Nonparallel effects of renin inhibitor treatment on plasma renin activity and angiotensins I and II in hypertensive subjects. An assay-related artifact.
Nonparallel effects of renin inhibitor treatment on plasma renin activity (PRA) and the plasma levels of angiotensins (ANG), as well as on blood pressure, have been observed in subjects with hypertension. This study addresses the possibility that renin inhibitors may show a high degree of plasma protein binding in vivo and that displacement of protein-bound inhibitor during the assay of PRA in vitro may lead to overestimation of renin inhibition. Indeed, with the ultrafiltration technique it was found that 96% of the novel renin inhibitor Ro 42-5892, when added to EDTA plasma, was bound to protein. The angiotensinase inhibitors phenylmethylsulfonyl fluoride (PMSF) and 8-hydroxy-quinoline sulfate (8-OHQ), which are currently used in PRA assays, caused a displacement of protein-bound inhibitor, thereby increasing its free concentration. This displacement was sufficient to explain the reduction in IC 50 of Ro 42-5892, which was seen in the PRA assay when PMSF and 8-OHQ were added to plasma. Such reductions in IC 50 were also seen with the renin inhibitors CGP 29-287, CGP 38-560A, and SR 43-845. When Ro 42-5892 was given, 1 mg/kg intravenously in 10 min, to subjects with hypertension, it appeared that plasma ANG I and II returned to baseline after 6-8 h, whereas PRA measured in the presence of PMSF and 8-OHQ was still suppressed. However, when PRA was measured without these angiotensinase inhibitors, the inhibition of PRA was parallel to the suppression of ANG I and II.(ABSTRACT TRUNCATED AT 250 WORDS)
Derkx
F H
FH
Department of Internal Medicine I, University Hospital Dykzigt, Erasmus University, Rotterdam, The Netherlands.
van den Meiracker
A H
AH
Fischli
W
W
Admiraal
P J
PJ
Man in't Veld
A J
AJ
van Brummelen
P
P
Schalekamp
M A
MA
D000328:Adult; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood*; D008297:Male; D008875:Middle Aged; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System / Q000502:physiology*; D000092502:Renin Inhibitors
D000803:Angiotensin I; D000804:Angiotensin II; D012083:Renin; D000092502:Renin Inhibitors