Investigating the function of an aldosterone response pathway in primary human adrenocortical cells obtained from Conn's and phaeochromocytoma patients

Burton, Timothy J.; Azizan, Elena

doi:10.1016/j.ejphar.2011.01.051

Cited by 6 publications

(6 citation statements)

References 25 publications

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“…Two reports are potentially relevant to these possibilities. In contrast to the present studies in normal ZG cells where RU 486 had no effect on aldosterone secretion, in two altered conditions, primary aldosterone tumor cells (Burton et al 2011) and Zucker obese hypertensive rats (Clapham & Turner 1997), RU 486 suppressed plasma aldosterone but not plasma corticosterone levels. Similar to the present study, RU 486 did not alter aldosterone levels in the control rats (Clapham & Turner 1997).…”

Section: Discussioncontrasting

confidence: 99%

“…Activation of the MR was not performed. Because similar levels of aldosterone and cortisol were found in the cell preparations, cellular admixture was present or an altered cell type was present (Burton et al 2011). Finally, the results of the present study may be applicable to the regulation of steroids outside the adrenal with their likely physiologic and clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of aldosterone secretion by mineralocorticoid receptor–mediated signaling

Chong

Hamid

Yao

et al. 2017

Journal of Endocrinology

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We posit the existence of a paracrine/autocrine negative feedback loop, mediated by the mineralocorticoid receptor (MR), regulating aldosterone secretion. To assess this hypothesis we asked whether altering MR activity in zona glomerulosa (ZG) cells affects aldosterone production. To this end, we studied ex vivo ZG cells isolated from male Wistar rats fed chow containing either high (1.6% Na+ [HS]) or low (0.03% Na+ [LS]) amount of sodium. Western blot analyses demonstrated that MR was present in both the ZG and zona fasciculata/zona reticularis (ZF/ZR/ZR). In ZG cells isolated from rats on LS chow, MR activation by fludrocortisone produced a 20% and 60% reduction in aldosterone secretion basally and in response to angiotensin II (ANGII) stimulation, respectively. Corticosterone secretion was increased in these cells suggesting that aldosterone synthase activity was being reduced by fludrocortisone. In contrast, canrenoic acid, an MR antagonist, enhanced aldosterone production by up to 30% both basally and in response to ANGII. Similar responses were observed in ZG cells from rats fed HS. Modulating glucocorticoid receptor (GR) activity did not alter aldosterone production by ZG cells; however, altering GR activity did modify corticosterone production from ZF/ZR/ZR cells both basally and in response to adrenocorticotropic hormone (ACTH). Additionally, activating the MR in ZF/ZR/ZR cells strikingly reduced corticosterone secretion. In summary, these data support the hypothesis that negative ultra-short feedback loops regulate adrenal steroidogenesis. In the ZG, aldosterone secretion is regulated by the MR, but not the GR, an effect that appears to be secondary to a change in aldosterone synthase activity.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of aldosterone secretion by mineralocorticoid receptor–mediated signaling

Chong

Hamid

Yao

et al. 2017

Journal of Endocrinology

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“…The existence of an ultra-short intraadrenal regulatory loop involving cortisol has also been investigated in humans. The presence of glucocorticoid receptor mRNAs has been evidenced in normal cortex, as well as in cortisol-producing and non-functioning adrenocortical adenomas by northern blot, RT-PCR, and microarray experiments (181,184,185,186). However, other studies failed to detect the glucocorticoid receptor by binding experiments (187) or immunohistochemistry in normal cortex and benign adrenocortical tumors (186,188).…”

Section: Factorsmentioning

confidence: 98%

“…Molecular studies have revealed expression of mineralocorticoid receptor mRNA in normal adrenal gland and aldosterone-producing adenomas (180,181). Nevertheless, the lack of effect of the mineralocorticoid receptor antagonists, canrenoate and eplerenone, on aldosterone production by adrenocortical cells derived from normal gland and Conn's adenoma (181), indicates that aldosterone does not exert a control on its own release.…”

Section: Factorsmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Lefebvre

Prévost

Louiset

2013

European Journal of Endocrinology

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A wide variety of autocrine/paracrine bioactive signals are able to modulate corticosteroid secretion in the human adrenal gland. These regulatory factors, released in the vicinity of adrenocortical cells by diverse cell types comprising chromaffin cells, nerve terminals, cells of the immune system, endothelial cells, and adipocytes, include neuropeptides, biogenic amines, and cytokines. A growing body of evidence now suggests that paracrine mechanisms may also play an important role in the physiopathology of adrenocortical hyperplasias and tumors responsible for primary adrenal steroid excess. These intra-adrenal regulatory systems, although globally involving the same actors as those observed in the normal gland, display alterations at different levels, which reinforce the capacity of paracrine factors to stimulate the activity of adrenocortical cells. The main modifications in the adrenal local control systems reported by now include hyperplasia of cells producing the paracrine factors and abnormal expression of the latter and their receptors. Because steroid-secreting adrenal neoplasms are independent of the classical endocrine regulatory factors angiotensin II and ACTH, which are respectively suppressed by hyperaldosteronism and hypercortisolism, these lesions have long been considered as autonomous tissues. However, the presence of stimulatory substances within the neoplastic tissues suggests that steroid hypersecretion is driven by autocrine/paracrine loops that should be regarded as promising targets for pharmacological treatments of primary adrenal disorders. This new potential therapeutic approach may constitute an alternative to surgical removal of the lesions that is classically recommended in order to cure steroid excess.European Journal of Endocrinology 169 R115-R138

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“…In man, it appears that there is little long-term effect of amiloride on aldosterone. An initial increase in plasma aldosterone has been reported, possibly secondary to reflex activation of the renin-angiotensin system by acute BP-lowering or volume contraction,33,61 but this effect does not persist 34,62. Amiloride may have a nonuniform effect on BP and may be more effective in individuals with lower degrees of activation of the renin-angiotensin system, including African Americans 5 and patients with HA but further studies are needed.There are obvious limitations to the present study, which is purely observational in nature and as such is hypothesis-generating rather than hypothesis-testing.…”

mentioning

confidence: 99%

Maintenance of long‐term blood pressure control and vascular health by low‐dose amiloride‐based therapy in hyperaldosteronism

Izzo

Hong

Hussain

et al. 2019

J of Clinical Hypertension

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Whether aldosterone itself contributes directly to macro‐ or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long‐term single‐practice experience in an unusual group of five patients with chronic hyperaldosteronism (HA, including three with glucocorticoid‐remediable aldosteronism, GRA) treated with low‐dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5‐10 (mean 7) mg daily for 14‐28 (mean 20) years. Except for one GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normalized within 1‐4 weeks after starting amiloride and office BP’s remained well controlled throughout the next two decades. 24‐hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, reflection magnitude), regional pulse wave velocities, pulse stiffening ratio, ankle‐brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio were measured after a mean of 18 years; all of these indicators were essentially normal. Over two additional years of observation (100 patient‐years total), no cardiovascular or renal event occurred. We conclude that long‐term ENaC blockade with amiloride can normalize BP and protect macro‐ and microvascular function in patients with HA. This suggests that either (a) putative vasculopathic effects of aldosterone are mediated via ENaC or (b) aldosterone may not play a direct role in age‐dependent vasculopathic changes in humans independent of blood pressure. These findings, coupled with our literature review in both animal and human results, underscore the need for additional studies.

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Investigating the function of an aldosterone response pathway in primary human adrenocortical cells obtained from Conn's and phaeochromocytoma patients

Cited by 6 publications

References 25 publications

Regulation of aldosterone secretion by mineralocorticoid receptor–mediated signaling

Regulation of aldosterone secretion by mineralocorticoid receptor–mediated signaling

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Maintenance of long‐term blood pressure control and vascular health by low‐dose amiloride‐based therapy in hyperaldosteronism

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