Substance P stimulates aldosterone secretion via NK1 receptors in adrenal cells, and the NK1R antagonist aprepitant reduced aldosterone by ~30% in a human clinical trial.
~30%reduction in aldosterone production with NK1R antagonist aprepitant in human trial
What the researchers found
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.
Why it matters
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.
The numbers in context
Substance P stimulated aldosterone via NK1R/ERK pathway; overactivation found in primary aldosteronism.
How the study worked
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.
Who was studied
Human adrenal tissue from patients, including primary aldosteronism cases
What this study cannot tell us
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.
How to read the evidence
Strong evidence combining mechanistic in vitro studies with a properly designed double-blind, placebo-controlled human clinical trial. Small sample size limits definitive conclusions.
When this study was published
Published in 2020. Follow-up clinical studies on NK1R antagonists for aldosterone disorders would strengthen these findings.
The bigger picture
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.
Questions still open
- Could NK1R antagonists like aprepitant be used to treat primary aldosteronism or resistant hypertension?
- Is substance P-mediated aldosterone regulation involved in stress-induced hypertension?
- Would combining NK1R antagonists with existing aldosterone pathway drugs provide additive benefit?
Common questions
What is substance P?
What is aprepitant?
Read the original research
The neuropeptide substance P regulates aldosterone secretion in human adrenals.
Nature communications, 11(1), 2673
Citation
Wils, Julien; Duparc, Céline; Cailleux, Anne-Françoise; Lopez, Antoine-Guy; Guiheneuf, Caroline; Boutelet, Isabelle; Boyer, Hadrien-Gaël; Dubessy, Christophe; Cherifi, Saloua; Cauliez, Bruno; Gobet, Françoise; Defortescu, Guillaume; Ménard, Jean-François; Louiset, Estelle; Lefebvre, Hervé. (2020). The neuropeptide substance P regulates aldosterone secretion in human adrenals.. Nature communications, 11(1), 2673. https://doi.org/10.1038/s41467-020-16470-8