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

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) modulates the access of corticosteroids to their receptors and is important in blood pressure control. The excretion of renal 11 beta-HSD (ie, NAD(+)-dependent isoform) is thought to protect renal mineralocorticoid receptors from cortisol. To examine whether endogenous renal 11 beta-HSD inhibitory factor(s) may be involved in the pathophysiology of hypertension, we studied the urinary excretion of such inhibitors in 30 patients with low-renin essential hypertension and 20 normotensive control subjects. The effect of sodium restriction on the urinary excretion of the inhibitors wa also evaluated in six normotensive control subjects. Urine was extracted with Sep-Pak cartridges and high-performance liquid chromatography. Endogenous renal 11 beta-HSD inhibitors were measured by the inhibition of 11 beta-HSD bioactivity in microsomes from the human kidney. The urinary excretion of the inhibitors was significantly increased in patients with low-renin essential hypertension (1280 +/- 88 nmol/d, mean +/- SEM) compared with normotensive control subjects (704 +/- 56 nmol/d) (P < .05). Ratios of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone did not differ significantly. Sodium restriction reduced the urinary excretion of the endogenous renal 11 beta-HSD inhibitors but did not affect the ratio of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone. Endogenous renal 11 beta-HSD inhibitory factors may contribute to the pathogenesis of low-renin essential hypertension by modulating the activity of 11 beta-HSD. Sodium intake may directly or indirectly regulate the inhibitory factors.
Hypertension 1996 Feb
PMID:Endogenous renal 11 beta-hydroxysteroid dehydrogenase inhibitory factors in patients with low-renin essential hypertension. 856 41

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) modulates glucocorticoid interactions with mineralocorticoid and glucocorticoid receptors in vivo, by converting 11 beta-hydroxyglucocorticoids to their inactive 11-ketone derivatives. Defective 11 beta-oxidation of glucocorticoids has been associated with hypertension. The objective of this study was to investigate whether 11 beta-HSD contributes to the occurrence of hypertension in spontaneously hypertensive rats (SHRs). The liver and kidney microsomal oxidations of corticosterone (the physiological glucocorticoid in rats) in organs from juvenile (3 weeks old) and adult (3 months old) SHR and Wistar-Kyoto (WKY) rats, with NAD and NADP, show no differences between rat strains. For cortisol, with NADP, adult SHRs show (1.3-3 times; P < 0.05) lower kidney microsomal oxidation rates. The liver microsomal reduction of cortisone shows remarkable interstrain differences; with NADH, reduction is conducted only by adult WKY rats, whereas with NADPH, juvenile animals show similar reduction rates, but at adulthood, only WKYs reduce cortisone. Using Western blot analysis with antibodies against 11 beta-HSD1, positive signals are obtained only for liver microsomes, appearing somewhat lower in SHRs for juvenile but not adult animals. Urinary corticosterone/11-dehydrocorticosterone ratios (measured in adult animals) are not different between rat strains, but are elevated after administration of corticosterone in both strains (although significant only in SHRs). The data provide no indications for exaggerated stimulation of renal corticosteroid receptors, due to modified 11 beta-HSD, in SHRs. However, the experiments suggest the existence of multiple 11 beta-HSDs, in addition to 11 beta-HSD1 and 11 beta-HSD2, some of which may be modified in SHR, but the nature and physiological role of these 11 beta-HSDs is unclear.
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PMID:Comparison of 11 beta-hydroxysteroid dehydrogenase in spontaneously hypertensive and Wistar-Kyoto rats. 858 2

The progesterone derivatives 11 alpha- and 11 beta-hydroxyprogesterone are potent inhibitors of 11 beta-hydroxysteroid dehydrogenase (isoforms 1 and 2) in vitro and can confer mineralocorticoid activity on corticosterone in the rat in vivo. 11 beta-Hydroxysteroid dehydrogenase metabolizes active glucocorticoids to their inactive 11-dehydro products and protects renal mineralocorticoid receptors from the high circulating levels of endogenous glucocorticoids. 11 beta-Hydroxysteroid dehydrogenase has been suggested to be important not only in the control of renal sodium retention but also of blood pressure. To assess the possible blood pressure-modulating effects of 11 alpha- and 11 beta-hydroxyprogesterone, we infused these substances into both intact and adrenalectomized Sprague-Dawley rats continuously for 14 days. Both 11 alpha- and 11 beta-hydroxyprogesterone caused a significant elevation in blood pressure within 3 days, an effect that persisted throughout the 14-day infusion. The hypertensive effects of 11 alpha-hydroxyprogesterone were abolished by adrenalectomy and significantly attenuated when 11 alpha-hydroxyprogesterone was infused together with the specific mineralocorticoid receptor antagonist RU28318. In an additional series of experiments, 11 alpha-hydroxyprogesterone significantly amplified the hypertensive effects of corticosterone in adrenalectomized spontaneously hypertensive rats but had no effects by itself in this experimental animal. These results demonstrate that both 11 alpha- and 11 beta-hydroxyprogesterone are potently hypertensinogenic in the rat and that this activity depends on an intact adrenal and at least in part on the activation of mineralocorticoid receptors. 11 beta-Hydroxyprogesterone, and similar endogenous progesterone metabolites that inhibit 11 beta-hydroxysteroid dehydrogenase, may be involved in the pathology of certain hypertensive states.
Hypertension 1996 Mar
PMID:11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase, possess hypertensinogenic activity in the rat. 869 48

11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) specifically modulates access of the mineralocorticoid aldosterone to the kidney mineralocorticoid type 1 receptors in a physiological environment in which there is a molar excess of cortisol. Cortisol and aldosterone have similar affinities for mineralocorticoid receptors. Mechanistically, 11 beta-HSD2 converts cortisol to cortisone. The other known isoform, 11 beta-HSD1, not only catalyzes the cortisol to cortisone reaction but also the reverse reaction, making it unlikely to play an important role in modulating the access of aldosterone to mineralocorticoid receptors. Mutations in the HSD11B2 gene (both exonic and intronic) have been demonstrated to cause reduced activity of this enzyme in the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disorder. We hypothesized that this locus is also involved in the etiology of essential hypertension. To test this locus and flanking chromosomal regions for allelic association and genetic linkage to essential hypertension, it is necessary to have informative genetic markers. To this end, we have refined the localization of 11 beta-HSD2 to 16q22.1. We genotyped subjects using the nearest flanking microsatellites (D16S301 and D16S496). We conducted an association study using black subjects with hypertensive end-stage renal disease, black normotensive control subjects, and black and white individuals from the general population. We used chi 2 analysis and Fisher's exact test to test for association with these candidate gene markers. No significant association was found between D16S301 and hypertension. However, a positive association with hypertension was found at the D16S496 microsatellite locus (chi 2 = 6.98, df = 1, P < or = .008). Our data suggest that HSD11B2 is associated with hypertension in our black subjects with hypertensive end-stage renal disease. The 16q22.1 chromosome region potentially harbors a candidate gene for essential hypertension. Confirmation of our findings in another independently ascertained group of hypertensive subjects will provide a basis for proceeding with sib-pair linkage analyses.
Hypertension 1996 Sep
PMID:Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks. 879 36

Increasing human epidemiological data suggest that events that subtly retard intrauterine growth may determine common disorders, such as hypertension and non-insulin-dependent diabetes, in adult life. The underlying mechanisms are unknown. However, excessive fetal exposure to glucocorticoids retards growth and "programs" adult hypertension in rats. 11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) catalyzes the rapid inactivation of cortisol and corticosterone to inert 11 keto-products. Normally, 11 beta-HSD2 in the placenta and some fetal tissues is thought to protect the fetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11 beta-HSD2, and enzyme activity correlates with birth weight. Moreover, inhibition of feto-placental 11 beta-HSD2 in the rat reduces birth weight and produces hypertensive and hyperglycaemic adult offspring, many months after prenatal treatment; effects are dependent upon intact maternal adrenals, suggesting a direct action on the fetus or placenta. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11 beta-HSD2 activity. These data suggest that feto-placental 11 beta-HSD2, by regulating fetal exposure to maternal glucocorticoids, crucially determines fetal growth and the programming of later disorders. Deficiency of the barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and feto-placental programming of later disease. These data may, at least in part, explain the human observations linking early life events to the risk of subsequent disease.
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PMID:Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. 902 21

CONVERSION OF CORTISOL TO CORTISONE: 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) is a microsomal enzyme complex which, in humans, catalyses the interconversion between biologically active cortisol and inactive cortisone. This prereceptor signalling mechanism is essential for maintaining the aldosterone selectivity of the intrinsically non-specific mineralocorticoid receptor and for modulating glucocorticoid access to the glucocorticoid receptor. Apparent mineralocorticoid excess (AME) is a syndrome of severe low-renin mineralocorticoid hypertension associated with marked hypokalaemia which arises from a congenital deficiency of 11 beta-HSD. In AME patients, therefore, it is cortisol and not aldosterone which behaves as a potent mineralocorticoid. ISOFORMS OF 11 BETA-HSD: Two isoforms of human 11 beta-HSD have now been characterized and cloned. The type 1 isoform (11 beta-HSD1) is a low-affinity reduced nicotinamide adenine dinucleotide phosphate (NADP) dependent dehydrogenase-oxoreductase which is expressed in predominantly glucocorticoid target tissues and the encoding sequence of which is normal in patients with AME. In contrast, the type 2 isoform (11 beta-HSD2) is a high-affinity NADP-dependent unidirectional dehydrogenase which is expressed in placenta and mineralocorticoid target tissues such as renal collecting ducts and distal colonic epithelia. Exon- and intron-specific polymerase chain reaction amplification of the 11 beta-HSD2 gene from genomic DNA from members of a consanguinous kindred with AME consistently revealed a single missense mutation (C1228T) in two affected sibs and twin stillbirths. This mutation in codon 374 of exon 5 of the 11 beta-HSD2 gene creates an inframe premature stop (TGA) and, as such, results in a truncated 11 beta-HSD2 protein lacking the carboxyl-terminal proline-rich 32 amino acids. In keeping with an autosomal recessive mode of inheritance, both parents were phenotypically and biochemically normal but were heterozygous for this mutation. Unique to this kindred were expression analyses of the native mutant 11 beta-HSD2 enzyme in the stillbirth-affected placenta, which was almost completely devoid of NADP-dependent 11 beta-dehydrogenase activity. Immunohistochemical and Western blot analyses revealed the absence of 11 beta-HSD2 protein using antisera raised against synthetic peptide sequences corresponding either to the carboxyl terminus or other domains of the enzyme. MISSENSE MUTATION: In this kindred with AME, congenital deficiency of 11 beta-HSD activity is due to a single missense mutation in exon 5 of the 11 beta-HSD2 gene. Simultaneous studies by two other groups have similarly revealed no gross deletions or rearrangements of the 11 beta-HSD2 gene, but have described a number of single point mutations and oligonucleotide deletions in exons 3, 4 and 5, and adjacent to a splice site in intron 3. Recombinant expression analysis of site-directed mutant 11 beta-HSD2 complementary DNA constructs suggests a correlation between the predicted severity of these mutations and the biochemical and clinical phenotype. AME AS A CAUSE OF HYPERTENSION: The mutations in the 11 beta-HSD2 gene, together with those currently being sought by us for other kindreds with AME, establishes AME as a monogenic cause of human hypertension and will provide insight into the structure-function relationships of this important enzyme.
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PMID:Human hypertension caused by mutations in the 11 beta-hydroxysteroid dehydrogenase gene: a molecular analysis of apparent mineralocorticoid excess. 912 Jun 78

The type of small-vessel disease in small deep (lacunar) infarcts (SDIs) remains contentious as opposed to that in primary intracerebral haemorrhage (PICH), which is lipohyalinosis in most cases. Therefore, we compared risk factor profiles as indicators of underlying vessel pathology, between patients with SDI and patients with PICH, and those with a non-cardio-embolic infarct involving the cortex (CORTI). Multivariate regression analysis showed the diabetes mellitus [odds ratio (OR) 0.56; 95% confidence interval (CI) 0.34-0.90] and hypercholesterolaemia (OR 0.63; 95% CI 0.40-0.99) were more strongly associated with CORTI than with SDI. Carotid stenosis was associated with SDI in comparison with PICH (OR 7.5; 95% CI 1.02-54.94). Compared with PICH, CORTI was more strongly associated with diabetes mellitus (OR 3.27; 95% CI 1.38-7.76), carotid stenosis (OR 24.42; 95% CI 4.99-119.45), and hypercholesterolaemia (OR 3.12; 95% CI 1.47-6.65), whereas hypertension was associated with PICH (OR 0.37; 95% CI 0.18-0.79). These data support the hypothesis that small-vessel atheromatosis rather than small-vessel lipohyalinosis underlies lacunar infarcts in most cases.
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PMID:Different vascular risk factor profiles among cortical infarcts, small deep infarcts, and primary intracerebral haemorrhage point to different types of underlying vasculopathy. A study from the L'Aquila Stroke Registry. 964 76

11beta-Hydroxysteroid dehydrogenases (11beta-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. The diminished dehydrogenase activity (cortisol to cortisone) has been demonstrated in patients with essential hypertension and in resistance vessels of genetically hypertensive rats. 11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) catalyzes only 11beta-dehydrogenation. However, a functional relationship between diminished vascular 11beta-HSD2 activity and elevated blood pressure has been unclear. In this study we showed the expression and enzyme activity of 11beta-HSD2 and 11beta-HSD type 1 (which is mainly oxoreductase, converting cortisone to cortisol) in human vascular smooth muscle cells. Glucocorticoids and mineralocorticoids increase vascular tone by upregulating the receptors of pressor hormones such as angiotensin II. We found that physiological concentrations of cortisol-induced increase in angiotensin II binding were significantly enhanced by the inhibition of 11beta-HSD2 activity with an antisense DNA complementary to 11beta-HSD2 mRNA, and the enhancement was partially but significantly abolished by a selective aldosterone receptor antagonist. This may indicate that impaired 11beta-HSD2 activity in vascular wall results in increased vascular tone by the contribution of cortisol, which acts as a mineralocorticoid. In congenital 11beta-HSD deficiency and after administration of 11beta-HSD inhibitors, suppression of 11beta-HSD2 activity in the kidney has been believed to cause renal mineralocorticoid excess, resulting in sodium retention and hypertension. In the present study we provide evidence for a mechanism that could link impaired vascular 11beta-HSD2 activity, increased vascular tone, and elevated blood pressure without invoking renal sodium retention.
Hypertension 1999 May
PMID:11beta-hydroxysteroid dehydrogenase in cultured human vascular cells. Possible role in the development of hypertension. 1033 8

We analyzed the association between salt sensitivity in essential hypertension and 8 genetic polymorphisms in 6 genes of the renin-angiotensin aldosterone system. Seventy-one patients with essential hypertension were classified as salt sensitive or salt resistant by means of the 24-hour ambulatory blood pressure (BP) change to high salt intake. The polymorphisms evaluated correspond to the following genes: ACE (I/D), angiotensinogen (M235T), angiotensin II type 1 receptor (A1166C), 11beta-Hydroxysteroid dehydrogenase type 2 (11betaHSD2) (G534A), aldosterone synthase (C-344T and Intron 2 conversion), and the mineralocorticoid receptor (G3514C and A4582C); all were determined using standard polymerase chain reaction methods. Thirty-five patients (49%) were classified as salt sensitive. We analyzed the BP response to high salt intake among genotypes and found a significant association for ACE I/D and 11betaHSD2 G534A polymorphisms. Patients homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake than did patients homozygous for the deletion allele (DD). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension was also significantly higher (P=0.003) in II (68%) and DI patients (59%) compared with DD hypertensives (19%). With respect to 11betaHSD2 G534A, patients with the GG genotype had a significantly higher systolic BP increase with high salt intake than did GA patients. In addition, plasma renin activity suppression in response to high salt was significantly greater in GA patients than in GG patients. The prevalence of salt-sensitive hypertension was 14.3% in GA patients and 50.8% in GG patients (P=0.067). In conclusion, the I allele of ACE I/D polymorphism is significantly associated to salt-sensitive hypertension. The BP response to high salt intake was different among genotypes of ACE I/D and 11betaHSD G534A, suggesting that these polymorphisms may be potentially useful genetic markers of salt sensitivity.
Hypertension 2001 Nov
PMID:Molecular basis of salt sensitivity in human hypertension. Evaluation of renin-angiotensin-aldosterone system gene polymorphisms. 1171 24


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