Effects of angiotensin, prostaglandin E2 and indomethacin on the early and late steps of aldosterone biosynthesis in isolated adrenal cells.

The involvement of prostaglandins in the regulation of aldosterone biosynthesis was investigated in isolated adrenal glomerulosa cells. Cells were treated with cyanoketone to inhibit the 3 beta-hydroxy-steroid dehydrogenase and isolate the early step of aldosterone synthesis and the late step. Angiotensin II and PGE2 stimulated the synthesis of aldosterone in a concentration-related manner. The stimulation by both compounds was inhibited by indomethacin, a prostaglandin synthesis inhibitor. Indomethacin also inhibited arachidonic acid-stimulation of 6-keto PGF1 alpha synthesis, whereas cyanoketone was without effect. Both angiotensin II and PGE2 stimulated the synthesis of pregnenolone (the early step) in a concentration-related manner. At higher concentrations, angiotensin II also stimulated the conversion of [3H]corticosterone to [3H]aldosterone (the late step). PGE2 did not alter the late step significantly. Indomethacin had no effect on either biosynthetic step when added alone. However, it inhibited the angiotensin- and PGE2-stimulated pregnenolone synthesis by 41 and 59%, respectively (P less than 0.05). Indomethacin did not alter angiotensin stimulation of the conversion of corticosterone to aldosterone. These findings indicate that PGE2 increases the synthesis of aldosterone by stimulating the conversion of cholesterol to pregnenolone. Indomethacin inhibits angiotensin II- and PGE2-induced steroidogenesis at the same early biosynthetic step. These findings suggest that indomethacin may act by a mechanism other than a reduction in the concentration of prostaglandins.