Endocrine Abstracts

In the human adrenal gland, serotonin (5-HT), released by subcapsular mast cells strongly stimulates aldosterone production via activation of the type 4 serotonin receptor (5-HT4R). Consistently, plasma aldosterone levels increase after administration of 5-HT4R agonists like cisapride to healthy volunteers. Previous studies performed in aldosterone producing adenomas (APA) have shown an increase in mast cells density and an overexpression of HTR4 gene, encoding 5-HT4R, in APA tissues in comparison to normal adrenal. Moreover, administration of cisapride to patients with APA induced an exaggerated plasma aldosterone response. These results suggested that 5-HT could play a role in the pathophysiology of APA. The aim of our study was to examine expression of genes and proteins involved in aldosterone production and actors of the serotonergic pathway in a series of adenomas removed from patients with primary aldosteronism. We have also investigated the in vitro effect of various 5-HT4R ligands on aldosterone production by tissue explants or cultured cells derived from adenoma tissues obtained at surgery. Among the 72 tissues studied, 65% were identified as classical APAs, according to classification of the new international histopathology consensus for unilateral Primary aldosteronism. The presence of 5-HT was detected by immunohistochemistry in 75% of the classical adenomas. 5-HT was principally detected in adenoma tissues, in mast cells but also in steroidogenic cells. 5-HT4R immunostaining was widely distributed in most APA tissues, a pattern which was not exclusively noticed in AS-positive adenomas. Expression of the gene encoding the 5-HT-synthesizing enzyme tryptophan hydroxylase was similar in APA and normal adrenals. HTR4 overexpression was more pronounced in classical than non-classical APAs and HTR4 mRNA levels were positively correlated to those of CYP11B2 mRNA encoding AS. Administration of 5-HT to normal adrenocortical or APA cells in culture stimulated CYP11B2 gene expression and aldosterone production. In addition, in cultured APA cells, BIMU-8 and prucalopride, two 5-HT4R agonists, stimulated aldosterone synthesis in a dose-dependent manner with a higher efficiency than that observed in normal adrenocortical cells. Moreover, BIMU-8, strongly increased aldosterone production by perifused APA explants, an effect which was blocked by administration of GR-113808, a 5-HT4R antagonist. Administration of 48/80 compound, a mast cell degranulator, to perifused APA explants induced a 5-HT release immediately followed by an increase in aldosterone levels. These data indicate that the 5-HT signalling pathway, which is enhanced in APAs, exerts an autocrine/paracrine stimulatory action on aldosterone synthesis and may thus participate in the pathophysiology of primary aldosteronism.