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Mineralocorticoid Receptor Blockade by Canrenoate Increases Both Spontaneous and Stimulated Adrenal Function in Humans¹

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, 10126 Turin, Italy

Address all correspondence and requests for reprints to: Ezio Ghigo, M.D., Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it

Abstract

Animal studies indicate that mineralocorticoid receptors (MR) in the hippocampus play a major role in the glucocorticoid feedback control of the hypothalamo-pituitary-adrenal (HPA) axis. Specifically, MR mediate the proactive feedback of glucocorticoids in the maintenance of basal HPA activity. The stimulatory effect of intracerebroventricular and intrahippocampal MR blockade on the HPA axis in animals has been clearly shown, whereas the effect of systemic administration of mineralocorticoid antagonists in humans is still contradictory. To clarify this point, in seven normal young women (aged 25–32 yr; body mass index, 19.0–23.0 kg/m²) we studied the effects of canrenoate (CAN; 200 mg as iv bolus at 2000 h, followed by 200 mg infused in 500 mL saline over 4 h up to 2400 h) or placebo (saline, 1.0 mL as iv bolus at 2000 h, followed by 500 mL over 4 h up to 2400 h) on the spontaneous ACTH, cortisol, dehydroepiandrosterone (DHEA) and aldosterone secretion as well as on the ACTH, cortisol, and DHEA responses to human CRH (2.0 µg/kg as iv bolus at 2200 h) or arginine vasopressin (AVP; 0.17 U/kg as im bolus at 2200 h). Blood samples were taken every 15 min from 2000–2400 h. During placebo, spontaneous ACTH and cortisol levels showed progressive decreases (P < 0.05) from 2000–2400 h (baseline vs. nadir, mean ± SEM, 2.0 ± 0.3 vs. 1.4 ± 0.2 pmol/L and 115.1 ± 23.7 vs. 63.5 ± 24.3 nmol/L), whereas DHEA and aldosterone levels did not change. CRH induced clear increases in ACTH, cortisol, and DHEA levels (peaks, mean ± SEM, 7.1 ± 1.1 vs. 1.6 ± 0.2 pmol/L, 322.9 ± 19.5 vs. 92.8 ± 24.5 nmol/L, and 44.2 ± 2.7 vs. 20.0 ± 3.0 nmol/L; P < 0.05). Similarly, AVP elicited significant increases in ACTH, cortisol, and DHEA levels (3.8 ± 0.3 vs. 1.5 ± 0.1 pmol/L, 211.9 ± 27.2 vs. 67.7 ± 9.7 nmol/L, and 51.6 ± 4.0 vs. 16.3 ± 2.0 nmol/L; P < 0.05). During CAN treatment, ACTH, cortisol, and DHEA levels showed progressive rises, which begun at approximately 60 min and peaked between 2300 and 2400 h (ACTH, 3.4 ± 0.4 vs. 1.1 ± 0.3 pmol/L; cortisol, 314.5 ± 49.6 vs. 123.3 ± 13.2 nmol/L; DHEA, 52.0 ± 8.8 vs. 21.0 ± 2.3 nmol/L; P < 0.05 vs. baseline as well as vs. the same time points during placebo). Aldosterone secretion was not modified by CAN. The ACTH, cortisol, and DHEA responses to human CRH were enhanced by CAN (10.0 ± 1.7 pmol/L, 462.2 ± 36.9 nmol/L, and 66.3 ± 8.8 nmol/L), although statistical significance (P < 0.05) was obtained for cortisol and DHEA only. Also the ACTH, cortisol and DHEA responses to AVP were amplified by CAN (8.0 ± 2.6 pmol/L, 324.0 ± 34.8 nmol/L, and 77.8 ± 4.0 nmol/L); again, statistical significance (P < 0.05) was obtained for cortisol and DHEA only. In conclusion, our study shows that the blockade of MR by CAN significantly enhances the activity of the HPA axis in humans, indicating a physiological role for MR in its control. These results also suggest that the stimulatory effect of CAN on HPA axis is mediated by concomitant modulation of CRH and AVP release.

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