Investigating a Mineralocorticoid Receptor Mediation of an Ultra‐Short Feedback Loop Regulating Aldosterone Production in Humans

BACKGROUND: Preclinical studies suggest a novel aldosterone regulation pathway: the mineralocorticoid receptor (MR) on the adrenal cortex is a part of an MR-mediated ultra-short feedback loop regulating aldosterone production. Activation of MR on the adrenal decreases aldosterone; blockade of the MR increases aldosterone. Whether this regulatory pathway exists in humans is unknown. METHODS: This was a double-blinded, 3-way crossover study of 23 healthy participants on a low sodium diet (10 mEq/day). Participants received three study drugs in random order: MR antagonist (eplerenone), MR agonist (fludrocortisone), and placebo. Study drugs were administered at 6:30AM on three separate days with 48 h between each administration. After 90 min, participants received sequential infusions of angiotensin-II (ANGII) for 45 min followed 60 min later by cosyntropin for 45 min. Aldosterone was measured before and after each infusion. Multi-level mixed effects linear regression was used to analyze the data. RESULTS: The change in aldosterone between baseline and post-cosyntropin infusion was greater after treatment with eplerenone as compared to placebo (5.16 ± 2.01 ng/dL, p = 0.01). There were no differences with fludrocortisone as compared to placebo. With ANGII stimulation, there were no differences in the change in aldosterone with either eplerenone or fludrocortisone versus placebo. CONCLUSIONS: In humans, MR antagonist treatment led to a greater increase in aldosterone in response to cosyntropin stimulation as compared to placebo, but not after ANGII stimulation. Future studies are needed to investigate the presence of a MR-mediated ultra-short feedback loop at the level of the adrenal gland regulating aldosterone production in humans. CLINICAL TRIAL REGISTRATION NUMBER: NCT02871648.