Characterization of dimethylguanosine, phenylethylamine, and phenylacetic acid as inhibitors of Ca2+ ATPase in end-stage renal failure.
The activity of the plasma membrane Ca2+ ATPase of chronic renal failure patients is decreased by circulating inhibitors yet to be characterized. In this study, inhibitors of Ca2+ ATPase were isolated from ultrafiltrate of patients with end-stage renal failure. They were identified as dimethylguanosine, phenylethylamine, and phenylacetic acid by chromatography and mass spectrometry. Ca2+ ATPase activity was measured spectrophotometrically as the difference in hydrolysis of ATP in the presence and absence of Ca2+ with different concentrations of ATP and the isolated substances. All of the identified compounds are sufficiently lipophilic to penetrate the blood-brain barrier and to accumulate in cerebral tissue. The inhibitory effects of these agents were additive. The apparent K(m) values for ATP and Ca2+ were not altered by these substances, suggesting a noncompetitive mechanism of inhibition. In plasma of healthy subjects, the substances were not detectable. The Ca2+ ATPase inhibitors identified may play a role in the pathophysiology of end-stage renal failure and, potentially, in monitoring toxic effects on cellular Ca2+ metabolism in renal failure.
Jankowski
J
J
Medizinische Klinik I, Universitäts-Klinik Marienhospital, Ruhr University of Bochum, Herne, Germany.
Luftmann
H
H
Tepel
M
M
Leibfritz
D
D
Zidek
W
W
Schlüter
H
H
D000328:Adult; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000097:blood; D002462:Cell Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010627:Phenethylamines / Q000097:blood*; D010648:Phenylacetates / Q000097:blood*; D012016:Reference Values; D018709:Statistics, Nonparametric
D010627:Phenethylamines; D010648:Phenylacetates; D006151:Guanosine; C008940:N(2),N(2)-dimethylguanosine; D000252:Calcium-Transporting ATPases