Impaired 11-β Hydroxysteroid Dehydrogenase Type 2 Activity in Sweat Gland Ducts in Human Essential Hypertension

Abstract

Abstract-The enzyme 11-␤ hydroxysteroid dehydrogenase type 2 plays a major role in blood pressure regulation. It metabolizes glucocorticoid hormones into derivatives with low affinity for the mineralocorticoid receptor, preventing its permanent occupancy by circulating cortisol, which is 100-to 1000-fold more abundant than aldosterone in the plasma. Inactivating mutations of the enzyme result in severe hypertension, as seen in children with apparent mineralocorticoid excess syndrome. In patients with essential hypertension, however, attempts to evidence enzyme deficiency have been inconclusive. In this pilot study, its catalytic activity was measured directly in aldosterone-sensitive sweat gland ducts collected from skin biopsy samples of 10 male normotensive subjects and 10 subjects with essential hypertension (more than 140 to 90 mm Hg) with no sign of hypermineralocorticism. Isolated ducts were assayed for nicotinamide-dinucleotide-dependent dehydrogenase activity (transformation of tritiated corticosterone into tritiated-11 dehydrocorticosterone, as measured by high-pressure liquid chromatography). Hypertensive patients exhibited significantly lower 11-␤ hydroxysteroid dehydrogenase type 2 activity (9.7Ϯ4.7 femtomoles per 3 mm length of duct and per 10 minutes incubation, medianϮSD) than did normotensive subjects (15.9Ϯ2.6). Such defect was undetectable using the classical urinary corticosteroid metabolism indexes, probably because of compensatory mechanisms. Relations between these findings and blood pressure levels should benefit from direct enzyme measurements in the vasculature. In conclusion, this cross-sectional study points to partial 11-␤ hydroxysteroid dehydrogenase type 2 deficiency as a novel feature of essential hypertension, which should stimulate search for new signaling pathways and therapeutical targets. Key Words: mineralocorticoids Ⅲ aldosterone Ⅲ corticosterone Ⅲ hypertension Ⅲ clinical trials H ypertension has a major impact on population morbidity, justifying sustained efforts to search for novel pathogenic pathways to improve our understanding of blood pressure regulation. The enzyme 11-␤ hydroxysteroid dehydrogenase type 2 (HSD2) could be a candidate in the pathogenesis of essential hypertension in humans. HSD2 metabolizes glucocorticoid hormones into 11-dehydroderivatives with low affinity for the mineralocorticoid receptor (MR), preventing permanent occupancy of MR by circulating cortisol, which is 100-to 1000-fold more abundant in the plasma than the MR ligand aldosterone. [1][2][3][4] The clinical importance of HSD2 is highlighted by inactivating mutations found in the syndrome of apparent mineralocorticoid excess, a rare genetic defect characterized by early onset of severe low-renin hypokalemic hypertension. 5-7 Hypertension also occurs after chronic ingestion of liquorice, whose active metabolite, glycyrrhetinic acid, inhibits HSD2 activity. 8 -10 More recently, it has been proposed that reduced activity of HSD2 could contribute to the pathogenesis of human essential hyperten...

11β Hydroxysteroid dehydrogenase type 2 and dietary acid load are independently associated with blood pressure in healthy children and adolescents

“…The importance of the enzymatic inactivation of cortisol to cortisone by 11bHSD2 for BP regulation, apart from the clinical syndrome of apparent mineralocorticoid excess, has been suggested by lower 11bHSD2 activity in hypertensive than normotensive adults in several studies (8,9,33). However, few studies have tried to determine whether 11bHSD2 may also be relevant for BP regulation in the normotensive and prehypertensive range.…”

The Dehydrogenase Hypothesis

“…Measuring salivary cortisone has been postulated a potential biomarker of serum free cortisol [ 176 ]. In addition, reduced activity of 11β (Beta)-HSD2 in sweat glands has also been linked with essential hypertension [ 177 ].…”

The Role of Aldosterone Blockade in Patients with Hypertensive Heart and Cardiovascular Disease

“…[20][21][22][23][24][25][26] In the renal tubule the MR is protected from activation by cortisol, which has a greater affinity for the MR than aldosterone, by the enzyme 11 Beta HSD 2. This enzyme may however be down regulated in patients with essential hypertension [27][28][29] such that cortisol may also play a role in MR activation in the renal tubule. In the myocardium this enzyme is less abundant and it is thought that cortisol occupies the MR and under circumstances of increased oxidative stress cortisol may activate the MR with all of its deleterious consequences.…”