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The renin-mediated formation of Angiotensin I from angiotensinogen is a well-characterized enzymatic reaction providing the input for the RAS. The renin reaction is rate-limiting and resulting Angiotensin I is immediately further metabolized to downstream angiotensin metabolites including Angiotensin II, taking over distinct physiologic functions in human physiology. All molecular components of the RAS are present in the plasma compartment, resulting in a continuous flow of angiotensin metabolites throughout the body, originating in the vascular compartment.

Design and Method:

Our laboratory investigated the utilization of equilibrium angiotensin peptide levels for the biochemical characterization of the circulating RAS. We extensively compared the correlation between angiotensin levels obtained using state-of the art sampling procedures and equilibrium analysis, which involves a post-sampling equilibration step of a serum or heparin-plasma sample at 37°C.


Investigation of healthy volunteers receiving different RAS blockers revealed, that the ratios between metabolically related peptides reflect the activity of the corresponding enzymes. Surprisingly, a strong correlation between equilibrium and stabilized angiotensin levels was observed. The relative differences between stabilized and equilibrium angiotensin levels were peptide specific, with Angiotensin II showing an up to 20-fold increase from “stabilized“ to “equilibrium”, while Angiotensin I changes were limited to a 5-fold increase.


The increase of angiotensin levels during ex vivo equilibration of plasma might be caused by the absence of the tissue as angiotensin acceptor. Given that AT1 receptors have been reported to be effectively internalize bound Angiotensin II, the extraordinary strong increase of Angiotensin II in equilibrium suggests that equilibrium levels could serve as a surrogate for Angiotensin II acting on tissues and might represent a diagnostic tool to characterize RAS at the interface between the circulation and the tissue.

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