Prolonged ACTH infusion suppresses aldosterone secretion in spite of high renin activity

Oelkers, W.; Harendt, H.; Exner, P.

doi:10.1530/acta.0.1080091

Cited by 40 publications

(20 citation statements)

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“…As a consequence, over a period of many years, the adrenal will be exposed to a hyperplastic influence of this peptide. We have speculated that, in contrast to previous studies which showed a decrease in aldosterone production following chronic stimulation with supraphysiological concentrations of ACTH (Oelkers 1985), this subtle increase in ACTH over time leads to increased sensitivity of aldosterone to a range of trophins, including Ang II and K + . In subjects with high Na + intake (and possibly in the context of other permissive genetic variations) this will progress to an eventual phenotype of PA with bilateral adrenal hyperplasia.…”

Section: Aldosterone Deficiencycontrasting

confidence: 64%

The new biology of aldosterone

Connell¹,

Davies²

2005

Journal of Endocrinology

311

258

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Classically, aldosterone is synthesised in the adrenal zona glomerulosa and binds to specific mineralocorticoid receptors located in the cytosol of target epithelial cells. Translocation of the resulting steroid receptor complex to the cell nucleus modulates gene expression and translation of specific 'aldosterone-induced' proteins that regulate electrolyte and fluid balance. However, non-epithelial and rapid non-genomic actions of aldosterone have also been described that account for a variety of actions of aldosterone that contribute to blood pressure homeostasis. These include key actions on endothelial cells and on cardiac tissue.There is also evidence that aldosterone can be synthesised in other tissues; the most convincing evidence relates to the central nervous system. However, suggestions that aldosterone is produced in the heart remain controversial, and adrenal derived aldosterone is the principal source of circulating and locally available hormone.Recent studies have shown major therapeutic benefits of mineralocorticoid receptor antagonism in cardiac failure, which emphasise the importance of aldosterone in causing adverse cardiovascular pathophysiological effects. Additional evidence demonstrates that aldosterone levels predict development of high blood pressure in normotensive subjects, while it is now clear that increased aldosterone action contributes to hypertension and cardiovascular damage in approximately 10% of patients with established hypertension.These new findings highlight the role of aldosterone as a key cardiovascular hormone and extend our understanding of its role in determining adverse cardiovascular outcomes.

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Section: Aldosterone Deficiencycontrasting

confidence: 64%

The new biology of aldosterone

Connell¹,

Davies²

2005

Journal of Endocrinology

311

258

View full text Add to dashboard Cite

show abstract

“…Although ACTH is a potent stimulant of aldosterone secretion in acute conditions, prolonged administration in humans or rats causes a decline of plasma aldosterone to basal levels (37)(38)(39)(40)(41), associated with decreases in adrenal glomerulosa All receptors, increases in side-chain cleavage activity, and marked decreases in aldosterone synthetase activity (37). Studies in humans have shown that prolonged ACTH administration inhibits aldosterone secretion in spite of high renin activity (41), which would be homologous to the present experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Hyperreninemic hypoaldosteronism after chronic stress in the rat.

Aguilera¹,

Kiss²,

Sunar-Akbasak³

1995

J. Clin. Invest.

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The effects of chronic stress on the renin-angiotensin-aldosterone system were studied by analysis of plasma hormone levels, kidney renin mRNA levels, adrenal angiotensin II receptors, and steroidogenesis in rats subjected to repeated immobilization (2 h daily) or intraperitoneal injections of 1.5 M NaCl for 14 d. 24 h after the last stress in both stress models, plasma aldosterone levels were reduced in spite of significant increases in plasma renin activity. Repeatedly intraperitoneal hypertonic saline-injected rats showed plasma renin activity responses to acute immobilization similar to controls, but markedly reduced plasma aldosterone responses. Concomitant with the increases in plasma renin activity, renin mRNA levels in the kidney were significantly increased in intraperitoneal hypertonic saline-injected rats, and these increases were prevented by ,B-adrenergic receptor blockade with propranolol. In isolated adrenal glomerulosa cells from chronically stressed rats, maximum aldosterone responses to angiotensin II, ACTH, and 8-Br-cAMP were significantly decreased, whereas pregnenolone responses were increased. P450-aldosterone synthetase mRNA levels and binding of '"I-[Sar',Ile8]angiotensin II were significantly reduced in the adrenal zona glomerulosa of stressed rats. These studies show that chronic repeated stress leads to renin stimulation due to sympathetic activation, and inhibition of aldosterone secretion due to inhibition of the late steroidogenic pathway. The data provide evidence for a role of chronic stress in the development of hyperreninemic hypoaldosteronism. (J. Clin. Invest. 1995. 96:1512-1519

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“…43 Although ACTH is reported to cause only short-term stimulation of aldosterone secretion, experiments have concentrated on very unphysiological exposure of the adrenal to grossly excessive amounts of ACTH, in which aldosterone production decreases within a few days. 44 It is noteworthy that in patients with ACTH-dependent Cushing's disease, who have exposure of the adrenal cortex to stimulation by ACTH for a sustained period, aldosterone concentrations are neither diminished nor increased. 4 In this circumstance, the secretion of 18-oxocortisol is also increased, confirming that chronic ACTH excess does not lead to downregulation of expression of CYP11B2.…”

Section: Implications Of Altered 11␤-hydroxylation In Hypertensionmentioning

confidence: 99%

Is Altered Adrenal Steroid Biosynthesis a Key Intermediate Phenotype in Hypertension?

et al. 2003

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Abstract-Approximately 10% of patients with hypertension have a high ratio of aldosterone to renin, but the reason for this and the relationships among low-renin essential hypertension, elevation of the ratio, and true primary aldosteronism are unclear. We have previously reported that a polymorphism of the gene (C-to-T conversion at position Ϫ344) encoding aldosterone synthase is associated with hypertension, particularly in patients with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11␤-hydroxylation. In this review, we propose that altered conversion of deoxycortisol to cortisol leads to a subtle, chronic increase in adrenocortrophin drive to the adrenal cortex, with eventual development of hyperplasia. In combination with other genetic or environmental factors (such as dietary sodium intake), we suggest that this might be responsible for the long-term development of a resetting of the aldosterone response to angiotensin II, giving rise to the phenotype of hypertension with a raised ratio.In some subjects, this may progress further to true primary aldosteronism with a dominant adrenal nodule. Thus, there may be a genetically influenced continuum from hypertension with a normal ratio, through hypertension with a raised ratio, and primary aldosteronism. Key Words: hypertension, mineralocorticoid Ⅲ adrenal gland Ⅲ aldosterone Ⅲ adrenocorticotropic hormone Despite many years of research, the pathophysiology of essential hypertension remains uncertain, and it seems likely that no single cause exists. This may best be appreciated by considering the lessons from rodent models of hypertension. Here, selective inbreeding has generated strains that develop high blood pressure through a range of distinct mechanisms. For example, the role of adducin in the Milan hypertensive rat contrasts with the involvement of corticosteroids in the Dahl salt-sensitive strain; in each instance, distinct genetic loci can be identified to account for the development of high blood pressure. 1,2 Nevertheless, in both types of hypertension, the phenotype is exacerbated by sodium loading, and only careful study of the intermediate phenotype (in this instance, measurement of adrenal steroid production) allows the pathogenesis to be understood. The same argument can be applied to human hypertension, and it would be naïve to anticipate that the same underlying mechanism was present in all patients with high blood pressure. However, careful study of subgroups might identify common mechanisms that account for the rise in pressure and offer guidance to the best therapeutic option. In this regard, the contribution of adrenal steroids deserves careful review. At a gross level, of course, corticosteroids clearly do have an important role in the development of hypertension. Patients with Addison's disease are hypotensive, 3 glucocorticoid excess in patients with Cushing's syndrome is associated with high blood pressure, 4 and the role of a major excess of aldosterone in classic Conn's synd...

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Prolonged ACTH infusion suppresses aldosterone secretion in spite of high renin activity

Cited by 40 publications

References 0 publications

The new biology of aldosterone

The new biology of aldosterone

Hyperreninemic hypoaldosteronism after chronic stress in the rat.

Is Altered Adrenal Steroid Biosynthesis a Key Intermediate Phenotype in Hypertension?

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