Loss of noradrenaline transporter sites in frontal cortex of rats with acute (ischemic) liver failure.
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 [3H]-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 [3H]-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.
Michalak
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A
Neuroscience Research Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Campus Saint-Luc, 1058 St. Denis Street, Quebec, H2X3J4, Montreal, Canada.
Rose
C
C
Butterworth
R F
RF
D000208:Acute Disease; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000378:metabolism*; D007511:Ischemia / Q000150:complications*; D008099:Liver / Q000098:blood supply*; D017093:Liver Failure / Q000150:complications*; D008297:Male; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011167:Portacaval Shunt, Surgical; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters; D013788:Thalamus / Q000378:metabolism
D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; D027981:Symporters; D005473:Fluoxetine; C011386:nisoxetine; D000641:Ammonia; D009638:Norepinephrine