Evidence for altered central noradrenergic function in experimental acute liver failure in the rat

Michalak, Adrianna; Rose, Christopher F.; Buu, Paul; Butterworth, Roger F.

doi:10.1002/hep.510270208

Cited by 22 publications

(15 citation statements)

References 38 publications

(46 reference statements)

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“…The finding of decreased transporter sites in frontal cortex of rats with acute liver failure due to hepatic devascularization offers a cogent explanation for the findings in a previous (and the present) study of increased NA concentrations in brain extracellular fluid of these animals at coma stages of encephalopathy (Michalak et al, 1998). Similar mechanisms could be implicated in hepatectomized rats in which significant increases of NA were described in ventriculocisternal perfusates (McKinzie et al, 1996).…”

Section: Discussionsupporting

confidence: 84%

“…Administration of noradrenergic receptor antagonists to experimental animals results in delayed acquisition of motor tasks (Heron et al, 1996). A previous study showed a selective loss of α and β noradrenergic receptor sites in brains of rats with acute liver failure (Michalak et al, 1998) where loss of adrenergic sites was restricted to frontal cortex and thalamus, brain regions shown, in the present study, to express decreased amounts of NA transporter sites in acute liver failure. Together, these findings suggest that acute liver failure may result in a deficit in central NA synaptic regulation.…”

Section: Discussionsupporting

confidence: 62%

“…NA concentrations were measured by HPLC with electrochemical detection as previously described (Michalak et al, 1998).…”

Section: Measurement Of Na In Microdialysatesmentioning

confidence: 99%

“…Studies in several animal models of acute liver failure including hepatectomy (Hadesman et al, 1995, Tyce and Owen, 1978and Herlin et al, 1983, liver devascularization (Murakami et al, 1992) and thioacetamide-induced liver injury (Yurdaydin et al, 1990) in the rat have consistently shown decreases in brain tissue concentrations of noradrenaline (NA). Moreover, hepatectomy results in increased NA release in ventriculocisternal perfusates (McKinzie et al, 1996) and in vivo microdialysis studies have shown that liver devascularization results in increased extracellular brain concentrations of NA as a function of the severity of encephalopathy (Michalak et al, 1998). These latter two findings could be the consequence of impaired high affinity uptake of NA into neural cells.…”

Section: Introductionmentioning

confidence: 99%

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Loss of noradrenaline transporter sites in frontal cortex of rats with acute (ischemic) liver failure

Michalak

Rose

Butterworth

2001

Neurochemistry International

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There is increasing evidence that central noradrenaline (NA) transport mechanisms are implicated in the central nervous system complications of acute liver failure. In order to assess this possibility, binding sites for the high affinity NA transporter ligand [3 H]-nisoxetine were measured by quantitative receptor autoradiography in the brains of rats with acute liver failure resulting from hepatic devascularization and in appropriate controls. In vivo microdialysis was used to measure extracellular brain concentrations of NA. Severe encephalopathy resulted in a significant loss of [ 3 H]-nisoxetine sites in frontal cortex and a concomitant increase in extracellular brain concentrations of NA in rats with acute liver failure. A loss of transporter sites was also observed in thalamus of rats with acute liver failure. This loss of NA transporter sites could result from depletion of central NA stores due to a reserpine-like effect of ammonia which is known to accumulate to millimolar concentrations in brain in ischemic liver failure. Impaired NA transport and the consequent increase in synaptic concentrations and increased stimulation of neuronal and astrocytic noradrenergic receptors could be implicated in the pathogenesis of the encephalopathy and brain edema characteristic of acute liver failure.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 62%

“…NA concentrations were measured by HPLC with electrochemical detection as previously described (Michalak et al, 1998).…”

Section: Measurement Of Na In Microdialysatesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of noradrenaline transporter sites in frontal cortex of rats with acute (ischemic) liver failure

Michalak

Rose

Butterworth

2001

Neurochemistry International

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“…In this context, it is interesting that norepinephrine neurotransmission has been reported compromised in this region in rats with experimental acute liver failure. 25 There are at least 5 possibilities explaining why a frontal CBF reduction takes place: (1) unconsciousness, (2) pharmacological induction, (3) hyperventilation, (4) alcohol related, and (5) specific alterations caused by FHF.…”

Section: Discussionmentioning

confidence: 99%

Regional cerebral blood flow during mechanical hyperventilation in patients with fulminant hepatic failure

et al. 1999

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Hyperventilation is frequently used to prevent or postpone the development of cerebral edema and intracranial hypertension in patients with fulminant hepatic failure (FHF). The influence of such therapy on regional cerebral blood flow (rCBF) remains, however, unknown. In this study the CBF-distribution pattern was determined within the first 12 hours after development of hepatic encephalopathy (HE) stage 4 before and during hyperventilation. Ten consecutive patients (median age 48 [range 33-57] years) with FHF and 9 healthy controls (median age 54 [24-58] years) had rCBF determined by single photon emission computed tomography (SPECT) using intravenous injection of 133Xenon. For determination of high resolution CBF pattern, the patients were also studied with 99mTc-hexa-methylpropyleneamine oxime (HMPAO) in the hyperventilation condition. There was no significant difference in the rCBF distribution pattern during normoventilation as compared with hyperventilation. The anterior to posterior (AP) ratio was significantly lower in patients as compared with healthy controls. After hepatic recovery and disappearance of HE, 3 patients had restored normal rCBF distribution pattern as compared with healthy controls. We conclude that in sedated patients with FHF, a relatively lower rCBF is found in the frontal regions and in the basal ganglia as compared with posterior regions. This rCBF-distribution pattern was not aggravated during hyperventilation. It is speculated that this change of rCBF in patients with FHF may render the frontal brain regions more susceptible to hypoxia. The relative frontal rCBF decrease was shown to be reversible with hepatic recovery and alleviation of HE. (HEPATOLOGY 1999;30:1368-1373.)Cerebral edema and intracranial hypertension are frequent complications in patients with fulminant hepatic failure (FHF). The pathophysiology of these complications remains unknown, but there is some evidence that changes in cerebral blood flow (CBF) play a role. 1,2 In patients with FHF, both increases and decreases in global CBF have been reported. [3][4][5][6] It has been suggested that differences in the timing of the CBF studies in relation to the onset of hepatic encephalopathy (HE) and differences in the applied methods may explain these discrepancies. 1 However, other factors may also be of importance to explain this wide interindividual and intraindividual CBF variation. Among these, we have previously shown that CBF autoregulation is absent in patients with FHF, which means that CBF depends linearly on mean arterial blood pressure. 7 Patients with global cerebral hyperemia seem to have higher intracranial pressure than patients with low or normal CBF values. 4,8 The presence of cerebral hyperemia in some patients with FHF indicates that the cerebrovascular tone is gradually decreased during the course of the illness, and this may be of pathophysiological importance for the formation of cerebral edema as the hydrostatic capillary pressure is not controlled, i.e., vasogenic edema formation. [9][10][11] We...

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Neurotransmitter receptor alterations in hepatic encephalopathy

Palomero-Gallagher¹,

Reifenberger²,

Kostopoulos³

et al.

Hepatic Encephalopathy and Nitrogen Metabolism

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Evidence for altered central noradrenergic function in experimental acute liver failure in the rat

Cited by 22 publications

References 38 publications

Loss of noradrenaline transporter sites in frontal cortex of rats with acute (ischemic) liver failure

Loss of noradrenaline transporter sites in frontal cortex of rats with acute (ischemic) liver failure

Regional cerebral blood flow during mechanical hyperventilation in patients with fulminant hepatic failure

Neurotransmitter receptor alterations in hepatic encephalopathy

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