Locally Generated Angiotensin II in the Adrenal Gland Regulates Basal, Corticotropin-, and Potassium-Stimulated Aldosterone Secretion

Abstract

Abstract The zona glomerulosa cells of the adrenal gland have an intrinsic renin-angiotensin system that appears to modulate the aldosterone response to potassium and corticotropin. The actions of circulating angiotensin II (Ang II) are mediated by the activation of the Ang II type 1 (AT 1 ) receptor on the adrenal cortex. In this study we examined the effects of the AT 1 receptor antagonist DuP 753 and other antagonists on aldosterone secretion in cultured bovine zona glomerulosa cells. Zona glomerulosa cells were cultured in PFMR-4 medium containing 10% fetal calf serum for 72 hours, and the medium was replaced with serum-free medium for the next 24-hour experimental period. DuP 753 (10 μmol/L) inhibited basal aldosterone secretion (from 88.6±7.1 to 54.8±9.6 pg/10 6 cells per hour; 38% inhibition). EXP 3174, an active metabolite of DuP 753, also inhibited aldosterone dose dependently (from 88.6±7.1 to 55.9±8.4 at 1 μmol/L and 88.6±7.1 to 21.7±3.3 at 100 μmol/L; 37% and 75% inhibition, respectively). Another and more potent AT 1 receptor antagonist, L158,809, showed significant inhibition at 100 nmol/L, and at 10 μmol/L it inhibited basal aldosterone secretion (from 144.7±18.2 to 83.4±17.1 pg/10 6 cells per hour; 42% inhibition). DuP 753 inhibited Ang II (100 nmol/L)–stimulated aldosterone production in a dose-dependent fashion, with a 30% reduction at 100 nmol/L and complete inhibition at 100 μmol/L. DuP 753 also inhibited potassium (12 nmol/L) and corticotropin (1 nmol/L) stimulation of aldosterone in a dose-dependent fashion. There was no evidence of cell toxicity as judged by gross and microscopic appearance of the cell culture, trypan blue exclusion, and the ability of cells to synthesize the protein renin. Furthermore, the AT 2 receptor antagonist PD 123319 did not inhibit basal, Ang II–, corticotropin-, or potassium-stimulated aldosterone. In conclusion, the AT 1 receptor antagonists inhibit basal, corticotropin-, and potassium-stimulated aldosterone. These data suggest that the adrenal renin-angiotensin system plays an important role in the regulation of aldosterone secretion.