The effects of castration and treatment with testosterone on the biliary excretion of (3H)aldosterone in rats.

The rate of excretion of aldosterone radiometabolites into the bile duct cannulation, and the intravenous injection of (3H)aldosterone, was demonstrated to be markedly increased in male rats following castration. In 1 h, 72% of the injected 3H-radioactivity was excreted in the bile of castrated male rats compared with 26% in the intact male control rats. Castration of the males led to the increased biliary excretion of aldosterone metabolites and the elimination of the sex-dependence of this process in rats. The ovariectomy of female rats did not substantially increase the rate of excretion of aldosterone metabolites via the bile. Castrated male rats treated with testosterone excreted aldosterone metabolites into the bile at a slower rate. A similar treatment of ovariectomized female rats with testosterone also significantly slowed the rate of biliary excretion of the aldosterone metabolites. These findings suggest that the presence of androgens plays an important role in regulating the routes of hepatic metabolism of aldosterone and the rates of clearance of aldosterone and its metabolites from the plasma into the bile of rats.

The role of aldosterone in the development of hypertension in spontaneously hypertensive rats.

A continuous sc infusion of aldosterone for 2 weeks (10 micrograms/day) markedly increased the blood pressure of male, adrenalectomized (ADX), spontaneously hypertensive rats (SHR) from 142 to 178 mm Hg, which was similar to the increase seen in a group of sham-operated SHR. The blood pressure in a group of ADX SHR maintained without aldosterone declined from 141 to 119 mm Hg during the 2 weeks after surgery. Wistar Kyoto (WKY) and Sprague-Dawley (SD) rats treated in an identical fashion remained normotensive throughout. Adrenalectomy caused hyperkalemia in all strains of rat. Plasma potassium levels in aldosterone-treated WKY and SD rats were lower than those in sham-operated controls, but were similar to those in corresponding groups of SHR. Acute renal responses of ADX male rats showed that SHR reabsorbed more water and sodium of an injected isotonic saline load than WKY rats and excreted less potassium than either WKY or SD rats. Sensitivity to aldosterone in the three strains of rats was compared using the urinary sodium to creatinine and potassium to creatinine ratios 1-3 h postinjection of aldosterone. Decreases in the urinary ratio of sodium to creatinine in response to various doses of aldosterone (0-1.25 micrograms aldosterone) were similar for the three strains of rat. ADX SHR appeared to be less responsive to the kaliuretic actions of aldosterone than WKY and SD rats. The present studies show that aldosterone is essential to the development of hypertension in SHR. The hypertensinogenic actions of aldosterone in these rats may be related to a blunted kaliuretic response to mineralocorticoids.

Antinatriuretic and kaliuretic activities of the reduced derivatives of aldosterone.

The mineralocorticoid activities of the two dihydro- and the four tetrahydroisomers of the ring A-reduced derivatives of aldosterone were tested in adrenalectomized male rats. Potency was assessed by three criteria. Overall mineralocorticoid activity is expressed as the ability to reduce the urinary Na+/K+ ratio; antinatriuretic activity is represented by decreases in urinary Na+/creatinine; kaliuretic activity is shown by increases in K+/creatinine. All measurements were made on urine collected in the period 1-3 h postinjection. Measurements of overall activity indicate that the potency of aldosterone is greater than 5 alpha-dihydroaldosterone (DHA) greater than 3 alpha, 5 alpha-tetrahydroaldosterone (THA) greater than 3 alpha, 5 beta-THA greater than 3 beta, 5 alpha-THA greater than 5 beta-DHA greater than 3 beta, 5 beta-THA. Measurements of individual cation effects indicated that reduced derivatives generally, and the 5 alpha-reduced derivatives in particular, have greater antinatriuretic than kaliuretic activity. For example 5 alpha-DHA possesses between 7% and 17% of the antinatriuretic activity of aldosterone but only 0.7-2.7% of the kaliuretic activity. 5 alpha-DHA and 3 alpha, 5 beta-THA at concentrations of 10(-7)M were also shown to have mineralocorticoid activity in the isolated toad bladder; both caused an increase in the short circuit current across this epithelium although not to the level shown by a similar concentration of aldosterone. 5 beta-DHA appeared to be inactive at this dose.

Sex dependence of clearance rates of aldosterone and its metabolites from plasma of intact rats.

Following I.V. injection of 3H-aldosterone, the rates of clearance of plasma 3H-radioactivity was demonstrated to be sex-dependent in intact rats. Even though the percentages of CH2Cl2-extractable plasma radioactivity are greater in female than in male rats, the quantities of CH2Cl2-extractable label are similar until 60 min post-injection. However, the quantities of non-extractable, polar metabolites of aldosterone (NEPD) are markedly greater in the plasma of males and rapidly reach peak levels 10 min post-injection of aldosterone. In females, these polar metabolites (NEPD) are rapidly cleared from the blood. After bile-duct cannulation, the rate of excretion of aldosterone radiometabolites was demonstrated to be rapid and sex-dependent. Within 1 hr., female rats excreted via the bile 82% of the injected dose of 3H-aldosterone, compared to 49% in male rats. In both sexes, greater than 95% of the total radioactivity excreted in the bile are non-extractable polar metabolites of aldosterone (NEPD). The sex hormones appear to influence not only the nature of metabolism of aldosterone in the liver, but also the rates of clearance of aldosterone and its metabolites from the plasma into the bile.