Neuropeptide Substance P Directly Controls Aldosterone Production in Human Adrenal Glands

Substance P stimulates aldosterone secretion through NK1 receptors via the ERK pathway. In a double-blind placebo-controlled trial, the NK1R antagonist aprepitant decreased aldosterone production by approximately 30% in healthy males.

Combined in vitro mechanistic studies (adrenal cell cultures, signaling pathway analysis) with a prospective, double-blind, placebo-controlled clinical trial in healthy male volunteers testing aprepitant vs. placebo over 7-day treatment periods.

Excess aldosterone causes hypertension and cardiovascular disease. Discovering that the nervous system directly controls aldosterone through substance P opens a completely new therapeutic pathway — and aprepitant, an already-approved drug, could potentially be repurposed for aldosterone excess syndromes.

Most treatments for excess aldosterone target the renin-angiotensin system. The discovery that substance P and the autonomic nervous system independently regulate aldosterone adds a new dimension to blood pressure control and could lead to novel treatments for resistant hypertension and primary aldosteronism.

Small proof-of-concept trial in healthy male volunteers only. Long-term effects and clinical relevance in patients with aldosterone excess syndromes need investigation. The ~30% reduction may not be sufficient as monotherapy for clinical hyperaldosteronism.