Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes

Abstract

Lingis M, Richards EM, Keller-Wood M. Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes. Am J Physiol Endocrinol Metab 300: E592-E599, 2011. First published January 4, 2011; doi:10.1152/ajpendo.00560.2010.-During pregnancy, plasma ACTH and cortisol are chronically increased; this appears to occur through a reset of hypothalamo-pituitary-adrenal (HPA) activity. We have hypothesized that differences in mineralocorticoid receptor activity in pregnancy may alter feedback inhibition of the HPA axis. We tested the effect of MR antagonism in pregnant and nonpregnant ewes infused for 4 h with saline or the MR antagonist canrenoate. Pregnancy significantly increased plasma ACTH, cortisol, angiotensin II, and aldosterone. Infusion of canrenoate increased plasma ACTH, cortisol, and aldosterone in both pregnant and nonpregnant ewes; however, the temporal pattern of these responses differed between these two reproductive states. In nonpregnant ewes, plasma ACTH and cortisol transiently increased at 1 h of infusion, whereas in pregnant ewes the levels gradually increased and were significantly elevated from 2 to 4 h of infusion. MR blockade increased plasma aldosterone from 2 to 4 h in the pregnant ewes but only at 4 h in the nonpregnant ewes. In both pregnant and nonpregnant ewes, the increase in plasma aldosterone was significantly related to the timing and magnitude of the increase in plasma potassium. The results indicate a differential effect of MR activity in pregnant and nonpregnant ewes and suggest that the slow changes in ACTH, cortisol, and aldosterone are likely to be related to blockade of MR effects in the kidney rather than to effects of MR blockade in hippocampus or hypothalamus.cortisol; adrenocorticotropic hormone; pregnancy; canrenoate; aldosterone IN STUDIES OF BOTH WOMEN (8) and ewes (3), basal plasma adrenocorticotropic hormone (ACTH) and cortisol have been shown to increase during pregnancy. The increase in adrenal steroid secretion is critical for normal pregnancy. Reduction of either maternal cortisol or maternal aldosterone results in alterations in maternal and fetal physiology (19 -21). We have hypothesized that there is a change in the regulation of basal ACTH in the pregnant state. Previous studies in our laboratory in adrenalectomized sheep have shown that the concentration for cortisol replacement required to normalize basal plasma ACTH is increased in pregnancy and that replacement of pregnant ewes with cortisol to plasma concentrations similar to those measured in nonpregnant ewes increases both basal and hypotension-stimulated ACTH release (23,26). On the other hand, in studies using adrenal-intact ewes, the inhibition of ACTH produced by raising plasma cortisol above resting levels is not different during pregnancy (23). Therefore, we have hypothesized that during pregnancy the "set point" of the negative feedback regulation by cortisol is increased, and/or a greater increase in cortisol is required in the pregnant s...

Interactions of Enhanced Urocortin 2 and Mineralocorticoid Receptor Antagonism in Experimental Heart Failure

“…38,39 Both Ucn2 and CA treatments enhanced plasma cortisol levels in the present study. A stimulatory effect of MR blockade by CA on the hypothalamus-pituitary-adrenocortical axis is consistent with previous reports, 34,40 whereas the Ucn2-induced rise in cortisol may be because of an attendant increase in plasma Ucn1 (which we have formerly shown occurs after Ucn2 administration 12 presumably as a consequence of competition for the CRF 2 receptor) with subsequent activation of CRF 1 and the hypothalamus-pituitary-adrenocortical axis. 41 Although hypothalamus-pituitary-adrenocortical activation is obviously not salutary, this consequence of Ucn2 administration has been shown to be a transient event (unlike the more sustained hemodynamic, vasoactive hormone, and renal responses) both previously 15 and in the present study.…”

“…We found that CA had little impact on either PRA or plasma Ang IIresults comparable to those reported by other investigators after acute MR antagonism, 25,33,34 and although a stimulatory effect of CA on renin secretion might have been anticipated secondary to the fall in arterial pressure, this may have been countered by the concomitant renin-inhibitory increase in sodium excretion. In contrast, Ucn2, both alone and in combination with CA, significantly reduced circulating levels of both PRA and Ang II.…”

“…35 Moreover, there is some evidence suggesting that the Ucns may antagonize Ang II production via suppression of ACE levels. 18 As noted by others investigating the short-term effects of MR antagonism, 25,34,36 CA in the present study was characterized by marked (>2-fold) increases in plasma aldosterone levels, indicating successful blockade of the MR throughout the experiment. Contrarily, Ucn2 induced a significant decline in circulating aldosterone that presumably reflects the coincident decreases in plasma Ang II and perhaps potassium levels, although the latter was not reduced in a sustained fashion (≤2 hours postinfusion) as were with both Ang II and aldosterone.…”

Hypothalamic‐Pituitary‐Adrenal Axis—Feedback Control

“…MR antagonists administered intracerebroventricularly increase ACTH and/or corticosterone in rats (8,66,90,217,238,297) and MRmediated effects appear to occur over a time course of 20 min to 1 h. This is consistent with the higher affinity of the MR as compared to the GR for cortisol or corticosterone, which has been demonstrated in all species studied (243,246,249,256), and results in relatively high receptor occupancy in vivo even at basal concentrations (279). MR blockers also increase ACTH in the sheep, a species with high MR occupancy under basal conditions (186,249). In humans, inhibition of evening ACTH concentrations after administration of an oral MR agonist has been shown; this is a time when endogenous MR occupation would be low (27).…”

Serotonergic effects on feeding, but not hypothalamus-pituitary-adrenal secretion, are altered in ovine pregnancy

“…Our previous studies suggest that alterations in corticosteroid feedback effects through mineralocorticoid action and increased sensitivity to stresses, such as perceived hypovolemia, are more likely contributors to the increase in plasma ACTH (30). In contrast, our results do indicate that the role of serotonin in control of appetite may be altered in pregnancy.…”