The pathogenesis of pseudohyperaldosteronism from carbenoxolone

Armanini, Decio; Scali, M.; Zennaro, Maria Christina; Karbowiak, I.; Wallace, C.; Lewicka, Sabina; Vecsei, P.; Mantero, Franco

doi:10.1007/bf03350002

Cited by 19 publications

(13 citation statements)

References 6 publications

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“…hypovolemia, suppressed renin activity and decreased aldosterone levels. The biochemical abnormal ities are the same as in liquorice-induced hypertension 114], whereas carbenoxolone fails to induce any change in the F/E metabolite ratio, in spite of an overall decrease in F metabolite [ 15] which mimics the findings of type 2 AME syndrome 113].…”

Section: Apparent Mineralocorticoid Excess Syndromementioning

confidence: 65%

New Aspects of Mineralocorticoid Hypertension

et al. 1990

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Primary aldosteronism is the principal disorder of the zona glomerulosa, and a number of subsets have been identified: unilateral adenoma, bilateral micro- or macronodular hyperplasia (idiopathic aldosteronism) primary hyperplasia, and aldosterone-producing carcinoma, either adrenal or ectopic. The diagnostic criteria for a correct differential diagnosis of these subsets are now quite reliable, and our experience is presented in detail. Unfortunately, the pathogenesis of most of these forms is still poorly recognized and requires further investigation. An extreme sensitivity to angiotensin II is present in patients with idiopathic aldosteronism, and a role of adrenal renin is now being advocated. A peculiar form of hyperaldosteronism is the glucocorticoid-remediable subtype. An unusual sensitivity of aldosterone to ACTH is present in this form. The qualitative biochemical abnormality in this disorder consists of a marked overproduction of products of the cortisol C-18-oxidation pathway, 18-hydroxycortisol and 18-oxocortisol, which are more abundant than aldosterone and 18-hydroxycorticosterone. A family with 3 affected sibs has been studied by our group. In other clinical situations, classical zona fasciculata mineralocorticoids (deoxycorticosterone [DOC], corticosterone, and their 18-hydroxy compounds) are secreted in excess. The hypertensive diseases of this zone are rare DOC-secreting tumors and two forms of congenital adrenal hyperplasia, the 11β-hydroxylase and 17α-hydroxylase deficiency syndromes, which are identified by the presence of hypokalemia and suppressed renin activity. DOC is the only mineralocorticoid hormone (MCH) oversecreted in the 11-hydroxylase deficiency syndromes, while all ACTH-dependent MCH levels are very high in the 17-hydroxylase deficiency syndromes. The molecular basis of the gene abnormalities in these disorders is currently under investigation, and preliminary data obtained in some of our patients are presented. Finally, a syndrome of apparent mineralocorticoid (MC) excess, which is not a primary disorder of the adrenal cortex, shows the association of unexplained hypermineralocorticoid state with a decreased rate of peripheral 11β-hydroxyde-hydrogenation of cortisol (F) to cortisone (E). Studies on this syndrome have led to the hypothesis that peripheral F inactivation is the normal mechanism permitting specific MC recognition. The syndrome exists in two forms both characterized by a decreased turnover of a normal level of plasma F, but in the type 1 variant, an elevated F/E metabolite ratio is found, whereas in the type 2 variant, this ratio is normal. Three patients with the latter form have recently been described by us and are shortly illustrated. A possible role of this impaired F metabolism in the pathogenesis of other forms of hypertension, such as liquorice- and carbenoxolone-induced hypertension, has recently been suggested.

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Section: Apparent Mineralocorticoid Excess Syndromementioning

confidence: 65%

New Aspects of Mineralocorticoid Hypertension

et al. 1990

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“…CBX can inhibit the enzyme complex 11-␤-hydroxysteroid dehydrogenase and significantly suppress the reninaldosterone system (12). The partial attenuation of 11-␤-hydroxysteroid dehydrogenase activity is also believed to contribute to the suppression of PRA and to the decrease of plasma cortisol and aldosterone (1). The literature has reported that CBX, by inhibiting 11-␤-hydroxysteroid dehydrogenase type 1, may decrease the amount of active glucocorticoid in the brain and, as a result, improve verbal fluency in elderly healthy men (aged 55-75; Ref.…”

Section: Discussionmentioning

confidence: 99%

Effects of carbenoxolone on flow-mediated vasodilatation in healthy adults

Lan

Hou

Yen

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Gap junctions play a key role in maintaining the functional integrity of the vascular wall. Using carbenoxolone (CBX) as a gap junction blocker, we aimed to assess the contribution of gap junctions in the vascular wall to flow-mediated vasodilatation (FMD) in healthy adults. Percentage FMD (%FMD) and circulating vasoactive molecules/activity, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), aldosterone, cortisol, plasma renin activity (PRA), and endothelin (ET-1) , were measured in 25 healthy volunteers (mean age: 30.1 Ϯ 5.4 yr; 14 males) before and after oral administration of CBX (100 mg). %FMD decreased after ingestion of CBX (9.71 Ϯ 3.1 vs. 3.40 Ϯ 2.0%; P Ͻ 0.0001). The levels of ANP, BNP, cortisol, and ET-1 remained stationary, while both PRA and aldosterone decreased (P Ͻ 0.005) after CBX ingestion. Blood pressure and heart rate were minimally changed by CBX. Inhibition of gap junctional communication by CBX impairs FMD in healthy persons, suggesting that physiologically, vascular gap junctions participate in the maintenance of FMD. CBX does not induce the release of vasoconstricting molecules or enhance vasoconstriction, suggesting that inhibition of gap junctional communication by CBX underlies the impairment of FMD. Therefore, administering CBX in FMD examination can be a way to follow the effect of gap junctions on endothelial function, but further work remains to verify the specificity of CBX effect. flow-mediated dilation; gap junctions; vasoactive molecules THE VASCULAR ENDOTHELIUM PLAYS a central role in the regulation of vasomotor tone, thrombogenecity, and inflammation (33). Endothelial dysfunction, an indicator of impairment of these regulatory mechanisms, is a systemic disorder and a key early event in the pathogenesis of atherosclerosis (29,44). In fact, endothelial dysfunction can be detected long before the appearance of structural atherosclerotic disease and is associated with increased cardiovascular risk (47). Accumulated data indicated that atherosclerotic cardiovascular disease also affects endothelial gap junctions, which are involved in maintaining functional integrity of the endothelium (21,22,48).Gap junctions are cell membrane protein channels made of connexins. Our previous study showed that downregulation of endothelial gap junctions is a common phenomenon in various disorders that induce and accelerate atherosclerosis (16), such as hypertension (23), hyperlipidemia (49), and diabetes (15) in cases where endothelial dysfunction exists. In addition, we (46) recently reported that in cultured endothelial cells, reduction of gap junctions per se leads to the development of endothelial dysfunction. However, all of this information comes from cell culture and animal experiments; thus, the contribution of gap junctions to the maintenance of endothelial function in humans remains unclear. To clarify the role of gap junctions, we hypothesized that gap junction blockade impairs flow-mediated vasodilatation (FMD), a clinically applicable examination for evaluat...

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“…81 • Radioreceptorassay for plasma mineralocorticoid receptor activity. 84,96,97 • Binding of aldosterone to MR in kidney cytosol and mononuclear leukocytes. 18 • Urinary tetrahydrocortisol (THF), tetrahydrocortisone (THE), allo-THF, cortisol and cortisone; with calculation of the ratios THF+alloTHF/THE and cortisol/cortisone.…”

Section: Table 1 Methods That Evaluate the Effect Of Aldosterone And mentioning

confidence: 99%

“…By means of this method, the in vivo interaction of licorice and carbenoxolone metabolites with MR was investigated in the plasma of treated subjects. 84,85,97 In recent years, new methods have been developed that evaluate in vitro gene expression.…”

Section: Table 1 Methods That Evaluate the Effect Of Aldosterone And mentioning

confidence: 99%

“…The same authors also demonstrated the pathogenetic mechanism of carbenoxolone in humans, which is due both to a direct binding of the drug to MR and to an enhancement of the activity of endogenous aldosterone or cortisol. 84 • In 1989 Agarwal et al cloned the gene for 11HSD1. 34 All these findings sparked intense research on 11HSD and mineralocorticoid receptors, and in the following years the progress of genetic studies produced a great amount of work, which continues to this day, on the different genes involved in pseudohyperaldosteronism syndromes, their expression, their regulatory mechanisms, and their mutations.…”

Section: Historical Notesmentioning

confidence: 97%

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Pseudohyperaldosteronism: Pathogenetic Mechanisms

Armanini

Calò

Semplicini

2003

Critical Reviews in Clinical Laboratory Sciences

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Pseudohyperaldosteronism is characterized by a clinical picture of hyperaldosteronism with suppression of plasma renin activity and aldosterone. Pseudohyperaldosteronism can be due to a direct mineralocorticoid effect, as with desoxycorticosterone, fluorohydrocortisone, fluoroprednisolone, estrogens, and the ingestion of high amounts of glycyrrhetinic acid. A block of 11-hydroxysteroid-dehydrogenase type 2 (11HSD2), the enzyme that converts cortisol into cortisone, at the level of epithelial target tissues of aldosterone, is involved in other cases. This mechanism is related either to a mutation of the gene, which encodes 11HSD2 (apparent mineralocorticoid excess syndrome and some cases of low renin hypertension) or to an acquired reduction of the activity of the enzyme due to glycyrrhetinic acid, carbenoxolone, and grapefruit juice. In other cases saturation of 11HSD2 may be involved as in severe Cushing's syndrome and chronic therapy with some corticosteroids. Recently, an activating mutation of the mineralocorticoid receptor gene has been described. Another genetic cause of pseudohyperaldosteronism is the syndrome of Liddle, which is due to a mutation of the gene encoding for beta and gamma subunits of the sodium channels.

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The pathogenesis of pseudohyperaldosteronism from carbenoxolone

Cited by 19 publications

References 6 publications

New Aspects of Mineralocorticoid Hypertension

New Aspects of Mineralocorticoid Hypertension

Effects of carbenoxolone on flow-mediated vasodilatation in healthy adults

Pseudohyperaldosteronism: Pathogenetic Mechanisms

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