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Aldosterone Metabolism in the Isolated Perfused Liver of Female and Male Rats^*

Medical Department P, Division of Nephrology, and the Department of Experimental Pathology, Rigshospitalet Copenhagen, Denmark

Address all correspondence and requests for reprints to: M. Egfjord, M.D., Medical Department P 2131, Division of Nephrology, Rigshospitalet, 9 Blegdamsvej, 2100 Copenhagen, Denmark.

Abstract

A sex-dependent metabolism of aldosterone has been reported in intact rats. To further characterize the hepatic elimination of aldosterone and its sex dependence, the metabolism of d-[4-¹⁴C]aldosterone was studied in isolated perfused liver from male and female Wistar rats, from male rats castrated 3 weeks before experiments, and from younger male rats (same body weight as the female rats). The livers were perfused at a constant flow rate in a recirculating mode with a hemoglobinfree medium containing aldosterone at initially 1 nM. Perfusate aldosterone was measured by a specific RIA. Total 4-¹⁴C radioactivity in perfusate and bile was determined. The perfusate [4-¹⁴C]aldosterone radiometabolite concentration was calculated. The radiometabolite pattern in additional experiments was studied by HPLC.

The male rats exhibited 10% higher systolic blood pressure (P < 0.05) and 51% higher fasting values of plasma aldosterone (P < 0.05) compared to those in the female rats. In female rats the hepatic clearance rate of aldosterone per 100 g BW was 72% higher than that in male rats (11.2 ± 2.7 to 6.5 ± 1.8 ml/min; P < 0.01), and that expressed per g liver wet wt was 75% higher (3.5 ± 1.0 to 2.0 ± 0.7 ml/min; P < 0.01). When female rats were compared to younger male rats with the same body weight, 33% higher hepatic aldosterone clearance rates were still found in female rats (21.0 ± 5.4 to 15.8 ± 3.2 ml/min; P < 0.05), and 51% higher values when expressed per g liver wet wt (3.5 ± 1.0 to 2.3 ±0.5 ml/min; P < 0.01). No difference in the aldosterone clearance rate was observed in castrated male rats compared to that in noncastrated male rats.

4-¹⁴C-Labeled radiometabolite levels accumulated similarly in the perfusate of livers of both sexes. Perfusate 4-¹⁴C-labeled radiometabolites after 90 min of perfusion were lower in livers of castrated male rats than in noncastrated male rats (P < 0.001). The final perfusate ¹⁴C-labeled radiometabolite concentration correlated inversely with the total ¹⁴C in bile (P < 0.01). All ¹⁴C-labeled radiometabolites detected in perfusate and bile after 90 min were more polar than aldosterone. After enzymatic hydrolysis, some of the metabolites from the male livers cochromatographed with tetrahydro- and dihydroaldosterone, while other fractions remained more polar. Only more polar metabolites were detected in the perfusate and bile of female livers.

In conclusion, the liver is of major importance for the maintenance of aldosterone levels, as aldosterone was rapidly converted to more polar metabolites. The aldosterone metabolites were extensively and rapidly released into the circulation before biliary elimination. In male rats a relatively lower capacity of hepatic aldosterone metabolism was found, together with a lower clearance rate of aldosterone in livers of younger male rats with the same body weight as the female rats, demonstrating a sex difference not alone attributable to a difference in body weight. Castration of male rats did not eliminate this sex dependence.

Footnotes

^* This work was supported by grants from the Danish Medical Research Council, the Dagmar Marshalls Foundation, the Helen and Ejnar Bj0rnows Foundation, the Elin Hartelius Foundation, the Novo Foundation, the Nordisk Insulin Foundation, the Dr. August Petersen and Dr. Thorkil Petersen Foundation, the Karla Marie J0rgensen Foundation, the Oldermand, Slagtermester Peter Ryholts Foundation, and the S0ren A. Andersen Foundation.

Received April 17, 1989.