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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the conversion of cortisol to cortisone and plays an important role in the mammalian kidney in regulating cortisol access to the mineralocorticoid receptor. 11 beta HSD-deficient states, such as the syndrome of apparent mineralocorticoid excess (AME), and licorice ingestion result in hypertension in which cortisol acts as a mineralocorticoid. A gene and complementary DNA sequence encoding type I human 11 beta HSD have been described, but this gene is normal in patients with AME. Separate 11 beta HSD isoforms have been described in rat and rabbit kidney, but 11 beta HSD has not been characterized in human kidney. Kinetic analysis of 11 beta HSD activity in human fetal kidney microsomes revealed only a high affinity isoform (apparent Km, 60 nmol/L for cortisol, 13 nmol/L for corticosterone), the activity of which was exclusively nicotinamide adenine dinucleotide (NAD) dependent. No 11-oxo-reductase activity was seen in either renal homogenates or microsomes. 11 beta-Dehydrogenase activity was inhibited by glycyrrhetinic acid (the active ingredient in licorice) in a competitive fashion, with a Ki of 8.7 nmol/L. This 11 beta HSD isoform was clearly distinct from the type I h11 beta HSD enzyme, in that COS-1 cells transfected with type I h11 beta HSD complementary DNA expressed a low affinity (apparent Km, 2.13 mumol/L) isoform, the activity of which was NAD phosphate dependent. 11-Oxo-reductase activity was present in intact transfected cells (apparent Km for cortisone, 0.36 mumol/L), but not in cell lysates. In contrast to the cloned, low affinity, type I h11 beta HSD enzyme, human kidney contains a high affinity NAD-dependent 11 beta HSD isoform. It seems probable that this isoform is responsible for protecting the renal mineralocorticoid receptor from glucocorticoid excess, and a defect in its activity may explain AME.
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PMID:Human kidney 11 beta-hydroxysteroid dehydrogenase is a high affinity nicotinamide adenine dinucleotide-dependent enzyme and differs from the cloned type I isoform. 804 66

The role of adrenal steroid hormones in hypertension has, until recently, focused on disorders of secretion. We describe a new form of mineralocorticoid hypertension which arises from impaired metabolism of physiological glucocorticoid. 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) is responsible for the inactivation of cortisol to cortisone. Congenital absence of this enzyme (the syndrome of apparent mineralocorticoid excess) results in cortisol acting as a potent mineralocorticoid. Furthermore, inhibition of this enzyme by glycyrrhizic and glycyrrhetinic acids also accounts for the mineralocorticoid excess states seen following licorice and carbenoxolone ingestion. Whilst impaired 11 beta-HSD activity has been shown in patients with "essential" hypertension, the significance of this finding remains unknown. These clinical studies, however, have uncovered a novel physiological mechanism, whereby the mineralocorticoid receptor (which in vitro has an equal affinity for cortisol and aldosterone) is protected from cortisol excess by the action of 11 beta-HSD. Thus 11 beta-HSD plays a crucial role in determining the in vivo specificity for this receptor.
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PMID:Steroid hormones and hypertension: the cortisol-cortisone shuttle. 811 18

Colocalization of mineralocorticoid receptors (MR) and 11 beta-hydroxysteroid dehydrogenase (11-HSD), the enzyme acting as a protector of MR, in the same cell of mineralocorticoid (MC)-responsive tissues is crucial to the concept of enzymic regulation of intracellular cortisol levels in these tissues. Such colocalization was demonstrated in the epithelial cells of the renal distal tubule. The aim of the present study was to examine if MR and 11-HSD activity can be colocalized in cells of another target tissue to mineralocorticoids, the arteries. Vascular smooth muscle (VSM) cells were cultured, and absence of dedifferentiation was ascertained up to the eighth passage. High affinity binding of [3H]aldosterone (ALDO) was demonstrated in the intact cultured cells, and Kd and Bmax values were calculated from Scatchard plots. The activity of 11-HSD was demonstrated in the cultured cells by incubating them with [3H]-cortisol in the presence of cofactors, and isolating [3H]-cortisone. Other [3H]-metabolites formed were 11 beta-hydroxy- and 11-keto-androstenedione. These data support the view that arterial tree is a target organ for mineralocorticoids and may be of importance in the pathogenetic mechanism of MC-induced hypertension.
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PMID:Colocalization of 11 beta-hydroxysteroid dehydrogenase and mineralocorticoid receptors in cultured vascular smooth muscle cells. 813 2

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) modulates the access of corticosteroids to their receptors and plays an important role in controlling blood pressure. We determined 11 beta-HSD activity and mRNA levels in the mesenteric arteries of genetically hypertensive rats, the Dahl salt-sensitive hypertensive rat, and compared them with Dahl salt-resistant and Sprague-Dawley rats. 11 beta-HSD activity was expressed as the percent conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone. 11 beta-HSD activity was significantly decreased in the mesenteric arteries of 8-week-old Dahl salt-sensitive hypertensive rats (11.4 +/- 1.4%) compared with Dahl salt-resistant rats (17.4 +/- 1.4%) or Sprague-Dawley rats (18.0 +/- 1.5%) of the same age (P < .05). There were no significant differences in 11 beta-HSD activity between 4-week-old Dahl salt-sensitive hypertensive and Dahl salt-resistant rats of the same age (15.3 +/- 1.3% and 15.1 +/- 1.9%, respectively). The concentration of 11 beta-HSD mRNA in the mesenteric arteries of 8-week-old Dahl salt-sensitive hypertensive rats was significantly lower than in Dahl salt-resistant or Sprague-Dawley rats of the same age (P < .05). There were no significant differences in the concentration of 11 beta-HSD mRNA in the mesenteric arteries of 4-week-old Dahl salt-sensitive hypertensive rats, Dahl salt-resistant rats, and Sprague-Dawley rats. These results indicate that 11 beta-HSD in the vascular wall may play a role in the pathogenesis of hypertension in this rat model.
Hypertension 1994 May
PMID:Gene expression of 11 beta-hydroxysteroid dehydrogenase in the mesenteric arteries of genetically hypertensive rats. 817 64

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) activity in mesenteric arteries of 4-week- and 8-week-old Dahl rats was determined to evaluate the relationship between glucocorticoids and norepinephrine in hypertension, 11 beta-HSD activity (expressed as the percentage conversion of 3H-corticosterone (B) to 3H-11-dehydrocorticosterone (A)) significantly decreased in 8-week-old Dahl salt-sensitive (DS) rats (11.4 +/- 1.4%) compared with Dahl salt-resistant (DR) rats (15.3 +/- 0.3%) (p < 0.05) when each group was fed a high-sodium chow (7%) for 4 weeks. There were no significant differences in 11 beta-HSD activity in the 4-week-old DS and DR rats. The enhanced response of mesenteric arteries to norepinephrine was observed only in 8-week-old DS rats. Our results suggest that a decreased 11 beta-HSD activity in the vascular walls contributes to the increased response of norepinephrine by local increment of glucocorticoids in DS hypertensive rats.
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PMID:Decreased activity of 11 beta-hydroxysteroid dehydrogenase in mesenteric arteries of Dahl salt-sensitive rats. 819 6

1. 11 beta-Hydroxysteroid dehydrogenase (11-HSD) activity in mesenteric arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was determined and expressed as the percentage conversion of [3H]-corticosterone to [3H]-11-dehydrocorticosterone. 2. 11-HSD activity was significantly decreased in mesenteric arteries of both 4 and 9 week old SHR (8.4 +/- 0.8%, 5.0 +/- 1.5%, respectively) compared with WKY rats (12.4 +/- 0.6%, 15.8 +/- 0.7%, respectively; P < 0.05). 3. Total RNA from rat vascular smooth muscle cells (VSMC) and endothelial cells (EC) were prepared with selective precipitation in 3 mol/L LiCl/6 mol/L urea. The expression of 11-HSD mRNA was confirmed in the rat VSMC but its mRNA expression was not detected in EC, using northern blot analysis. 4. The results in this study indicate that 11-HSD in the vascular wall may play a role in the pathogenesis of hypertension in SHR.
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PMID:11 beta-Hydroxysteroid dehydrogenase activity in mesenteric arteries of spontaneously hypertensive rats. 826 57

11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyzes the reversible conversion of physiological glucocorticoids (cortisol, corticosterone) to inactive products. The enzyme thus protects non-selective renal mineralocorticoid receptors from circulating glucocorticoids (ensuring aldosterone-selectivity in vivo), excludes maternal glucocorticoids from the foetal circulation and modulates glucocorticoid access to glucocorticoid receptors in other tissues. 11 beta-HSD has been purified from rat liver, antisera raised, a cDNA isolated and its human homologue cloned. However, it is difficult to reconcile all of the actions of 11 beta-HSD with a single enzyme. Here data are reviewed that demonstrate not only molecular heterogeneity of the 'liver-type' 11 beta-HSD, but also the existence of a novel high affinity isoform in the placenta and perhaps distal nephron. These data are discussed in the light of their potential physiological and pathological importance, with particular reference to the pathogenesis of hypertension.
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PMID:11 beta-hydroxysteroid dehydrogenase isoforms and their implications for blood pressure regulation. 828 78

Apparent mineralocorticoid excess (AME) is a rare form of low renin hypertension caused by deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme responsible for conversion of cortisol to the bio-inactive metabolite, cortisone. This results in prolonged cortisol half-life, activation of type I (mineralocorticoid) receptors by cortisol, sodium and fluid retention, and consequent childhood-onset hypertension. The cortisol secretion rate is low, perhaps due to cortisol's binding to type II (glucocorticoid) receptors and suppressing corticotropin secretion. Patients with AME thus lack stigmata of Cushing's syndrome. To evaluate any potential contribution of the type II (glucocorticoid) receptor to the development of hypertension in AME patients, we administered RU486, a steroid analogue that acts as a pure type II receptor blocker. Selective glucocorticoid receptor blockade did not decrease blood pressure in our patient; instead, a significant increase in average blood pressure was observed (125.1 +/- 1.7 pre-RU486 v 144.7 +/- 1.2 during RU486 treatment, P = .0001). We conclude that the type II receptor does not contribute to the development of hypertension in patients with AME.
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PMID:Investigation of the mechanism of hypertension in apparent mineralocorticoid excess. 839 54

A characteristic feature of the ectopic ACTH syndrome is a state of mineralocorticoid excess, although the etiology remains obscure. Some forms of endocrine hypertension, such as licorice ingestion, have been explained by cortisol acting as a mineralocorticoid in the setting of inhibition or deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme is responsible for the conversion of cortisol (F) to hormonally inactive cortisone, and its activity in vivo can be inferred from the ratio of the urinary excretion of tetrahydrocortisol (THF) and its isomer (5 alpha THF) to tetrahydrocortisone. Twenty-two patients with Cushing's syndrome (11 pituitary dependent, 9 ectopic, and 2 adrenal adenomas) and 13 controls were studied. Compared to controls. Cushing's patients had a significant increase (P < 0.001) in the excretion of all principal metabolites of F, secondary to a 5- to 6-fold increase in the cortisol secretion rate [median, 34.0 (range, 13.3-327) mg/day in Cushing's vs. 6.1 (range, 2.5-10.3) mg/day in controls]. The THF plus 5 alpha THF/tetrahydrocortisone ratio was significantly increased in Cushing's syndrome regardless of etiology [mean, 1.81 (range, 1.09-9.99) in Cushing's vs. 0.81 (range, 0.51-1.47) in controls; P < 0.001), indicative of defective 11 beta HSD activity. Furthermore, compared to patients with pituitary-dependent Cushing's, this ratio was significantly higher in patients with the ectopic ACTH syndrome (4.12 vs. 1.49; P < 0.01) and was inversely correlated with serum potassium levels (r = -0.57; P = 0.01; n = 22). One explanation for the mineralocorticoid excess state of the ectopic ACTH syndrome appears to be that cortisol gains inappropriate access to the mineralocorticoid receptor through failure of its normal metabolism by 11 beta HSD. The reason for the defective 11 beta HSD activity is unclear, but it may be secondary to substrate saturation, inhibition by other adrenal steroids, or product inhibition.
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PMID:11 beta-Hydroxysteroid dehydrogenase activity in Cushing's syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome. 853 Jun 9

Excessive foetal exposure to glucocorticoids retards growth and "programmes" adult hypertension in rats. Placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which catalyses the conversion of corticosterone and cortisol to inert 11 keto-products, normally protects the foetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11 beta-HSD, and enzyme activity correlates with birth weight. Moreover, inhibition of placental 11 beta-HSD in the rat reduces birth weight and produces hypertensive adult offspring, many months after prenatal treatment with enzyme inhibitors; these effects are dependent upon maternal adrenal products. These data suggest that placental 11 beta-HSD, by regulating foetal exposure to maternal glucocorticoids, crucially determines foeto-placental growth and the programming of hypertension. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11 beta-HSD activity. Thus, deficiency of the placental barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and foeto-placental programming of later disease. These data may, at least in part, explain the human epidemiological observations linking early life events to the risk of subsequent hypertension. The recent characterization, purification and cDNA cloning of a distinct human placental 11 beta-HSD (type 2) will aid the further study of these intriguing findings.
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PMID:Placental 11 beta-hydroxysteroid dehydrogenase and the programming of hypertension. 854 69


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