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

The adrenal cortex synthesizes and releases steroid hormones, mainly mineralocorticoids and glucocorticoids. There is a functional zonation of the adrenal cortex and steroid synthesis is thoroughly regulated. Overproduction of aldosterone, primary aldosteronism, may be much more common than previously known and may be responsible for 10% of essential hypertension. Primary aldosteronism is characterized by autonomous production of aldosterone, suppressed renin activity, hypokalemia, and hypertension. The two most common forms are unilateral adenoma and bilateral hyperplasia. In spite of thorough clinical workup and careful histopathology it is often difficult to differentiate between adenoma and hyperplasia. The gene CYP11B2 encodes the steroid synthesizing enzymes for aldosterone production, while the genes CYP17 and CYP11B1 are needed for cortisol production. Most normal controls show expression of CYP11B2 in zona glomerulosa. Expression of CYP11B1 and CYP17 is seen in zona fasciculata and reticularis, whereas the expression of CYP21 is present in all three cortical layers. Adenomas from patients with primary aldosteronism show considerable variation in the expression of CYP11B2. Adenomas from patients with Cushing's syndrome have a strong expression of CYP11B1 and CYP17. In a patient material of 29 cases of primary aldosteronism, 4 patients had small nodules detected with expression of CYP11B2 gene. These nodules were not visualized on CT, whereas adrenal masses seen on CT in these patients showed CYP11B1 and CYP17 gene expression. This suggests that these small nodules are responsible for the aldosterone production and this is characteristic of nodular hyperplasia in patients with primary aldosteronism. In conclusion, this method to visualize mRNA gene expression of steroidogenic enzymes, and especially expression of CYP11B2, has increased the knowledge of adrenal pathophysiology. The results emphasize the value to include functional studies (venous sampling and/or scintigraphy) in the preoperative work up of patients with primary aldosteronism.
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PMID:New aspects on primary aldosteronism. 1260 5

About 3% of our hypertensive patients have high blood pressure induced by corticosteroids. Muscle weakness, tiredness, polyuria and polydipsia may indicate hypokalaemia. Hypokalaemic hypertension in the presence of a low plasma renin activity is the typical finding of corticosteroid hypertension. The most frequent cause of corticosteroid hypertension is primary aldosteronism (Conn's syndrome) due to an adrenal adenoma or bilateral hyperplasia of the adrenal glands. The plasma concentration of aldosterone and the ratio between plasma aldosterone and renin concentrations are high, and the kaliuresis exceeds 30 mmol/24 h in the presence of hypokalaemia. Adrenal carcinomas are rare and very malignant. The localization of an adrenal tumour is made by computer tomography (CT-scan) or nuclear magnetic resonance imaging and by measurement of the aldosterone/cortisol concentrations in the adrenal venous blood. Adenomas are removed under laparoscopy, and adrenal hyperplasias are treated with spironolactone (50-400 mg daily) or amiloride (5-30 mg daily). In rare cases (<1%), excessive stimulation of the mineralocorticoid receptor is due to cortisol (apparent mineralocorticoid excess, Cushing's disease, liquorice, or hereditary deficiency of 11beta-hydroxysteroid dehydrogenase) or to a chimeric gene coding for 11beta-hydroxylase (CYP11B1/CYP11B2). In these rare cases, the synthesis of aldosterone is under the control of the adrenocorticotrophic hormone, so treatment with glucocorticoids (dexamethasone 0.25-1.0 mg daily) is therefore possible (glucocorticoid-remediable aldosteronism). Excessive deoxycorticosterone (DOC) causes the same symptoms and signs as hyperaldosteronism. Excessive DOC is found in patients with adrenal tumours that secrete DOC, in those with hereditary or acquired disorders with dysfunctioning glucocorticoid receptors, or in those with congenital hyperplasia of the adrenal glands (deficiency of 17alpha-hydroxylase or 11beta-hydroxylase). Liddle's syndrome is a constitutive hyperactivity of the transepithelial transport of sodium, which under normal conditions is controlled by the mineralocorticoid receptor. Plasma renin and aldosterone concentrations are suppressed and the plasma potassium concentration may be normal. In contrast, plasma aldosterone and renin concentrations are increased in patients with hypokalaemic hypertension which represents secondary aldosteronism. The increased aldosterone is the consequence of stimulated renin activity due to renal or renovascular or other disorders, antihypertensive drugs or other medications. In conclusion, a work-up for corticosteroid-induced hypertension is indicated in patients with hypokalaemic hypertension and in those with severe hypertension even in the absence of hypokalaemia, and in hypertensive patients with a family history of cardiovascular diseases.
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PMID:Investigating mineralocorticoid hypertension. 1292 4

11beta-hydroxylase deficiency, an autosomal recessive disorder, is the second most common cause of congenital adrenal hyperplasia. We studied four subjects with classic 11beta-hydroxylase deficiency and severe hypertension: a 46,XX affected subject from a Turkish family with severe ambiguity of the external genitalia and hypertension, and three affected 46,XY subjects from a Dominican kindred with isosexual precocious puberty and severe hypertension. The affected subjects had significantly elevated plasma 11-desoxycortisol, 11-desoxycorticosterone, Delta4-androstenedione, and testosterone. To determine the molecular genetic defects, genomic DNA was isolated from the leukocytes of affected subjects and their family members. The encoding region of the 11beta-hydroxylase gene (CYP11B1) was amplified by PCR with specific primers. Using single-stranded DNA conformational polymorphism (SSCP) and DNA sequencing, a nonsense mutation in exon 6 of CYP11B1 in the affected 46,XX subject from the Turkish family was identified, where a cytosine was substituted by a thymidine, resulting in the replacement of glutamine (CAG) by a stop codon (TAG) at amino acid position 338 (Q338X). In the three 46,XY Dominican boys, the mutation was also a nonsense mutation in exon 6 of CYP11B1, where a cytosine was substituted by a thymidine, resulting in the replacement of glutamine (CAG) by a stop codon (TAG) at amino acid position 356 (Q356X). Both mutations result in the biosynthesis of a truncated 11beta-hydroxylase protein with loss of enzymatic activity. Heterozygosity was determined in family members of both probands including parents and siblings. These results indicate that mutations of CYP11B1 in these subjects are responsible for their clinical syndromes.
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PMID:Mutations in CYP11B1 gene: phenotype-genotype correlations. 1296 19

Using the genome-wide screening data of the Framingham Heart Study (394 nuclear families, 1328 genotyped subjects, 397 marker loci) we have quantified the underlying genetic diversity through high-dimensional genetic feature vectors and constructed a genetic vector space for the analysis of population substructure. Adaptive clustering procedures led to three major subgroups that were regarded as being related to "biological" ethnicity and that included more than 70% of the subjects. Based on these subgroups we addressed the question of ethnicity-related and ethnicity-independent risk factors for coronary heart disease (CHD). To this end, we relied upon hypertension as an endophenotype of CHD and applied a multivariate sib-pair method in order to search for oligogenic marker configurations for which the sib-sib similarities deviated from the parent-offspring similarities. Indeed, the latter similarities are always "0.5" irrespective of the affection status of parents and offspring. Loci with significant contributions to the oligogenic marker configuration constituted a CHD-specific genetic vector space. We found several ethnicity-independent signals. One signal on chromosome 8 may relate to the CYP11B1/CYP11B2 genes.
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PMID:Similarity by state/descent and genetic vector spaces: analysis of a longitudinal family study. 1497 27

Genetic polymorphisms of the aldosterone synthase gene (CYP11B2) have been major targets of studies into the genetic factors involved in hypertension. We have identified three genetic variants of CYP11B2, -344C/T at the promoter region, a conversion in intron 2 from the CYP11B2 sequence to the CYP11B1 sequence, and R173K in exon 3, in the Japanese population. -344C/T and R173K were in complete linkage disequilibrium in CYP11B2, and -344C/T was in strong, but not complete, linkage disequilibrium with the polymorphism in intron 2. Thus, two genetic polymorphisms, -344C/T and the gene conversion in intron 2, were investigated in association with home blood pressure (BP) values and clinical parameters in 1,242 subjects aged 40 and over in Ohasama, a rural Japanese community. Hypertension was defined as being treated with antihypertensive medication and/or having home BP values of more than 135 mmHg in systole and/or 85 mmHg in diastole. The results demonstrated that the -344T allele was significantly associated with increased prevalence of hypertension (p=0.015 in multiple logistic regression analysis, adjusted by age, gender, BMI, and smoking status), though BP level was unaltered. This allele was also significantly related to the prevalence of cardiovascular diseases in the older population (60 < or = age, p=0.014). The resting polymorphism, a gene conversion in CYP11B2 intron 2, was not associated with any clinical parameters. Therefore, -344C/T polymorphism in CYP11B2 was considered an independent genetic factor possibly associated with hypertension or atherosclerotic diseases in the Japanese population.
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PMID:CYP11B2 polymorphisms and home blood pressure in a population-based cohort in Japanese: the Ohasama study. 1505 49

Over the last few years, much progress has been made in understanding the genetic basis of primary aldosteronism. This has led to the diagnosis of the familial forms and has aided the understanding of the basis of sporadic forms of the disease. Such information can be exploited to improve the therapeutic approaches used not only for patients with primary aldosteronism, but also with other forms of hypertension. Here, we review the genetic and the phenotypic features of the familial forms, the genetic variants that influence the sporadic forms and the structure and regulation of the CYP11B1 and CYP11B2 genes.
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PMID:Genetics of primary aldosteronism. 1512

Two key players in adrenal steroid hormone biosynthesis are the human mitochondrial cytochrome P450 enzymes CYP11B1 and CYP11B2 that catalyze the final steps in the biosynthesis of cortisol and aldosterone, respectively. Overproduction of both hormones contributes to a number of severe diseases, as illustrated by the association of elevated aldosterone levels with hypertension and higher mortality in congestive heart failure, and by Cushing's syndrome as the clinical correlate of chronic hypercortisolism. Thus, CYP11B1 and CYP11B2 comprise new targets for drug treatment and selective inhibitors of both enzymes are of high pharmacological interest. To facilitate the search for such compounds, we have established novel test procedures using recombinant fission yeast strains that stably express these enzymes. The aim of this study was to compare the inhibition profiles displayed by these enzymes in established mammalian cell culture test systems to those obtained with the new fission yeast assays, and to evaluate the usefulness of the Schizosaccharomyces pombe strains as screening systems for the identification of novel lead compounds. Using these test systems, we were able to identify a new and very selective CYP11B2 inhibitor (SIAS-1) that displayed no detectable interference with CYP11B1 activity.
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PMID:Development of test systems for the discovery of selective human aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) inhibitors. Discovery of a new lead compound for the therapy of congestive heart failure, myocardial fibrosis and hypertension. 1513 25

The terminal stages in the synthesis of aldosterone and cortisol are catalysed by the enzymes aldosterone synthase and 11beta-hydroxylase respectively. We have previously reported that polymorphic variation in the 5' promoter region (-344C/T) of the gene encoding aldosterone synthase (CYP11B2) is associated with increased aldosterone metabolite excretion and with hypertension associated with a raised aldosterone to renin ratio (ARR). Additionally, basal and ACTH-stimulated plasma levels of 11-deoxycortisol, the precursor of cortisol, are higher in subjects carrying the T-allelic variant. We have now identified in a family study (573 individuals from 105 extended families ascertained through a hypertensive proband) that excretion of the main metabolite of this steroid (tetrahydro-11-deoxycortisol, THS) is heritable (19.4%) and that the T-allele of CYP11B2 is more strongly associated with higher THS levels than the C-allele. Raised plasma and urinary levels of 11-deoxycortisol suggest that there is relative inefficiency of 11beta-hydroxylation in the zona fasciculata; the P450 enzyme responsible for this step is encoded by the gene CYP11B1, which is highly homologous with and adjacent to CYP11B2. The association of genetic variation in the promoter of CYP11B2 which, in the adrenal cortex, is only expressed in zona glomerulosa, and zona fasciculata 11beta-hydroxylation function is paradoxical. There may be linkage dys-equilibrium between this polymorphism and a quantitative trait locus (QTL) in CYP11B1. Chronic alteration of 11beta-hydroxylase activity may increase ACTH drive to the adrenal cortex, altering the regulation of aldosterone synthesis. This may explain, at least partly, the association between CYP11B2 polymorphisms and hypertension.
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PMID:The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation. 1513 24

After earlier studies in which secretion of aldosterone was demonstrated to be important in rat arterial smooth muscle cell (RASMC) proliferation in vitro, the presence of both 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) gene transcription were shown in these cells by real-time reverse transcription-polymerase chain reaction (RT-PCR). In proliferation studies, tritiated thymidine incorporation into RASMC and RASMC cell number were both significantly increased by angiotensin II (Ang II) (10(-7) mol/L) compared with controls (P<0.01), but this effect was inhibited by the 3beta-hydroxysteroid-dehydrogenase inhibitor trilostane (10(-6) mol/L and 10(-5) mol/L, P<0.05). Aldosterone alone added to RASMC did not significantly change tritiated thymidine incorporation when compared with controls, but the Ang II-induced increase was significantly enhanced by aldosterone at 10(-10) mol/L and 10(-8) mol/L (P<0.05). Neither corticosterone nor 18-hydroxydeoxycorticosterone had any such potentiating effect. RT-PCR analysis and real-time quantitative RT-PCR revealed an increase of Ang II type-1 (AT1) receptor mRNA in RASMC treated by aldosterone (10(-8) mol/L) compared with untreated controls, and this was correlated with a small but significant increase in AT1 receptor protein (P<0.05), as assessed by immunoblotting analysis. These data confirm that steroid production by RASMC is critical in the response to Ang II, and the data support the view that aldosterone specifically is required for the full proliferative response to Ang II in RASMC. One way it may act is by modulating the expression and functions of the AT1 receptor.
Hypertension 2004 Sep
PMID:Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation. 1530 41

Primary aldosteronism is a disorder characterized by hypertension and hypokalemia due to aldosterone secretion out of renin-angiotensin control. It is generally caused by aldosterone-producing adenoma or adrenocortical hyperplasia but, in some cases, it is due to genetic alterations. Familial type I hyperaldosteronism is the result of anomalous regulation of aldosterone secretion from ACTH (which normally regulates cortisol synthesis). Aldosterone hypersecretion can be suppressed by exogenous glucocortcoids such as dexamethasone. This autosomal dominant disorder is caused by unequal cross-over between two genes with wide sequence homology: CYP11B1 and CYP11B2. The hybrid gene is the product of fusion between the ACTH-responsive regulatory portion of the 11b-hydroxylase gene (CYP11B1) and the coding region of the aldosterone synthase gene (CYP11B2). Familial type I hyperaldosteronism is a disease with incomplete penetration and variable expressivity, especially in relation to hypertension. The marked variability in hypertension severity can mirror an interaction between the hybrid gene and other hereditary factors involved in the regulation of blood pressure. Familial type II hyperaldosteronism is another autosomal dominant form of hyperaldosteronism due to aldosterone hyper-secretion not suppressible by dexamethasone. This disorder is unrelated to mutation of the hybrid gene. The genetic cause of type II hyperaldosteronism is presently unknown, but a genome-wide search has revealed that the disorder is linked with a locus on chromosome 7 in a region that corresponds to cytogenetic band 7p22.
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PMID:[Familial hyperaldosteronism]. 1535 48


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