Actions of Angiotensin 11 on Aldosterone Adrenal Cortex EFFECTS ON CYTOCHROME P-450 ENZYMES OF THE EARLY Biosynthesis in the Rat

Previous studies have shown that angiotensin I1 increases aldosterone biosynthesis, but the mechanisms involved have not been clearly defined. The present studies were carried out to examine the effects of angiotensin I1 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 I1 administration to hypophysectomized rats. Mitochondrial llpand 18-hydroxylation of 11-deoxycorticosterone and microsomal 21-hydroxylation of progesterone were also unaffected. In contrast , angiotensin I1 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 I1 absorbance changes. In addition, angiotensin I1 increased the rate of conversion of corticosterone to 18-hydroxycorticosterone and aldosterone, an effect paralleled by an increase in the corticosterone-induced type I absorbance change. Treatment of hypophysectomized rats with cycloheximide had n o apparent effect on the action of angiotensin I1 to promote cholesterol side chain cleavage activity. The effect of angiotensin I1 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 b y angiotensin 11. The results indicate that angiotensin I1 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, b y enhanced association of cholesterol and corticosterone with mitochondrial cytochrome P450,,, and cytochrome P-45OIH, respectively. The effect of angiotensin I1 on cholesterol side chain cleavage is apparent ly independent of protein synthesis. In contrast, its effect on the conversion of corticosterone to aldosterone seems to require the production of a protein fac tor or factors.