Acute GLP-1 infusion lowers circulating angiotensin II in healthy men without altering key RAS component concentrations

Glucagon-like peptide-1 (GLP-1) receptor agonists are recognized for their substantial cardiovascular and renal protection beyond glycemic control. A key mechanism in hypertension and cardiovascular disease involves the Renin-Angiotensin System (RAS), particularly angiotensin II (ANGII), a potent vasoconstrictor. While GLP-1 is known to reduce plasma ANGII and increase renal perfusion, the precise mechanisms underlying this ANGII suppression—specifically, whether it involves changes in circulating angiotensinogen, ACE, or ACE2—have remained unclear, representing a critical gap in understanding GLP-1's cardioprotective effects.

Researchers conducted post-hoc analyses on stored arterial plasma samples from a randomized, placebo-controlled cross-over study involving eight healthy male adults. Participants followed a sodium-standardized diet for 4 days to achieve steady state. During the study, subjects received a 3-hour intravenous infusion of either GLP-1 (1.5 pmol/kg/min) or vehicle, concurrent with an intravenous infusion of 0.9% NaCl (750 mL/h) to expand extracellular volume. Primary endpoints included changes in plasma concentrations of ANGII, angiotensinogen, ACE, ACE2, and Ang-(1-7) peptides, measured using specific ELISA and mass spectrometry assays.

As previously published, GLP-1 infusion significantly increased urinary sodium excretion. The present analyses revealed that plasma ANGII concentrations decreased significantly only during GLP-1 infusion, confirming its direct impact. In contrast, plasma angiotensinogen and ACE concentrations decreased similarly in both the GLP-1 and vehicle groups, paralleling observed changes in renin concentrations. Plasma ACE2 and Ang-(1-7) peptide concentrations remained unchanged during infusions of saline with and without GLP-1. This indicates that the acute ANGII-lowering effect of GLP-1 is not mediated by alterations in circulating levels of these key RAS components. The study did not exclude potential changes in enzyme activities independent of their concentrations.

Plasma ANGII concentrations decreased significantly only during GLP-1 infusion, while plasma angiotensinogen, ACE, ACE2, and Ang-(1-7) concentrations remained unchanged or decreased similarly in both groups.