Context: The mechanism associated with the overproduction of aldosterone by aldosterone-producing adenomas (APA) is unknown.

Objective: To explore the role of the D2 dopamine receptor (D2R) on aldosterone synthesis and secretion, and clarify the clinical importance of this role on aldosterone overproduction in APA.

Results: D2R expression in APA was examined in 24 patients and was much less than that in the non-tumorous adrenal cortex. D2R mRNA levels in APA were inversely correlated with CYP11B2 mRNA levels and the patient's plasma aldosterone concentration. Angiotensin II (AII)-stimulated aldosterone secretion and CYP11B2 mRNA expression in human adrenocarcinoma cells (H295R) was attenuated by the D2 agonist, bromocriptine (BMC). BMC selectively attenuated AII-induced PKCµ phosphorylation and its translocation to the cell membrane. PKCµ -specific shRNA significantly decreased AII-induced CYP11B2 mRNA expression and aldosterone secretion. BMC also attenuated the AII-induced increase in cytoplasmic calcium, partially through an inhibition of cytoplasmic inositol 1, 4, 5 triphosphate production. In spite of similar total PKCµ levels in APA and the non-tumorous adrenal cortex, expression of phosphorylated PKCµ in APA was much higher.

Conclusion: This is the first study to demonstrate that the D2R modulated aldosterone secretion and synthesis through a specific attenuation of PKCµ activity, as well as the intracellular calcium level. Downregulation of the D2R in APA, in turn increased PKCµ activity and led to overproduction of aldosterone in affected patients. The D2R may thus serve as a potential treatment target for primary aldosteronism.