Actions of angiotensin II on aldosterone biosynthesis in the rat adrenal cortex. Effect on cytochrome P-450 enzymes of the early and late pathway

Previous studies have shown that angiotensin II increases aldosterone biosynthesis, but the mechanisms involved have not been clearly defined. The present studies were carried out to examine the effects of angiotensin II on cytochrome P-450 enzymes of the rat adrenal cortex. Microsomal and mitochondrial cytochrome P-450 levels in the zona glomerulosa were not affected by angiotensin II administration to hypophysectomized rats. Mitochondrial 11β- and 18-hydroxylation of 11-deoxycorticosterone and microsomal 21-hydroxylation of progesterone were also unaffected. In contrast, angiotensin II increased the rate of cholesterol side chain cleavage in glomerulosa mitochondria. The increase in cholesterol side chain cleavage activity correlated with an increase in the heat-generated type I and the pregnenolone-induced type II absorbance changes. In addition, angiotensin II increased the rate of conversion of corticosterone to 18-hydroxycorticosterone and aldosterone, and effect paralleled by an increase in the corticosterone-induced type I absorbance change. Treatment of hypophysectomized rats with cycloheximide had no apparent effect on the action of angiotensin II to promote cholesterol side chain cleavage activity. The effect of angiotensin II to increase the conversion of corticosterone to 18-hydroxycorticosterone and aldosterone, however, was completely abolished by cycloheximide. Activity of cytochrome P-450 enzymes in the zona fasciculata-reticularis was not significantly altered by angiotensin II. The results indicate that angiotensin II promotes aldosterone biosynthesis by increasing both the rate of cholesterol side chain cleavage and the conversion of corticosterone to aldosterone. Increased enzyme activities are mediated, at least in part, by enhanced association of cholesterol and corticosterone with mitochondrial cytochrome P-450(scc) and cytochrome P-450₁₈, respectively. The effect of angiotensin II on cholesterol side chain cleavage is apparently independent of protein synthesis. In contrast, its effect on the conversion of corticosterone to aldosterone seems to require the production of a protein factor or factors.