Derangements in acetylcholine metabolism in brain synaptosomes in chronic renal failure.
Chronic renal failure causes abnormalities in the central nervous system function and in norepinephrine metabolism of brain synaptosomes. The present study examined the effect of renal failure on the metabolism of another neurotransmitter, acetylcholine, which is involved in the modulation of behavioral and motor function. We measured acetylcholine content and release, choline content, uptake and release and activity of choline kinase in synaptosomes from rats with renal failure with various duration, renal failure-parathyroid-ectomized rats maintained normocalcemic, renal failure and normal rats treated with verapamil. Acetylcholine content increased while choline content decreased proportionally and significantly (P < 0.01) with the duration of renal failure; choline kinase activity was reduced (P < 0.01). These derangements were prevented by parathyroidectomy of renal failure rats or by their treatment with verapamil. Choline uptake and release were elevated in renal failure and these abnormalities were not corrected by parathyroidectomy or verapamil therapy. Acetylcholine release was elevated in renal failure and parathyroidectomy prevented this derangement. Verapamil reduced acetylcholine release in both normal and renal failure rats. The data show that: (a) renal failure causes significant derangements in acetylcholine metabolism leading to its accumulation in and an increase in its release from brain synaptosomes; (b) this is mainly due to reduced activity of choline kinase, most likely, mediated by the state of secondary hyperparathyroidism of renal failure; (c) blocking the parathyroid hormone-induced calcium influx into synaptosomes by verapamil prevented the abnormalities in acetylcholine metabolism; and (d) the derangement in choline uptake and release in CRF is not related to excess parathyroid hormone since parathyroidectomy or verapamil treatment did not correct them.
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Division of Nephrology, University of Southern California School of Medicine, Los Angeles.
Smogorzewski
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Massry
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D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D002797:Choline Kinase / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D008297:Male; D016105:Parathyroidectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D014700:Verapamil; D002797:Choline Kinase; D002794:Choline; D000109:Acetylcholine; D002118:Calcium