ESPE Yearbook of Paediatric Endocrinology

Nat Commun. 2020;11(1): 2673.https://pubmed.ncbi.nlm.nih.gov/32471973/

The authors conducted an experimental study in male human volunteers to examine the effects of a neurokinin type 1 receptor (NK1R) antagonist on aldosterone secretion. The findings show the presence of Substance P (SP)-positive nerve fibres in the human adrenal cortex in the vicinity of aldosterone-producing cells and with a role in mineralocorticoid synthesis.

Aldosterone plays a major role in the maintenance of water and mineral homeostasis and in the regulation of blood pressure. It is stimulated by the renin angiotensin system (RAS) and plasma potassium concentrations. However, other factors also appear to regulate its secretion. SP belongs to the family of tachykinins, which also includes neurokinins A and B (NKA and NKB), hemokinin-1 and endokinins. Although evidence suggests that SP may stimulate steroidogenesis and exert trophic actions on the rat adrenal cortex (1, 2), its role in the regulation of the aldosterone production remains unclear.

SP exerts a stimulatory tone on aldosterone secretion through a neurocrine mechanism involving the neurokinin type 1 receptor (NK1R), which is expressed by zona glomerulosa cells (3). The action of SP seems to be complementary to that of Angiotensin II (Ang II), which is involved in the aldosterone response to upright posture, while SP may mainly control basal aldosterone production. At the cellular level, binding of SP to the NK1R induces an activation of the ERK pathway, however, it has a minor effect on the calcium signaling pathway in contradistinction to Ang II. SP activation of aldosterone secretion may also be involved in pathophysiologic processes characterized by idiopathic aldosteronism, such as obesity and sleep apnea, which are associated with an increase in the autonomous nervous activity (4, 5). Therefore, SP blockade may offer alternative therapeutic pathways to both mineralocorticoid receptor antagonists. whose utilization is hampered by their antiandrogenic properties, and aldosterone synthase inhibitors, whose administration leads to accumulation of steroid precursors with mineralocorticoid activity.

Further to the above, the authors tested the hypothesis that aprepitant, a NK1R antagonist, reduces aldosterone production independently of the renin angiotensin system (RAS). They performed a prospective proof-of-concept, double blind, cross-over and placebo-controlled study in healthy adult male volunteers. Participants received during two 7-day treatment periods aprepitant or placebo in a random order at a 2-week interval. Primary endpoint was the plasma aldosterone concentrations during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycemia tests, and basal and stimulated alterations of renin, cortisol and ACTH concentrations during the three different stimulatory tests. Serum transaminase concentrations were determined as a safety measure. Aprepitant decreased aldosterone production by ~30% but did not influence the aldosterone response to upright position. These findings indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and therefore plays a role in the maintenance of hydromineral homeostasis.

Reference: 1. Hinson JP, Cameron LA, Purbrick A, Kapas S. The role of neuropeptides in the regulation of adrenal zona glomerulosa function: effects of substance P, neuropeptide Y, neurotensin, Met-enkephalin, Leu-enkephalin and corticotrophin-releasing hormone on aldosterone secretion in the intact perfused rat adrenal. J Endocrinol. 1994; 140(1): 91–6.2. Mazzocchi G, Macchi C, Malendowicz LK, Nussdorfer GG. Evidence that endogenous substance-P (SP) is involved in the maintenance of the growth and steroidogenic capacity of rat adrenal zona glomerulosa. Neuropeptides. 1995; 29(1): 53–8.3. Hattangady NG, Olala LO, Bollag WB, Rainey WE. Acute and chronic regulation of aldosterone production. Mol Cell Endocrinol 2012; 350: 151–162.4. da Silva AA, do Carmo J, Dubinion J, Hall JE. The role of the sympathetic nervous system in obesity-related hypertension. Curr Hypertens Rep 2009; 11: 206–211.5. Bisogni V, Pengo MF, Maiolino G, Rossi GP. The sympathetic nervous system and catecholamines metabolism in obstructive sleep apnoea. J Thorac Dis 2016; 8: 243–254.