Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. 11 beta-Hydroxysteroid dehydrogenase converts cortisol to inactive cortisone in man. In distal renal tubules, this inactivation protects mineralocorticoid receptors from cortisol. Congenital 11 beta-hydroxysteroid dehydrogenase deficiency and inhibition of 11 beta-hydroxysteroid dehydrogenase by liquorice or carbenoxolone result in cortisol-dependent hypokalaemia and hypertension. 2. 11 beta-Hydroxysteroid dehydrogenase is expressed in vascular smooth muscle. Both glucocorticoids and mineralocorticoids potentiate vascular responses to noradrenaline. 11 beta-Hydroxysteroid dehydrogenase activity may therefore influence vascular tone. 3. Experiments were performed in healthy subjects with and without 7 days of oral administration of 11 beta-hydroxysteroid dehydrogenase inhibitors (liquorice or carbenoxolone), and in a patient with congenital 11 beta-hydroxysteroid dehydrogenase deficiency. We measured the following parameters: dermal vasoconstriction after topical application of cortisol, forearm blood flow during brachial artery infusion of cortisol or noradrenaline, and blood pressure during systemic infusion of noradrenaline. 4. Cortisol-induced dermal vasoconstriction was increased by liquorice (23 +/- 6 to 52 +/- 7 units; P < 0.04) and in congenital 11 beta-hydroxysteroid dehydrogenase deficiency (87 units). In congenital 11 beta-hydroxysteroid dehydrogenase deficiency intraarterial infusion of cortisol caused vasoconstriction (20% reduction in blood flow in the infused arm) and accentuated the response to application of lower-body negative pressure, which stimulates sympathetically mediated vasoconstriction (35% reduction). However, intra-arterial infusion of cortisol had no effect in healthy subjects either with or without administration of liquorice. 5. Carbenoxolone potentiated both noradrenaline induced forearm vasoconstriction (P < 0.01) and pressor response (P < 0.001). 6. We conclude that 11 beta-hydroxysteroid dehydrogenase modulates the access of cortisol to vascular receptors and thereby influences vascular sensitivity to noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man. 132 32

Aldosterone, like other steroid hormones, initiates its effects by binding to intracellular receptors; these receptors are then able to control the transcription of several genes. The products of these genes eventually modulate the activity of ionic transport systems located in the apical and the basolateral membrane of specialized epithelial cells, thereby modulating the excretion of Na+ and K+ ions. Considerable progress has been made recently in understanding these mechanisms and the structure of the proteins involved in these processes. A novel principle has been discovered to explain the selective effect of aldosterone on its target epithelia. These tissues exclude competing glucocorticoid hormones by the activity of the 11 beta-hydroxysteroid dehydrogenase to allow aldosterone, an enzyme-resistant steroid, to bind to its receptors. Aldosterone induces numerous changes in the activity of membrane ion transport systems and enzymes and cell morphology. Although the enhancement of Na,K-ATPase synthesis and the increase of the number of active Na+ channels in the apical membrane appear as both direct and primary effects, the mechanisms of the other effects remain to be determined. The knowledge of the primary structure of several elements of the aldosterone response system (e.g., mineralocorticoid receptor and Na,K-ATPase) allows us to understand abnormal regulation of Na+ balance at the molecular level and, potentially, to identify genetic alterations responsible for these defects.
Hypertension 1992 Mar
PMID:Aldosterone regulation of gene transcription leading to control of ion transport. 137 88

The apparent mineralocorticoid excess syndrome of patients ingesting large amounts of licorice or its derivatives is thought to be caused by the antagonism by these compounds of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). 11 beta-HSD inactivates cortisol and corticosterone, allowing the more abundantly produced glucocorticoids access to the mineralocorticoid receptor (MR) in the kidney, where they act as mineralocorticoids. We have found that the infusion of both glycyrrhizic acid, an active principle of licorice, and carbenoxolone, a synthetic analogue, into a lateral ventricle of the brain [intracerebroventricular (icv)] of a rat, at a dose less than that which has an effect when infused subcutaneously, produces hypertension. Furthermore, the hypertension produced by the oral administration of carbenoxolone or glycyrrhizic acid is blocked by the icv administration of RU 28318, an MR antagonist, at a dose below that which has an effect on blood pressure when infused subcutaneously. While the oral administration caused saline polydipsia and polyuria typical of chronic systemic mineralocorticoid excess, the icv licorice derivatives produced hypertension without affecting saline appetite. Sensitizing the rats to mineralocorticoid hypertension by renal mass reduction and increasing salt consumption was not necessary for the production of hypertension. These findings provide additional evidence for a central role in blood pressure control by mineralocorticoids that is distinct from their renal effects. They also suggest that more is involved in licorice-induced hypertension than only inhibition of 11 beta-HSD.
 ...
PMID:Central hypertensinogenic effects of glycyrrhizic acid and carbenoxolone. 147 86

Eleven-beta-hydroxysteroid dehydrogenase (11 beta OHSD) protects the aldosterone receptor (MR) against its occupancy by glucocorticoid hormones. We examined the intrarenal distribution of 11 beta OHSD, as compared to that of MR. MR were localized in histological sections from rabbit kidney, using immunohistochemical methods with an anti-MR monoclonal antibody. 11 beta OHSD activity was measured in isolated tubular segments from rabbit, rat and mouse kidneys. Tubules were incubated in the presence of tritiated corticosterone (3H-B:2 x 10(-8)M). Then the rate of degradation of 3H-B into 3H-11-dehydrocorticosterone (3H-A) was determined by HPLC. MR was immunodetected in the distal tubule and the collecting duct. No positive staining was present in the proximal tubule. The conversion rate of 3H-B into 3H-A was high (approximately 80%) in the distal and collecting tubule. It was low in the proximal tubule (less than 15%) except in the rat (approximately 50%). These results indicate that MR and 11OHSD are colocalized along the mammalian nephron. This colocalization constitutes a strong argument in favor of the MR-protective role of 11 beta OHSD, and of a role of a defect of this enzyme in the genesis of some types of arterial hypertension.
 ...
PMID:[A new regulatory mechanism of the action of corticosteroid hormones: cellular 11beta-hydroxycorticosteroid dehydrogenase]. 150 75

Patients with the syndrome of apparent mineralocorticoid excess and those who ingest licorice show markedly decreased 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) and 5 beta-reductase activity; both are important for the deactivation of glucocorticoids and other steroid hormones. Glycyrrhetinic acid (GA), present as its glycoside in licorice, is a potent inhibitor of both 11 beta-OHSD and 5 beta-reductase and, as we have also shown, confers Na(+)-retaining properties on glucocorticoids and amplifies those of aldosterone and deoxycorticosterone. We report the results of our initial studies demonstrating the presence of naturally occurring substances, which inhibit both 5 beta-reductase and 11 beta-OHSD as does GA, in partially purified extracts of urine from normotensive men and nonpregnant and pregnant women. Since these substances exhibit GA-like activity, we have termed them GA-like factors (GALFs). This "inhibitory" material is heat stable and does not react with ninhydrin; the majority is not extractable with ethyl acetate and thus is not a "free" steroid. When further purified by high-performance liquid chromatography with a methanol/water gradient, the majority of these GALFs appeared in two regions of inhibitory activity. The chemical nature of this material is currently being investigated. These experiments indicate that normal human urine contains GALFs that may play a role in Na+ homeostasis and regulation of blood pressure.
Hypertension 1992 Sep
PMID:Detection of glycyrrhetinic acid-like factors (GALFs) in human urine. 151 55

Deficiency of steroid 11 beta-hydroxylase, which is a mitochondrial cytochrome P450 required for cortisol and aldosterone synthesis, causes hypertension as well as virilization. In addition, abnormal regulation of this enzyme or a closely related isozyme may be involved in an autosomal dominant form of inherited hypertension, dexamethasone-suppressible hyperaldosteronism. An enzyme that catalyzes the interconversion of cortisol and cortisone, 11 beta-hydroxysteroid dehydrogenase, may be defective in an autosomal recessive form of hypertension termed apparent mineralocorticoid excess. The molecular bases of these forms of hypertension will be elucidated by identifying mutations in the 11 beta-hydroxylase and 11 beta-hydroxysteroid dehydrogenase genes and expressing normal and mutagenized enzymes in cultured cells.
 ...
PMID:Defects in cortisol metabolism causing low-renin hypertension. 187 83

The Type I (mineralocorticoid) receptor has identical affinities in vitro for cortisol and aldosterone. It has been suggested that the selective role of aldosterone in regulating sodium homeostasis relies on the microsomal enzyme 11 beta-hydroxysteroid dehydrogenase (11-HSD). This enzyme converts cortisol to its inactive metabolite, cortisone, preventing cortisol from binding to the Type I receptor. We have isolated human cDNA clones encoding 11-HSD from a human testis cDNA library by hybridization with a previously isolated rat 11-HSD cDNA clone. The cDNA contains an open reading frame of 876 bases, which predicts a protein of 292 amino acids. The sequence is 77% identical at the amino acid level to rat 11-HSD cDNA. The mRNA is widely expressed, but the level of expression is highest in the liver. Hybridization of the human 11-HSD cDNA to a human-hamster hybrid cell panel localized the single corresponding HSD11 gene to chromosome 1. This gene was isolated from a chromosome 1 specific library using the cDNA as a probe. HSD11 consists of 6 exons and is at least 9 kilobases long. The data developed in this study should be applicable to the study of patients with hypertension due to apparent mineralocorticoid excess, a deficiency in 11-HSD activity.
 ...
PMID:The human gene for 11 beta-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization. 188 95

1. From an earlier cross-sectional survey of 343 public servants, 15 pairs of non-smoking teetotallers and heavy drinkers (alcohol intake more than 350 mL/week) were matched for age and adiposity and utilized for a case-control study of the effects of alcohol on 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) activity and blood pressure. 2. Two successive 24 h urine collections were analysed by radio-immunoassay (RIA) for cortisol excretion, and for the cortisol and cortisone metabolites, tetrahydrocortisol (THC), allo-tetrahydrocortisol (allo-THC) and tetrahydrocortisone (THE), by capillary column gas chromatography. 3. Heavy drinkers had higher systolic and diastolic blood pressure (BP) than teetotallers (132.6 +/- 2.5 vs 123.2 +/- 1.3 and 78.7 +/- 1.6 vs 71.7 +/- 1.4, respectively; unpaired t-test, P less than 0.01). Twenty-four-hour urinary sodium and cortisol excretion were similar in the two groups. 4. The THC plus allo-THC:THE ratio was similar in drinkers and teetotallers (1.81 +/- 0.20 vs 2.03 +/- 0.20), consistent with no effect of alcohol on 11 beta-OHSD activity. The ratio of THC to allo-THC was increased in drinkers compared with teetotallers (1.49 +/- 0.18 vs 1.05 +/- 0.13; unpaired t-test, P less than 0.05), consistent with either a decrease in 5 alpha-reductase activity or an increase in 5 beta-reductase activity. 5. This study provides no evidence for alcohol-related inhibition of 11 beta-OHSD, despite substantially higher blood pressures in heavy drinkers compared to teetotallers. Such an effect is, therefore, unlikely to contribute significantly to the mechanism of alcohol-related hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Urinary steroid profiles and alcohol-related blood pressure elevation. 206 72

Carbenoxolone sodium, CS, a liquorice derivative associated with hypertension and sodium retention, has been demonstrated to inhibit 11 beta-hydroxysteroid dehydrogenase, an enzyme that metabolizes cortisol and corticosterone to their respective inactive 11-dehydro products (cortisone and 11-dehydrocorticosterone). It has been proposed that the increased bioavailability of unmetabolized corticosterone and cortisol following 11 beta-OHSD inhibition allows these steroids to act on renal mineralocorticoid receptors to elicit the mineralocorticoid action. Here we describe how CS amplifies the antinatriuretic activity of aldosterone and deoxycorticosterone; the latter steroid is of particular importance in that it does not possess a hydroxyl group at the C-11 position in the steroid ring, indicating that another mechanism(s) in addition to 11 beta-OHSD inhibition is responsible for the amplification of the action of deoxycorticosterone.
 ...
PMID:The 11 beta-OHSD inhibitor, carbenoxolone, enhances Na retention by aldosterone and 11-deoxycorticosterone. 231 75

Ingestion of licorice or treatment with chemical derivatives of glycyrrhetinic acid (GA), an active principle of licorice, can cause hypertension, sodium retention, and hypokalemia. Although GA has been shown to inhibit 11 beta-hydroxysteroid dehydrogenase, it may not be the only hepatic enzyme affected by this licorice derivative. Therefore, we studied the effects of GA on other major hepatic steroid-metabolizing enzymes from adrenalectomized male rats using aldosterone as the substrate; namely, delta 4-5 alpha- and delta 4-5 beta-reductases and 3 alpha- and 3 beta-hydroxysteroid dehydrogenases (3 alpha- and 3 beta-HSD). From these in vitro studies, we demonstrated that GA does not affect either microsomal 5 alpha-reductase or cytosolic 3 alpha-HSD activity. However, GA is a potent inhibitor of cytosolic 5 beta-reductase; the K(is) and K(ii) were calculated from enzyme kinetic analysis to be 6.79 and 5.41 microM, respectively, using the Cleland equation, indicating that GA is a noncompetitive inhibitor of aldosterone. In addition, GA specifically inhibited microsomal 3 beta-HSD enzyme activity by what appears to be a competitive inhibition mechanism, causing a build-up of the intermediate, 5 alpha-dihydroaldosterone (DHAldo). Thus, this study has indicated that GA has a profound effect on hepatic ring A-reduction of aldosterone. Inhibition of 5 beta-reductase and 3 beta-HSD results in decreased synthesis of both 3 alpha, 5 beta-tetrahydroaldosterone (THAldo) and 3 beta, 5 alpha-THAldo and, hence, accumulation of aldosterone and 5 alpha-DHAldo, both potent mineralocorticoids.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The effects of the licorice derivative, glycyrrhetinic acid, on hepatic 3 alpha- and 3 beta-hydroxysteroid dehydrogenases and 5 alpha- and 5 beta-reductase pathways of metabolism of aldosterone in male rats. 232 27


1 2 3 4 5 6 7 8 9 10 Next >>