Evidence that high dose cortisol-induced Na+ retention in man is not mediated by the mineralocorticoid receptor.

Abstract

We have previously shown that high dose cortisol (F; 240 mg/day)-induced Na retention and systolic blood pressure (BP) increases are not inhibited by the glucocorticoid (type II) receptor antagonist RU486. Adequacy of type II receptor blockade with RU486 was clearly demonstrated, indicating that the Na retention was not mediated through the glucocorticoid receptor. Spironolactone (Sp; 400 mg/day), in a preliminary assessment, also did not inhibit F-induced Na retention. The purpose of this study was to determine whether the Na retention produced by F administration is mediated by the type I receptor by comparing the effects of F to a potent type I agonist [9a-fludrohydrocortisone (9aFF)] with and without Sp administration. The effects of the two agonists and Sp on urinary K excretion and BP were also compared. Normal male volunteers, on a constant daily diet for 10 days, received either F (240 nig/ day) or 9aFF (3.0 mg/day) with or without Sp (400 mg/day) for the last 5 days. The mean cumulative reductions in Na excretion during the 5 days compared to baseline values before hormone administration were 255 ± 38 and 494 ± 81 mmol/5 days for F (n = 9) and 9aFF (n = 5), respectively (P = 0.01). Sp (n = 5) completely inhibited 9aFF-induced Na retention (494 ± 81 vs. -37 ± 130 mmol/5 days; P < 0.01), but had no effect (n = 5) on F-induced Na retention (255 ± 38 us. 193 ± 50 mmol/5 days; P = NS). After the expected first day kaliuresis, the effects of both steroids on net cumulative urinary K excretion were minimal. Systolic BP was increased by F, but not 9aFF, and Sp did not inhibit this increase. A 2-fold greater Sp-inhibitable Na-retaining effect of the mineralocorticoid demonstrates that the failure of Sp to block F-induced Na retention is not due to inadequate type I receptor blockade. Based on these findings and earlier studies, we conclude that high dose (stress level) Finduced Na retention and systolic BP increase are not mediated by either the mineraloor glucocorticoid receptor in normal man. (J Clin Endocrinol Metab 72: 1060-1066,1991) ORTISOL (F) has mineralocorticoid as well as glucocorticoid effects (1), and it also binds to both type I (mineralocorticoid) and type II (glucocorticoid) receptors in renal cytosol in man (2, 3). However, the effects of F on renal electrolyte excretion are poorly understood. Acute administration of F variably produces either natriuresis or Na retention, but always kaliuresis; these changes may be associated with an increase in the glomerular filtration rate (GFR) (1). Comparison of the renal effects of F to those of more potent synthetic glucocorticoids has led to the conclusion that the increased GFR, acute kaliuresis, and associated natriuresis are glucocorticoid effects (1, 4-6). The Na-retaining Received October 2,1990. Address requests for reprints to: C. O. Watlington, M.D., Endocrine Division, Department of Medicine, MCV Station, Box 145, Richmond, Virginia 23298-0145. * This work was supported by NIH Grants R01-DK-35341 and R01DK-36822, Clinical Research Center Grant RR-00065, and a Grant-InAid from the A. D. Williams Foundation. t Postdoctoral fellow supported by NHLBI Training Grant HL07110. $ Recipient of a Clinical Associate Physician Award from the NIH. effects of F, more clearly demonstrable after the first 12 h of administration (5), are considered to be mediated by renal type I receptor activation (7). We have recently described the effects of RU38486 (RU486), a potent type II receptor antagonist, on the changes in urinary Na and K excretion produced by high dose F over a 5-day period in normal man (8). Despite ample evidence for adequate glucocorticoid blockade, RU486 did not alter F-induced urinary Na retention. These studies suggested that the Na retention was not mediated by type II receptors. Administration of the type I receptor antagonist spironolactone (Sp) at a dosage of 400 mg/day also did not inhibit F (240 mg/ day)-induced Na retention and only blunted a lesser effect produced by a lower dosage (120 mg/day). These findings raised the possibility that high dose F produces Na retention by a mechanism mediated by neither type I nor type II receptor activation. However, the evidence for adequacy of type I receptor blockade was not definitive (see Discussion). The present study was designed to determine whether F-induced Na retention is mediated