Canrenoate causes a set-point shift in the feed back regulation of the HPA axis

Abstract

Objective: The purpose of our study was to investigate the role of central mineral corticoid receptors (MR) in the regulation of the activated HPA axis in healthy humans. Experimental design: In a double blinded design two age-matched groups of 12 male volunteers were pre-treated with either placebo or the MR antagonist canrenoate 16 and 8h prior to the experiment. After an initial resting period of 60min. subjects were asked to perform sub maximal treadmill exercise (160 watts) for 90min. after which they had to rest for another 90min. During the whole experiment blood samples were drawn in 10 minutes intervals and analysed for adrenocorticotropin (ACTH), cortisol and growth hormone (GH). Results: There were no significant differences between both groups for basal and stimulated GH and ACTH secretion. Basal GH (±SEM) (ng/ml) was 0.71 (0.7) for placebo vs. 0.57 (0.33) for canrenoate. Maximal response under physical stress was 14.96 (2.90) vs. 14.59 (2.56) and GH levels in the post exercise period gradually decreased to basal levels. ACTH (±SEM) (pg/ml) was 21.18 (2.86) vs. 21.68 (3.85) for the basal period, maximal 45.90 (12.93) vs. 50.07 (12.22) during exercise and decreased to 18.28 (2.20) vs. 20.45 (2.58) in the post exercise period. There was, however, a significant difference in the secretory cortisol response. Basal cortisol levels were 9.92 (1.12) vs. 11.10 (1.10) being significantly higher in the canrenoate group (p<0.05). Canrenoate pre-treatment also caused a more pronounced increase and ended in higher levels during the post exercise period 7.18 (1.07) vs. 10.13 (1.28) (p<0.05). Discussion: Previous experiments have already shown a modifying role for canrenoate on the HPA axis during sleep and after stimulation with corticotropin releasing hormone. Our findings add up to these results. Since cortisol levels are higher in the canrenoate group in the presence of similar ACTH levels, we speculate whether canrenoate facilitates ACTH mediated cortisol release from the adrenal gland. Alternatively, cortisol metabolism might have been inhibited by canrenoate. In addition canrenoate must have shifted the feedback inhibition of the HPA axis to a higher set point since higher pre- and postexercise cortisol levels in the canrenoate group, did not suppress ACTH secretion as compared to the placebo group. This set point-shift is probably mediated by supra-pituitary regions since MR are predominantly located in the hippocampus.