Jankowski J, Luftmann H, Tepel M, Leibfritz D, Zidek W, Schlüter H
Medizinische Klinik I, Universitäts-Klinik Marienhospital, Ruhr University of Bochum, Herne, Germany.
J Am Soc Nephrol. 1998 Jul;9(7):1249-57. doi: 10.1681/ASN.V971249.
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.
慢性肾衰竭患者的质膜Ca2+ATP酶活性会因尚未明确特征的循环抑制剂而降低。在本研究中，从终末期肾衰竭患者的超滤液中分离出了Ca2+ATP酶抑制剂。通过色谱法和质谱法将它们鉴定为二甲基鸟苷、苯乙胺和苯乙酸。采用分光光度法测定Ca2+ATP酶活性，即测量在不同浓度的ATP和分离出的物质存在及不存在Ca2+的情况下ATP水解的差异。所有鉴定出的化合物都具有足够的亲脂性，能够穿透血脑屏障并在脑组织中蓄积。这些药物的抑制作用具有相加性。这些物质并未改变ATP和Ca2+的表观K(m)值，提示其抑制机制为非竞争性。在健康受试者的血浆中未检测到这些物质。所鉴定出的Ca2+ATP酶抑制剂可能在终末期肾衰竭的病理生理学中发挥作用，并且有可能用于监测肾衰竭时对细胞Ca2+代谢的毒性作用。
