Mineralocorticoid receptor blockade by canrenoate increases both spontaneous and stimulated adrenal function in humans

Animal studies indicate that mineralocorticoid receptors (MR) in the hippoc ampus play a major role in the glucocorticoid feedback control of the hypot halamo-pituitary-adrenal (HPA) axis. Specifically, MR mediate the proactive feedback of glucocorticoids in the maintenance of basal HPA activity. The stimulatory effect of intra cerebroventricular and intrahippocampal MR bloc kade on the HPA axis in animals has been clearly shown, whereas the effect of systemic administration of mineralocorticoid antagonists in humans is st ill contradictory. To clarify this point, in seven normal young women (aged 25-32 yr; body mass index, 19.0-23.0 kg/m(2)) we studied the effects of ca nrenoate (CAN; 200 Ng as iv bolus at 2000 h, followed by 200 mg infused in 500 mt saline over 4 hup to 2400 h) or placebo (saline, 1.0 mt as iv bolus at 2000 h, followed by 500 mt over 4 h up to 2400 h) on the spontaneous ACT H, cortisol, dehydroepiandrosterone (DHEA) and aldosterone secretion as wel l as on the ACTH, cortisol, and:DHEA responses to human CRH (2.0 mug/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 pla cebo, spontaneous ACTH and cortisol levels showed progressive decreases (P < 0.05) from 2000-2400 h (baseline us. nadir, mean +/- SEM, 2.0 +/- 0.3 us. 1.4 +/- 0.2 pmol/L and 115.1 +/- 23.7 us. 63.5 +/- 24.3 nmol/L), whereas D HEA and aldosterone levels did not change. CRH induced clear increases in A CTH, 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 increa ses 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 sh owed progressive rises, which begun at approximately 60 min and peaked betw een 2300 and 2400 h (ACTH, 3.4 +/- 0.4 vs. 1.1 ir 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 us. baseline as well as vs. the same time points during pl acebo). 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 signi ficance (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 sign ificance (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 an HPA axis is mediated by concomitant modulation of CRH and AVP releas e.