Effect of acute and prolonged mineralocorticoid receptor blockade on spontaneous and stimulated hypothalamic-pituitary-adrenal axis in humans.
ABSTRACT Mineralocorticoid receptors (MRs) in the hippocampus display an important role in the control of the hypothalamic-pituitary-adrenal (HPA) axis, mediating the proactive feedback of glucocorticoids, which maintains the basal HPA activity. The systemic administration of MR antagonists enhances spontaneous and CRH-stimulated ACTH, cortisol, and DHEA secretion, while the effects of chronic treatment with MR antagonists are scanty. Our study was performed in order to clarify this point.
ACTH, cortisol, and DHEA levels were studied during the infusion of placebo, canrenoate, a MR antagonist (CAN, 200 mg i.v. bolus at 1600 h followed by 200 mg infused over 4 h), and human CRH (hCRH; 2.0 microg/kg i.v. bolus at 1800 h) before and during the last week of 28-day treatment with CAN (200 mg/day p.o.) in eight young women.
Pre-treatment sessions: CAN and hCRH administration increased ACTH, cortisol, and DHEA levels versus placebo (P<0.05). Post-treatment sessions: during placebo infusion, cortisol and DHEA were significantly amplified versus pre-treatment session (P<0.05), while ACTH levels were not modified; CAN infusion, differently from pre-treatment session, was not able to significantly increase ACTH, cortisol, and DHEA levels; ACTH, cortisol, and DHEA responses to hCRH were amplified with respect to pre-treatment session, although statistical significance was obtained for cortisol and DHEA only.
MR blockade by acute CAN administration significantly enhances the HPA activity in the afternoon, during the quiescent phase of the circadian rhythm. At the same period, prolonged treatment with CAN amplifies both spontaneous and CRH-stimulated activities of the HPA axis, while it blunts the HPA responsiveness to a further MR-mediated stimulation.
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ABSTRACT: Effects of spironolactone, canrenone and canrenoate-K on adrenal cytochrome P450 (P450) and corticosteroid biosynthesis were examined by studying difference spectra, P450 reduction and corticoid hydroxylation in mitochondrial preparations isolated from zona fasciculata and zona glomerulosa of bovine adrenals and from adrenal adenoma and hyperplastic adrenal cortex removed from patients with hyperaldosteronism. All three agents bound to P450 producing type I difference spectra and underwent hydroxylation. They all inhibited 11beta-hydroxylation in bovine adrenal at 30 muM and higher concentrations. Canrenone, the most potent inhibitor, blocked enzyme activity by 60% at a concentration of 60 muM. Spironolactone stimulated P450 reduction. The order of potency of inhibition was found to correlate with the order of affinity of these agents for P450. 11beta-Hydroxylase in human adrenal appeared to be less sensitive to canrenone. All three agents or their hydroxylated metabolites blocked 18-hydroxylation in bovine adrenal at lower concentrations. Canrenoate-K, being the most effective, inhibited 52% at 20 muM. Low concentrations of canrenone (2.5-5.0 muM) were without effect on 11beta-hydroxylase but markedly inhibited 18-hydroxylation (62-76%) in hyperplastic human adrenals. The inhibitors produced mixed type inhibition of 11beta-hydroxylation and competitive type inhibition of 18-hydroxylation. These findings indicate that at low concentrations spironolactone and its major metabolites, canrenone and canrenoate-K, or their hydroxylated metabolites, can directly interfere with the biosynthesis of aldosterone in bovine and certain human adrenal cortical tissue.Endocrinology 11/1976; 99(4):1097-106. · 4.72 Impact Factor
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ABSTRACT: The nuclear hormone receptor gene superfamily encodes structurally related proteins that regulate transcription of target genes. These macromolecules include receptors for steroid and thyroid hormones, vitamins, and other proteins for which no ligands have been found. These receptors have modular domains. The DNA-binding domain directs the receptors to bind specific DNA sequences as monomers, homodimers, or heterodimers. The ligand-binding domain responds to binding of the cognate hormone; this domain and the amino terminal domain interact with other transcription factors. Nuclear receptor-specific actions are derived from a combination of diverse elements, including availability of ligand, receptors, and nonreceptor factors; target-site structure; interactions with other proteins, such as the general transcription factors; and influences of other signaling pathways. These interactions result in ligand-regulated and ligand-independent effects on initiation of transcription of the target genes. Understanding the mechanisms of nuclear receptor action will enhance our knowledge of transcription and hormone influences on disease and facilitate the design of drugs with greater therapeutic value.Annual Review of Medicine 02/1995; 46:443-53. · 14.60 Impact Factor
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ABSTRACT: The non-activated 9S forms of several steroid hormone receptors are heterooligomeric complexes consisting of the aporeceptor and three heat shock proteins, hsp90, hsp70 and hsp56. Hsp90 appears to play a facilitatory role in high-affinity steroid binding and to promote the efficacy of steroid actions on target tissues. Circulating glucocorticoid levels have a major regulatory impact on the binding capacity of hippocampal and hypothalamic corticosteroid receptors, a phenomenon that affects the activity of the hypothalamic-pituitary-adrenal axis and neuronal excitability in general. This study demonstrates that hsp90 mRNA is present in substantial amounts in hippocampal and hypothalamic areas characterized by high densities of corticosteroid receptors, and in the thymus. Steady-state levels of hsp90 mRNA in these regions were altered by chronic changes of circulating glucocorticoid concentrations in a site-specific fashion. In the hippocampus, mRNAs coding for hsp90 and both types of corticosteroid receptors (type I, MR and type II, GR) displayed a coordinate increase following adrenalectomy and castration (ADX/GX); in the hypothalamus only hsp90 mRNA levels were elevated, and none of the parameters studied was affected in the thymus by steroid hormone deprivation. Supplementation of ADX/GX rats with various doses of corticosterone in vivo elicited differential responses. Moderate elevation of circulating corticosterone levels normalized ADX/GX-increased hsp90 mRNA concentrations in the hippocampus and the hypothalamic paraventricular nucleus (PVN); this was associated with similar changes in GR and MR mRNA levels in the hippocampus, while GR mRNA concentrations in the PVN were not altered.(ABSTRACT TRUNCATED AT 250 WORDS)Molecular and Cellular Endocrinology 08/1994; 103(1-2):57-64. · 4.04 Impact Factor