisms, with altered blood-brain barrier permeability, appear to be involved in the cerebral edema of fulminant hepatic failure.

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Inhibition of Rat Brain Na+,K+−ATPase Activity by Serum from Patients with Fulminant Hepatic Failure†

Cited by 51 publications

References 24 publications

Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis

Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis

Digoxin-like immunoreactive substances in severe acute liver disease due to viral hepatitis and paracetamol overdose

Electron Microscopic Study of Brain Capillaries in Cerebral Edema From Fulminant Hepatic Failure

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