Altered acetylcholine metabolism of brain in uremia: role of secondary hyperparathyroidism.

OBJECTIVE

Cholinergic system and its neurotransmitter, acetylcholine (ACh), play a major role in both behavior and motor function of the nervous system. Cholinergic neurons synthesize ACh from choline and acetyl-CoA by choline acetyltransferase in the nerve ending. The release of ACh in response to nerve impulses is dependent on the intracellular calcium ([Ca2+]i) concentration and its gradient. The regulation of a synthesis of ACh after depolarization and ACh release is controlled by mass-action effect on choline acetyltransferase equilibrium. Behavioral and motor changes in uremia may be due in part to derangements in ACh metabolism and such possible abnormalities may be related to the state of secondary hyperparathyroidism of chronic renal failure (CRF).

DESIGN

We studied ACh and choline content, choline release, choline kinase activity in brain synaptosomes of CRF with and without secondary hyperparathyroidism and in CRF rats treated with verapamil which normalize [Ca2+]i in brain synaptosomes of CRF rats.

RESULTS

The content of ACh of brain synaptosomes increased progressively with the duration of CRF from 3 to 6 weeks. ACh and choline release as well as choline uptake were significantly higher in CRF rats at all time intervals studied.

CONCLUSION

Choline content and the activity of choline kinase of brain synaptosomes were deceased after 3 weeks of CRF and were significantly lower than in synaptosomes of normal. Normalization of ACh and choline content as well as ACh release and the activity of choline kinase by parathyroidectomy or treatment with verapamil but these maneuvers did not prevent the rise in choline uptake and choline release. Resting levels of cytosolic calcium of brain synaptosomes in rats with CRF were significantly higher (437 +/- 9 nM) as compared to normal rats (345 +/- 9 nM). This rise in [Ca2+]i was prevented either by parathyroidectomy prior induction of CRF or by treatment of CRF rats with calcium channel blocker verapamil.