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

The renin-angiotensin-aldosterone (RAA) system and the endothelin (ET) system entail the most potent vasopressor mechanisms identified to date. Although they were studied in depth in relation to arterial hypertension and cardiovascular diseases, limited information on their interrelationships in causing hypertension and related target organ damage exists. The identification of consensus sequences for jun in the regulatory region of the preproendothelin-1 (ppET-1) gene raised the possibility of its transcriptional regulation by angiotensin II (Ang II). This was confirmed by the finding that stimulation with Ang II of cultured vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) induced expression of the ppET-1 gene and synthesis of ET-1. Endogenously produced ET-1 was found to contribute to the hypertrophic response of cardiomyocytes to Ang II and thereby to cardiac hypertrophy. Furthermore, ET-1 exerts multifaceted effects on the RAA system, such as dose-dependent inhibition of renin synthesis, and stimulation of aldosterone secretion. The finding of abundant specific ET-1 receptors in the adrenocortical zona glomerulosa (ZG) suggested a direct secretagogue effect of ET-1. In rats, ETB receptors mediate such an effect, whilst in humans, both ETA and ETB receptor subtypes intervene in regulating the transcription of the aldosterone synthase gene. In addition, ET-1 stimulates DNA synthesis and proliferation of ZG cells via ETA receptors and, therefore, might play a role in cell turnover of the normal adrenal cortex and in the onset of adrenal tumours. Studies on the in vivo interactions between ETs and the RAA system have given conflicting results, insofar as some suggested a participation of ET-1 in the pressor and cellular effects of exogenously administered Ang II, whereas others did not in the transgenic TGR(Ren 2m)27 rats and in the two-kidney, one clip.
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PMID:Interactions between endothelin-1 and the renin-angiotensin-aldosterone system. 1069 Mar 21

The most potent corticosteroids are 11beta-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11beta-hydroxylase activity, catalysing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11beta-hydroxylase (P450c11), is expressed on high levels in the zona fasciculata and is regulated by ACTH. CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. Aldosterone synthase has 11beta-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase activity. The substrate for CYP11B2 is 11-deoxycorticosterone, that of CYP11B1 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension. Mutations in CYP11B2 cause congenital hypoaldosteronism (aldosterone synthase deficiency) which is characterized by life-threatening salt loss, failure to thrive, hyponatraemia and hyperkalaemia in early infancy. Both disorders have an autosomal recessive inheritance. Classical and nonclassical forms of 11beta-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11beta-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). In infants with congenital hypoaldosteronism, a comparable frequency of 18-hydroxylase deficiency (aldosterone synthase deficiency type I) and of 18-oxidase deficiency (aldosterone synthase deficiency type II) can be found. Molecular genetic studies of the CYP11B1 and CYP11B2 genes in 11beta-hydroxylase deficiency or aldosterone synthase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. In some of the patients with 18-oxidase deficiency (aldosterone synthase deficiency type II) no mutations in the CYP11B2 gene were identified. Refined methods for steroid determination are the basis for the diagnosis of inborn errors of steroidogenesis. Molecular genetic studies are complementary; on the one hand, they have practical importance for the prenatal diagnosis of virilizing CAH forms and on the other hand, they are of theoretical importance in terms of our understanding of the functioning of cytochrome P450 enzymes. Copyrightz1999S.KargerAG, Basel
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PMID:Disorders of the aldosterone synthase and steroid 11beta-hydroxylase deficiencies. 1055 65

Liddle's syndrome, apparent mineralocorticoid excess (AME) and glucocorticoid remediable aldosteronism (GRA) are inherited diseases characterized by hypertension and low plasma renin activity. Constitutive activation of distal renal epithelial sodium channel (Liddle's syndrome), defect in 11 beta-hydroxysteroid dehydrogenase activity (AME) and unequal crossing over, fusing regulatory sequences of 11 beta-hydroxylase gene to coding sequences of aldosterone synthase gene and forming a new chimeric gene (GRA), cause apparent or real mineralocorticoid excess. This diseases are often being unrecognized and classified as essential hypertension, especially in patients with normal serum potassium level. Family history of hypertension and characteristic serum and urine++ steroid profile direct us to diagnosis, and genetic analysis will confirm it.
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PMID:[Low-renin hypertension and inherited mineralocorticoid diseases]. 1057 60

Several polymorphisms in genes of the reninangiotensin-aldosterone system have been found to have pleiotropic effects on cardiovascular disorders. Recently, a polymorphism (-344 C/T) in the promoter region of the aldosterone synthase gene (CYP11B2), which may influence plasma aldosterone levels, has been reported to strongly influence left ventricular diameters and mass in young adults and arterial stiffness in essential hypertensives. We investigated any association with risk of myocardial infarction (MI). CYP11B2 -344 polymorphism genotypes were determined by polymerase chain reaction (PCR) in 542 acute MI cases and 500 control subjects without history of coronary disease. All subjects were white and <75 years old. There was no significant difference in either genotype distributions (cases CC 17%, CT 52%, TT 31%; controls CC 22%, CT 47%, TT 31%, P = .10) or allele frequencies (cases C/T 0.43/0.57, controls C/T 0.46/0.54, P = .39) between cases and controls. The odds ratio (OR) for MI associated with the CC genotype was 0.75 (0.54-1.05), and remained insignificant when analysis was restricted to the 129 (24%) cases and 193 (37%) controls < 55 years of age (OR 0.68 [0.36-1.27], P = .20). In further analyses, there was no interaction of the polymorphism with other cardiovascular risk factors (smoking, hypertension, diabetes, body mass index, or cholesterol level) in determining MI risk, and the polymorphism did not influence the frequency of these risk factors in either cases or controls. In the case cohort, age at MI was not significantly different in subjects with the three genotypes (CC 61.2 +/- 9.8 years, CT 61.8 +/- 9.1 years, TT 62.2 +/- 9.0 years, P = .69). We conclude that the aldosterone synthase -344 promoter region polymorphism does not significantly influence the risk of MI either directly or via interaction with other risk factors.
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PMID:Analysis of promoter region polymorphism in the aldosterone synthase gene (CYP11B2) as a risk factor for myocardial infarction. 1070 12

Primary aldosteronism is characterized by autonomous production of aldosterone and arterial hypertension, and it occurs in 2 principal forms: aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). APA can be cured through removal of the adenoma, whereas IHA leads to hypertension that must be treated with medication. The origin of the autonomous aldosterone production in IHA is poorly understood, but genetic factors may contribute to its cause. To test the hypothesis that variants of the aldosterone synthase gene may contribute to susceptibility to IHA, we compared genotypes at 3 polymorphic sites in the CYP11B2 gene in patients with IHA (n=90) with those found in patients with APA (n=38), in patients with essential hypertension (n=72), and in normotensive individuals (n=102). We observed significant linkage disequilibrium among the 3 polymorphisms with 2 frequent haplotypes in all groups studied. One haplotype (C2R) was found to be increased in frequency in the IHA group (47%) compared with the other groups, which had a similar haplotype frequency (36%). The 3 polymorphisms studied have been implicated in either essential hypertension or excess aldosterone production in previous studies. Because of the strong linkage disequilibrium, the observed results could be due to the action of any 1 of the 3 alleles or to another allele in linkage disequilibrium with them. Our results suggest that variations in the CYP11B2 gene may contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.
Hypertension 2000 Mar
PMID:CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism. 1072 May 80

Left ventricular remodeling after myocardial infarction involves activation of the renin-angiotensin-aldosterone system. Recently, the biallelic -344T/C polymorphism of the aldosterone synthase gene was associated with increased aldosterone levels, arterial hypertension, diastolic dysfunction, and left ventricular dilatation. We hypothesized that this polymorphism may also affect left ventricular geometry and function after myocardial infarction. By using a standardized questionnaire, as well as anthropometric and echocardiographic measurements, we thus studied 606 patients (533 men and 73 women) who had a myocardial infarction before the age of 60 years. The aldosterone synthase gene polymorphism was analyzed after polymerase chain reaction amplification and restriction enzyme digestion. The results demonstrated that there was no association of the aldosterone synthase gene polymorphism with echocardiographically determined left ventricular dimensions, wall thicknesses, or indexes of systolic or diastolic function. Furthermore, anthropometric data, including blood pressure levels, were balanced between the different genotypes. Finally, the allele frequency was similar for patients with myocardial infarction and a sample group from the normal population (n=1675). The data indicate that the allele status of the aldosterone synthase gene polymorphism is not useful for the identification of patients with myocardial infarction who have impaired left ventricular function or unfavorable remodeling.
Hypertension 2000 Mar
PMID:Evaluation of the aldosterone synthase (CYP11B2) gene polymorphism in patients with myocardial infarction. 1072 May 82

In familial hyperaldosteronism type I (FH-I), inheritance of a hybrid 11beta-hydroxylase/aldosterone synthase gene causes ACTH-regulated aldosterone overproduction. In an attempt to understand the marked variability in hypertension severity in FH-I, we compared clinical and biochemical characteristics of 9 affected individuals with mild hypertension (normotensive or onset of hypertension after 15 yr, blood pressure never >160/100 mm Hg, < or = 1 medication required to control hypertension, no history of stroke, age >18 yr when studied) with those of 17 subjects with severe hypertension (onset before 15 yr, or systolic blood pressure >180 mm Hg or diastolic blood pressure >120 mm Hg at least once, or > or = 2 medications, or history of stroke). Severe hypertension was more frequent in males (11 of 13 males vs. 6 of 13 females; P < 0.05). All 4 subjects still normotensive after age 18 yr were females. Of 10 other affected, deceased individuals (7 males and 3 females) from a single family, all six who died before 60 yr of age (4 by stroke) were males. Biochemical studies were conducted in 6 mild and 16 severe subjects. The 2 groups were similar in terms of urinary sodium excretion. Mild subjects tended, although not significantly, to have lower urinary 18-oxo-cortisol (mean +/- SD, 27.4 +/- 9.0 vs. 35.2 +/- 12.9 nmol/mmol creatinine x day), higher plasma potassium (4.0 +/- 0.3 vs. 3.6 +/- 0.4 mmol/L), and lower recumbent (0800 h after overnight recumbency) plasma aldosterone levels (498 +/- 279 vs. 744 +/- 290 pmol/L). Upright (midmorning after 2-3 h of upright posture) plasma aldosterone levels were similar (mild, 485 +/- 150; severe, 474 +/- 188 pmol/L). In 1 normotensive female, upright PRA was much higher, and the upright aldosterone/PRA ratio was much lower than that in the other subjects. The remaining mild subjects had similar upright PRA levels (mild, 2.8 +/- 1.4; severe, 3.7 +/- 3.2 pmol/ L x min) and aldosterone/PRA ratios (mild, 199.5 +/- 133.4; severe, 200.6 +/- 150.9) as severe subjects. During angiotensin II (AII) infusion studies (n = 6 mild and 10 severe), performed during recumbency, aldosterone levels were lower in the mild group both basally (404 +/- 144 vs. 843 +/- 498 pmol/L; P < 0.05) and after 60 min AII (2 ng/kg x min; 261 +/- 130 vs. 520 +/- 330 pmol/L; P < 0.05). Aldosterone was unresponsive (rose by <50%) to AII in all subjects. Day curve studies (blood collected every 2 h for 24 h; n = 2 mild and 7 severe) demonstrated abnormal regulation of aldosterone by ACTH rather than by AII in both groups. In conclusion, in this series of patients with FH-I, males had more severe hypertension, and the degree of hybrid gene-induced aldosterone overproduction may have contributed to the severity of hypertension.
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PMID:Severity of hypertension in familial hyperaldosteronism type I: relationship to gender and degree of biochemical disturbance. 1085 45

Primary aldosteronism (PAL) has been traditionally regarded as a rare cause of hypertension and not worth looking for in the absence of hypokalemia. However, the availability of the aldosterone/renin ratio as a screening test and its application to a wider population of hypertensives has resulted in a marked increase in detection rate, suggesting that PAL is common, with most patients being normokalemic. The spectrum of PAL has been expanded further by the study of familial varieties, in which family screening efforts have permitted the recognition of earlier, sometimes even pre-clinical, stages of disease. Familial hyperaldosteronism type I(FH-I) In FH-I, inheritance of a 'hybrid' 11beta-hydroxylase/aldosterone synthase gene causes adrenocorticotrophic hormone (ACTH)-regulated aldosterone and 'hybrid steroid' (18hydroxy-cortisol and 18-oxo-cortisol) overproduction. Genetic testing, by Southern blot or polymerase chain reaction-based techniques, has greatly facilitated detection, being more convenient and more reliable than dexamethasone suppression testing, and has led to a fuller appreciation of the marked phenotypic variability in this disorder. The demonstration of excessive, abnormally regulated aldosterone production in normotensive subjects with FH-I suggests that absence of hypertension in such individuals cannot merely be attributed to lack of expression of the hybrid gene. Determinants of hypertension severity may include patient gender, gender of affected parent, degree of hybrid gene expression, and interactions with other genetic and environmental factors. Detailed biochemical studies, including analyses of aldosterone/PRA/cortisol 'day-curve' levels, have led to a fuller understanding of aldosterone regulation both before and in response to glucocorticoid treatment in this condition, and prompted a re-examination of current approaches to treatment Unless ACTH is completely suppressed by glucocorticoid treatment, the hybrid gene dominates over the wild-type aldosterone synthase genes in terms of aldosterone production, both in untreated and treated FH-I. This may in part be due to an abnormality affecting the functional expression of the 'wild-type' genes. Demonstration of persisting hybrid gene expression in patients rendered normotensive by very low doses of glucocorticoids suggests that currently recommended doses, aimed at normalizing aldosterone regulation (rather than blood pressure), may be too high, and may therefore place patients at unnecessary risk of developing Cushingoid side effects. Familial hyperaldosteronism type II (FH-II) Like FH-I, FH-II is associated with hyperaldosteronism and probable autosomal dominant inheritance. Unlike FH-I, hyperaldosteronism in FH-II is not dexamethasone suppressible, and is not associated with the hybrid gene mutation. Detection of adrenal mass lesions, which are frequently (17 of 57 patients in the Greenslopes Hospital series) responsible for PAL in FH-II, does not help to differentiate FH-II from FH-I, since mass lesions may also be common in that condition (detected in seven of 21 patients). Biochemically and morphologically, FH-II is indistinguishable from apparently non-familial PAL, and demonstrates similar variability even among individuals of the same family. In one informative family available for linkage analysis, FH-II does not segregate with either the AT1 gene or the CYP11B2 gene, or any other genetic defect in the chromosome 8q21-8qtel region. A genome-wide search is in progress. As has already occurred in FH-I, the elucidation of underlying genetic mutations in FH-II is likely to facilitate early detection, thereby helping to broaden its spectrum and to permit close follow-up and appropriately timed institution of specific therapy, and wider detection among patients with hypertension of potentially curable or specifically treatable forms.
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PMID:Primary aldosteronism: learning from the study of familial varieties. 1099 47

In familial hyperaldosteronism type I, inheritance of a hybrid 11beta-hydroxylase/aldosterone synthase gene leads to ACTH-regulated overproduction of aldosterone (causing hypertension) and of "hybrid" steroids, 18-hydroxy- and 18-oxo-cortisol. To determine whether complete suppression of the hybrid gene is necessary to normalize blood pressure, we sought evidence of persisting expression in eight patients who were rendered normotensive for 1.3-4.5 yr by glucocorticoid treatment. At the time of the study, six patients were receiving dexamethasone (0.125-0.25 mg/day) and two patients were taking prednisolone (2.5 or 5 mg/day). Urinary 18-oxo-cortisol levels during treatment demonstrated close correlation with mean "day curve" (blood collected every 2 h for 24 h) cortisol (r = 0.74), consistent with regulation by ACTH. Although urinary 18-oxo-cortisol levels were lower during than before treatment (mean 12.6 +/- 2.4 SEM vs. 35.0 +/- 5.6 nmol/mmol creatinine; P < 0.01), they remained above normal (0.8-5.2 nmol/mmol creatinine) in all eight patients. Although mean upright plasma potassium levels during treatment were higher, aldosterone levels lower, PRA levels higher, and aldosterone to PRA ratios lower than before treatment, PRA levels were uncorrected (< 13 pmol/L x min) and aldosterone to PRA ratios were uncorrected (>65) during treatment in four patients. For each of the eight patients, day curve aldosterone levels during treatment correlated more tightly with cortisol (mean r for the eight patients, 0.87 +/- 0.05 SEM) than with PRA (mean r = 0.36 +/- 0.10 SEM). Hence, control of hypertension by glucocorticoid treatment was associated, in all patients, with only partial suppression of ACTH-regulated hybrid steroid and aldosterone production. Normalization of urinary hybrid steroid levels and abolition of ACTH-regulated aldosterone production is not a requisite for hypertension control and, if used as a treatment goal, may unnecessarily increase the risk of Cushingoid side effects.
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PMID:Treatment of familial hyperaldosteronism type I: only partial suppression of adrenocorticotropin required to correct hypertension. 1099 27

Aldosterone, the major circulating mineralocorticoid, participates in blood volume and serum potassium homeostasis. Primary aldosteronism is a disorder characterised by hypertension and hypokalaemia due to autonomous aldosterone secretion from the adrenocortical zona glomerulosa. Improved screening techniques, particularly application of the plasma aldosterone:plasma renin activity ratio, have led to a suggestion that primary aldosteronism may be more common than previously appreciated among adults with hypertension. Glucocorticoid-remediable aldosteronism (GRA) was the first described familial form of hyperaldosteronism. The disorder is characterised by aldosterone secretory function regulated chronically by ACTH. Hence, aldosterone hypersecretion can be suppressed, on a sustained basis, by exogenous glucocorticoids such as dexamethasone in physiologic range doses. This autosomal dominant disorder has been shown to be caused by a hybrid gene mutation formed by a crossover of genetic material between the ACTH-responsive regulatory portion of the 11ss-hydroxylase (CYP11B1) gene and the coding region of the aldosterone synthase (CYP11B2) gene. Familial hyperaldosteronism type II (FH-II), so named to distinguish the disorder from GRA or familial hyperaldosteronism type I (FH-I), is characterised by autosomal dominant inheritance of autonomous aldosterone hypersecretion which is not suppressible by dexamethasone. Linkage analysis in a single large kindred, and direct mutation screening, has shown that this disorder is unrelated to mutations in the genes for aldosterone synthase or the angiotensin II receptor. The precise genetic cause of FH-II remains to be elucidated.
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PMID:Familial hyperaldosteronism. 1100 15


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