CHARACTERIZATION OF DIMETHYLGUANOSINE, PHENYLETHYLAMINE, AND PHENYLACETIC ACID AS INHIBITORS OF CA2-STAGE RENAL-FAILURE( ATPASE IN END)

The activity of the plasma membrane Ca2+ ATPase of chronic renal failu re patients is decreased by circulating inhibitors yet to be character ized. In this study, inhibitors of Ca2+ ATPase were isolated from ultr afiltrate of patients with end-stage renal failure. They were identifi ed as dimethyl-guanosine, phenylethylamine, and phenylacetic acid by c hromatography 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 sufficien tly lipophilic to penetrate the blood-brain barrier and to accumulate in cerebral tissue. The inhibitory effects of these agents were additi ve. The apparent K-m values for ATP and Ca2+ were not altered by these substances, suggesting a noncompetitive mechanism of inhibition. In p lasma 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 effec ts on cellular Ca2+ metabolism in renal failure.