Investigating a Mineralocorticoid Receptor Mediation of an Ultra-Short Feedback Loop Regulating Aldosterone...

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.

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.

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.

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.

NCT02871648.