(Hypertension. 2000;35:780.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Angiotensinogen Concentrations and Renin Clearance
Implications for Blood Pressure Regulation
From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin (J.B., F.L.), and the Department of Clinical Pharmacology, Free University of Berlin (D.G.), Berlin, Germany, and INSERM U367 (J.M.), Paris, France.
Correspondence to Friedrich C. Luft, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany. E-mail luft{at}fvk-berlin.de
Abstract—Renin (REN) requires
seconds to convert angiotensinogen (AGT) to
angiotensin I. We tested the hypothesis that this long
catalytic cycle might indicate an influence of AGT concentrations on
REN clearance. We studied 2 transgenic rat (TGR) strains for human (h)
AGT; one strain has hAGT values 
7-fold higher than the other (68±18
versus 10±4 µg angiotensin I/mL). hREN (30 000 pg) was
bolus-infused into both lines and into nontransgenic controls. The
terminal half-life (T1/2ß) was increased (130 versus 82 minutes) and
the metabolic clearance rate (MCR) was decreased
(0.83±0.29 versus 2.2±0.66 µL ·
min-1 · g-1) in the high hAGT strain
compared with the low hAGT strain. The difference was not related to
volume of distribution at steady state. Infused hREN blocked with
remikiren resulted in T1/2ß and MCR values that were not different
from control values. Infused unblocked and blocked radiolabeled hREN
was distributed similarly in the hAGT TGR strains. Infused mouse REN,
which cannot convert hAGT, had similar T1/2ß and MCR values in hAGT
TGR. Measuring REN with direct radioimmunoassay or by enzyme kinetic
assay gave similar results. We next crossed homozygous hAGT TGR from
both strains with homozygous hREN TGR. Heterozygous offspring from the
low hAGT TGR strain had plasma REN activity, hREN concentration, and
rat AGT values that were no different from those of their parents.
However, TGR offspring with high hAGT values had massively elevated
plasma REN activity and hREN concentration as well as elevated blood
pressure, even though both the hREN and rREN genes are downregulated.
We conclude that increased AGT concentrations decrease REN MCR and
increase REN T1/2ß. The REN-AGT complex may stabilize plasma REN
concentration and regulate plasma REN activity independent of renal REN
secretion and angiotensin II–mediated feedback. These
effects could augment angiotensin I generation and
influence blood pressure. The notion that AGT is merely a passive
substrate reservoir for REN should be revised.
Key Words: angiotensinogen • blood pressure • rats, transgenic • renin
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