Substance P nerve fibers and their receptor (NK1R) are present in the vast majority of aldosterone-producing adenomas, and blocking this pathway with aprepitant reduced excess aldosterone production in lab studies.
90%The percentage of aldosterone-producing adenomas that contained Substance P nerve fibers, suggesting this neuropeptide pathway is widespread in these tumors
What the researchers found
Substance P (SP) nerve fibers were found in 90% of aldosterone-producing adenomas (APAs) examined, and the neurokinin 1 receptor (NK1R) was strongly expressed in these tumors. Functional experiments showed that SP stimulated aldosterone secretion in 6 out of 10 APA cultures. The NK1R antagonist aprepitant — an already approved drug — blocked SP-induced aldosterone secretion in 3 of 4 responsive cultures tested.
In perifused tissue explants, SP also influenced aldosterone pulsatility, enhancing overall mineralocorticoid output. These results suggest the SP-NK1R pathway may be a druggable target for treating primary aldosteronism in a subset of patients.
Why it matters
Primary aldosteronism is the most common cause of secondary hypertension, and aldosterone-producing adenomas are a major driver. Current treatment options are limited to surgery or lifelong mineralocorticoid receptor antagonists. Identifying a new signaling pathway (SP-NK1R) that drives excess aldosterone production opens the door to targeted pharmacological treatment — potentially using aprepitant, a drug already FDA-approved for other purposes, which could accelerate clinical translation.
The numbers in context
n=56 APA tissues · SP nerve fibers in 90% of tumors · SP stimulated aldosterone in 6/10 cultures · Aprepitant blocked secretion in 3/4 responsive cultures
How the study worked
The researchers analyzed 56 aldosterone-producing adenoma tissue samples using molecular biology, immunohistochemistry, and functional techniques. They mapped SP-positive nerve fibers and NK1R expression within and around adenomas. Functional studies used cultured APA cells and perifused tissue explants to measure aldosterone secretion in response to SP stimulation and NK1R blockade with aprepitant.
Who was studied
56 aldosterone-producing adenoma tissue samples from patients with primary aldosteronism
What this study cannot tell us
This is an in vitro study using excised tumor tissue — results may not directly predict drug responses in living patients. SP stimulated aldosterone in only 60% of cultures tested (6/10), and aprepitant was only tested on 4 responsive cultures, limiting generalizability. The variability in response suggests the SP-NK1R pathway is relevant in a subset, not all, APA patients.
How to read the evidence
This is a well-designed in vitro study with a relatively large tissue sample (56 APAs) using multiple complementary techniques. However, the functional experiments were performed on a smaller subset of cultures, and no in vivo or clinical data are presented. Evidence strength is preliminary but promising.
When this study was published
Published in 2026, this is a very recent study presenting novel findings about neuropeptide regulation of aldosterone-producing tumors.
The bigger picture
Primary aldosteronism affects an estimated 5–10% of all hypertensive patients, making it far more common than previously thought. The discovery that a neuropeptide signaling pathway (Substance P via NK1R) drives aldosterone production in many of these tumors adds a new chapter to our understanding of this condition. Importantly, aprepitant is already an approved drug with a known safety profile, which could significantly shorten the path from lab discovery to clinical trial. This work also highlights the broader theme of neuropeptide regulation of endocrine function — the adrenal gland is more under neural control than many clinicians appreciate.
Questions still open
- Could aprepitant or other NK1R antagonists be tested in clinical trials as a non-surgical treatment for primary aldosteronism?
- What determines whether an individual APA is responsive to Substance P — are there genetic or molecular markers that predict response?
- Does the SP-NK1R pathway also play a role in bilateral adrenal hyperplasia, the other major cause of primary aldosteronism?
Common questions
What is Substance P and what does it normally do?
Could the existing drug aprepitant be used to treat high blood pressure from these tumors?
Read the original research
Regulation of Aldosterone Secretion by Substance P and the Neurokinin Type 1 Receptor in Aldosterone-Producing Adenomas.
Journal of the American Heart Association, 15(2), e045539
Citation
Lopez, Antoine-Guy; Duparc, Céline; Renouf, Sylvie; D'Agostino, Margot; De Sousa, Kelly; Amar, Laurence; Defortescu, Guillaume; Manceau, Gilles; Sabourin, Jean-Christophe; Fernandes-Rosa, Fabio Luiz; Zennaro, Maria-Christina; Meatchi, Tchao; Nicolas, Gaël; Louiset, Estelle; Lefebvre, Hervé. (2026). Regulation of Aldosterone Secretion by Substance P and the Neurokinin Type 1 Receptor in Aldosterone-Producing Adenomas.. Journal of the American Heart Association, 15(2), e045539. https://doi.org/10.1161/JAHA.125.045539