Angiotensinogen concentrations and renin clearance -: Implications for blood pressure regulation

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 approximate to 7-fold higher than the other (68+/-18 versus 10+/-4 mu g angiotensin I/mL). hREN (30 000 pg) was bolus-infused into both lines and into nontransgenic controls. The terminal half-life (T1/2 beta) was increased (130 versus 82 minutes) and the metabolic clearance rate (MCR) was decreased (0.83+/-0.29 versus 2.2+/-0.66 mu L . 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 T1/2 beta 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 T1/2 beta 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 T1/2 beta. 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.