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Embryology, Anatomy, and Physiology of the Adrenal Glands
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Zona glomerulosa (ZG)Secretes the mineralocorticoid aldosterone and increases sodium reabsorption and potassium excretion.Expresses aldosterone synthase.
Cardiac Damage from Left Ventricular Hypertrophy to Heart Failure
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Enrico Agabiti Rosei, Maria Lorenza Muiesan, Cesare Cuspidi
Epidemiological data clearly indicate that dietary salt intake modifies the process of LVH in hypertensive subjects as well (27,28). This has been reported irrespective of whether dietary salt intake has been assessed by measuring 24-h urine sodium excretion in clinical stable conditions or by directly measuring the salt ingested with food. Of note, this relationship has been found to be independent of 24-h blood pressure, body weight and other clinical determinants of LVH (28,29). In normotensive and hypertensive rats, high salt intake induced myocardial hypertrophy and fibrosis that was found to be related to increased aldosterone synthase activity and production of aldosterone in the myocardium despite decreased plasma renin activity and lowered plasma aldosterone concentration in the systemic circulation (30). Most recent trials have indicated that increases in intracellular sodium lead to an up-regulation of growth-stimulating genes, thereby directly inducing growth-stimulating signals.
Endocrine hypertension
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Frances McManus, John M. Connell, Marie Freel
The etiology of these conditions remains largely unknown, and whether APAs arise from nodular adrenal glands or whether the two conditions are independent is a matter of much debate. However, it has been shown that tissue around the resected adenoma differs from normal adrenal tissue and has undergone remodeling with reduced vascularization and zona glomerulosa hyperplasia.13 In contrast, a comparison of the transcriptome of peritumoral tissue, APA tissue, and normal adrenal tissue suggests that it is not an intermediate step in the formation of APAs. Another interesting phenomenon observed is that, in contrast to what would be expected, aldosterone synthase expression elsewhere in the adrenal gland is not suppressed and indeed is persistently expressed in aldosterone-producing cell clusters, sometimes quite distant to the adenoma.13,14
A novel homozygous CYP17A1 mutation causes partial 17 α-hydroxylase/17,20-lyase deficiency in 46,XX: a case report and literature review
Published in Blood Pressure, 2023
Heye Chen, Yingting Chen, Hongxian Mao, Huaying Huang, Xueyong Lou
17-OHD usually causes low-renin, low-aldosterone hypertension. The low aldosterone levels in patients with 17-OHD was due to excessive accumulation of the mineralocorticoid precursors, and transcriptional downregulation of aldosterone synthase [17]. However, in our study, aldosterone level was unsuppressed in six out of eight patients, with one patient’s aldosterone level even elevated. This is consistent with a few studies which also found unsuppressed aldosterone level in some of patients with 17-OHD [9,11,18] and one recent study reported higher aldosterone levels in patients with 17-OHD than healthy controls (p = .003) [13]. These might be related to a cross-reaction between ALD and DOC or the function of the residual 17 α-hydroxylase/17,20-lyase activity. In a word, normal or elevated aldosterone level cannot rule out suspicion for 17-OHD.
A patent review of aldosterone synthase inhibitors (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Alternatively, inhibition of CYP11B2, a key enzyme involved in aldosterone biosynthesis pathway, represents another novel and effective approach to reduce aldosterone levels in circulating plasma. The safety and feasibility of AS inhibition has been well recognized in preclinical and clinical studies, both in vitro and in vivo by small molecule inhibitors. Since early PoC by a nonselective ASI FAD286 in several rat disease models, the discovery of ASI has been actively pursued by industrial and academia. The observation of decreased cortisol levels in clinical trials for LCI699 enabled subsequent efforts on improving selectivity over hCYP11B1. Since 2014, more than 28 patent applications have been published targeting aldosterone synthase for the treatment of disorders associated with elevated aldosterone levels. Even though most of the examples still share similar heme-binding scaffolds as previously patented, selectivity over hCYP11B1 has been significantly improved. In addition, novel chemo-types that lack a typical heme-binding group have also been described by Boehringer Ingelheim, including pyranoimidazolones, fused isoxazoles, and bicyclic-imidazoles. Furthermore, differences in the co-crystal structure of hCYP11B2 and hCYP11B1 in complex with fadrozole also provide more insight into the design of a selective inhibitor [100,101]. With several more selective ASI having been identified, further research is urgently required, particularly into areas such as long-term efficacy in protecting a diverse range of organs.
Familial hyperaldosteronism type 1 and pregnancy: successful treatment with low dose dexamethasone
Published in Blood Pressure, 2021
Viola Sanga, Livia Lenzini, Teresa Maria Seccia, Gian Paolo Rossi
The discovery of a chimeric gene highlighted the molecular basis of FH-1 in 1992 as this gene derives from an unequal crossing-over of two genes that are 95% homologous and map close on chromosome 8q24 [1]: the CYP11B1 gene encoding for 11-β hydroxylase, the enzyme forming cortisol, and the CYP11B2 gene that encodes for aldosterone synthase. The adrenocorticotropic hormone (ACTH) responsive elements in the chimeric gene accounted for the ectopic expression of aldosterone synthase, the CYP11B2 product, in the adrenocortical zona fasciculata and for FH-1 remittance in response to glucocorticoid treatment. Genetic testing now permits a conclusive diagnosis and institution of a glucocorticoid treatment to suppress the ACTH-drive, which corrects the hyperaldosteronism and normalises the high blood pressure (BP) values.