Norepinephrine (NE) content, release and uptake by brain synaptosomes are reduced in chronic renal failure (CRF), and this has been attributed to the state of secondary hyperparathyroidism. The decrease in NE content in CRF could not be explained by changes in NE uptake or release since in normal circumstances, NE content usually remains unchanged despite fluctuation in NE uptake and release. Since NE content is determined by its production and degradation, we examined the effect of CRF with and without excess parathyroid hormone (PTH) on the Michaelis-Menton constant (Km,) and Vmax of tyrosine hydroxylase (TH), the rate-limiting enzyme for NE production, and monoamine oxidase (MAO), an enzyme involved in NE degradation of brain synaptosomes. Brain synaptosomes from rats with a 21-day CRF have a significantly (p < 0.01) lower Vmax of TH (39.5 ± 5.3 pmol tritiated H2O/mg protein/min) than that of normal rats (61. ± 7.5 pmol tritiated H2O/mg protein/min) and a higher Km of MAO (59 ± 2.9 nM tyramine) than normal animals (46 ± 1.7 nM tyramine). Parathyroidectomy (PTX) in CRF rats normalized Vmax of TH (54 ± 4.5 pmol tritiated H2O/mg protein) and Km of MAO (48.4 ± 2.3 nMtyramine). Cytosolic calcium, [Ca2+]i, in brain synaptosomes is significantly (p < 0.01) higher in rats with CRF (488 ± 8.5 nM) than in normal (355 ± 6.0 nM) or PTX-CRF (360 ± 8.1 nM) rats. The data show that: (1) the synaptosomal activity of the key enzymes involved in NE production (TH) and degradation of MAO are impaired, and [Ca2+]i is elevated in CRF, and (2) PTX in CRF rats corrected these abnormalities, implying that they are mediated by excess PTH in CRF. The results indicate that the decrement in NE production is greater than in NE degradation leading to a reduced NE content in brain synaptosomes in CRF.

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