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)