Role of the Lipoxygenase Pathway in Angiotensin II-Mediated Aldosterone Biosynthesis in Human Adrenal Glomerulosa Cells*

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Abstract
We studied the role of the lipoxygenase pathway of arachidonic acid metabolism in angiotensin II (All)-stimulated aldosterone secretion in normal and adenomatous human adrenal glomerulosa tissue. In freshly isolated normal adrenal glomerulosa cells, the All-mediated stimulation of aldosterone secretion was not altered by cyclooxygenase blockade with ibuprofen. In contrast, BW755c (10−5 mol/L), a nonselective lipoxygenase inhibitor, and baicalein (10−6 mol/L), a more selective 12-lipoxygenase blocker, inhibited All-mediated aldosterone secretion, but did not alter basal aldosterone secretion. The glomerulosa cells produced the lipoxygenase products 12- and 15- hydroxyeicosatetraenoic acid (HETE) in the basal state, as measured by high pressure liquid chromatography and RIA. However, All selectively stimulated only 12-HETE production [basal, 1329 ± 207 (±se) pg (3.99 ± 0.62 pmol)/105 cells·h; All, 2365 ± 333 (7.09 ± 1.0); n = 9; P < 0.02], suggesting that 12- lipoxygenase activation may be involved in All-mediated aldosterone secretion by normal cells. In addition, the lipoxygenase inhibitors that blocked All-mediated aldosterone secretion also prevented All-mediated 12-HETE formation. In contrast, neither ACTH nor K+ stimulated 12-HETE formation, suggesting that 12-lipoxygenase activation is primarily involved in All action in normal glomerulosa cells. BW755c caused a marked dose-dependent inhibition of basal aldosterone secretion in freshly isolated cells from aldosteroneproducing adenomas [APA; basal, 66 ± 3 ng (182 ± 8 pmol)/106 cells·h; 10−5 mol/L BW755c, 49 ± 2 (136 ± 6); 10−4 mol/L BW755c, 30 ± 2 (83 ± 6)]. In contrast, the cyclooxygenase inhibitor indomethacin and the selective 5-lipoxygenase inhibitor U60257 did not alter basal aldosterone secretion by these cells. The APA cells produced 12- and 15-HETE, and BW755c at the same dose that inhibited aldosterone secretion also inhibited the production of both 12- and 15-HETE. In the cultured APA cells, All-stimulated aldosterone secretion was inhibited by BW755c [basal, 26 ± 8 pg/mL (72.0 ± 22.1 pmol/L); All, 336 ± 79 (930 ± 218); All plus BW755c, 92 ± 38 (255 ± 105) n = 13; P < 0.01]. The lipoxygenase products 12- and 15-HETE restored the stimulatory effect of All during inhibition by BW755c, indicating a role for these lipoxygenase pathways in All-mediated aldosterone secretion in APA cells. These results suggest that the stimulatory effects of AH on aldosterone secretion are mediated by stimulation of the lipoxygenase pathway in human zona glomerulosa cells.

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