Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0085580 (essential hypertension)
14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the relationship between 12 candidate genes responsible for water regulation, sodium metabolism and membrane ion transport and essential hypertension (EH) in the Chinese. Linkage analysis of EH was performed in 95 Chinese nuclear families including 477 subjects using a technique of fluorescence-based gene scanning with 12 microsatellite markers. Markers were selected on the chromosomal regions covering 12 candidate genes responsible for regulating water and sodium metabolism and membrane ion transport. These candidate genes included sodium hydrogen exchanger 3, sodium hydrogen exchanger 5, chloride bicarbonate exchanger 3, sodium calcium exchanger 1, mineralocorticoid receptor, plasma membrane calcium ATPase 2, ATPase,Na/K transporting alpha, a-adducin, SA gene, kidney epithelial sodium channel-gamma, vasopressin receptor 1A, and 11beta-hydroxysteroid dehydrogenase type 2 genes. Two-point non-parametric linkage analysis (NPL), maximum LOD score analysis and transmission/disequilibrium test (TDT) were performed using the GENEHUNTER software package. The NPL analysis and LOD score suggested a significant linkage at D12S398 (Z = 2.08, p<0.05 and LOD score = 1.26, p<0.01, respectively). TDT indicated a significant disequilibrium of transmission at the locus chi2 = 9.00, p < 0.005). No significant linkages were found at the other loci tested (p > 0.05 or LOD < -1). In conclusion, D12S398, a marker near the vasopressin receptor 1A gene (V1AR), showed a positive linkage with EH based on the results of three statistical methods (NPL, LOD score, and TDT). This region warrants further exploration.
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PMID:Linkage analysis of twelve candidate gene loci regulating water and sodium metabolism and membrane ion transport in essential hypertension. 1235 53

Mendelian forms of hypertension have delivered a treasure trove of novel genes. To date, the molecular mechanisms of five such syndromes have been largely clarified, including glucocorticoid-remediable aldosteronism, Liddle's syndrome, apparent mineralocorticoid excess, an activating mutation of the mineralocorticoid receptor, and pseudohypoaldosteronism type 2. Each of these conditions features salt sensitivity with increased sodium and volume reabsorption by the kidney and low plasma renin activity. None of the gene loci for these syndromes has been convincingly linked to hypertension in the general population. We are investigating kindreds who have autosomal-dominant hypertension and brachydactyly. Affected persons invariably have both anomalies. The hypertension is severe and results in death at about age 50 years from stroke. The condition resembles essential hypertension, because renin, aldosterone, and norepinephrine responses are normal and no salt sensitivity is present. The response to antihypertensive drugs is general. Another feature is diminished baroreflex sensitivity with markedly impaired blood pressure buffering. Furthermore, the ventrolateral medulla may be compromised in these patients, because neurovascular anomalies are a regular finding. We mapped the gene(s) for this disease to chromosome 12p and narrowed the chromosomal region by studying more affected families. Interestingly, the same locus was recently mapped in Chinese families with essential hypertension. Our 3-centimorgan region contains genes encoding a phosphodiesterase, an ATP-dependent potassium channel, and its regulator the sulfonylurea receptor 2. Screening of the coding regions revealed that none of these candidate genes harbor obvious mutations; however, other genetic mechanisms may nevertheless compromise their function. Our study underscores the importance of regulatory physiology to the understanding of a complex genetic syndrome.
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PMID:Mendelian hypertension with brachydactyly as a molecular genetic lesson in regulatory physiology. 1295 13

Mineralocorticoid receptor (MR) blockade is effective in reducing total mortality and the incidence of heart failure in patients with systolic left ventricular dysfunction (SLVD) associated with chronic heart failure or post myocardial infarction. Pre-clinical and clinical studies in SLVD have shown that MR blockade reduces sudden cardiac death, left ventricular remodelling, left ventricular hypertrophy, endothelial dysfunction, autonomic imbalance, renal dysfunction and improves fibrinolysis. While MR blockade promotes sodium excretion and the combination of an angiotensin-converting enzyme inhibitor and a MR blocker have been shown to be more effective than either alone in causing natriuresis, it is unlikely that their beneficial effects can be explained solely on this basis. Aldosterone has been shown to have a number of adverse effects, including activation of other neurohumeral mediators, stimulation of active reactive oxygen species (ROS), activation of the NF-Greek small letter kappa kappabeta and AP-1 signalling pathways, vascular inflammation and fibrosis, myocardial hypertrophy, autonomic imbalance, and a decrease in fibrinolysis. MR blockade is, however, effective both in situations with and without an increase in serum aldosterone level, since the MR can be occupied and activated by cortisol as well as by aldosterone. In view of these mechanisms, MR blockade may play an important role not only on SLVD, but also in essential hypertension with normal systolic function, diastolic heart failure, valvular heart disease, vascular stiffening with ageing, progression of renal disease, and diabetes mellitus. This hypothesis will, however, require further prospective evaluation.
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PMID:Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease. 1460 20

Primary aldosteronism causes severe hypertension in humans (Conn's syndrome) with cardiac hypertrophy, characterized by a fibrosis more severe than the one observed in patients with essential hypertension. This suggests that aldosterone by itself may have specific and direct effects on cardiac remodeling through the activation of the cardiac mineralocorticoid receptor. Experimental evidence obtained in studying uninephrectomized rats treated with aldosterone or deoxycorticosterone (DOC) together with salt loading has led to similar conclusions. To examine the direct consequences of chronically elevated aldosterone levels on cardiac pathophysiology, we analyzed a mouse model (alpha-epithelial Na channel -/-Tg) that is normotensive under normal-salt diet but exhibits chronic hyperaldosteronism. Sixteen-month-old transgenic rescue mice that were kept under a regular salt diet that contains a small amount of sodium (0.3% Na(+)) displayed a compensated PHA-1 phenotype with normal body weight, normal kidney index, normal blood pressure, but 6.3-fold elevated plasma aldosterone levels compared with the age-matched control group. Peripheral resistance of distal colon to aldosterone was shown by a significant decrease of the amiloride-sensitive rectal potential difference, and its diurnal cyclicity was blunted. Despite chronically high plasma aldosterone levels, these animals do not show any evidence of cardiac hypertrophy, remodeling, or fibrosis, using collagen staining and anti-alpha-skeletal and alpha-smooth actin immunochemical labeling of heart sections. Cardiac fibrosis as seen in DOC- or aldosterone/salt-treated animal models is therefore likely to be due to the synergistic effect of salt, aldosterone, and other confounding factors rather than to the elevated circulating aldosterone levels alone.
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PMID:Chronic hyperaldosteronism in a transgenic mouse model fails to induce cardiac remodeling and fibrosis under a normal-salt diet. 1476 62

The enzyme 11-beta hydroxysteroid dehydrogenase type 2 plays a major role in blood pressure regulation. It metabolizes glucocorticoid hormones into derivatives with low affinity for the mineralocorticoid receptor, preventing its permanent occupancy by circulating cortisol, which is 100- to 1000-fold more abundant than aldosterone in the plasma. Inactivating mutations of the enzyme result in severe hypertension, as seen in children with apparent mineralocorticoid excess syndrome. In patients with essential hypertension, however, attempts to evidence enzyme deficiency have been inconclusive. In this pilot study, its catalytic activity was measured directly in aldosterone-sensitive sweat gland ducts collected from skin biopsy samples of 10 male normotensive subjects and 10 subjects with essential hypertension (more than 140 to 90 mm Hg) with no sign of hypermineralocorticism. Isolated ducts were assayed for nicotinamide-dinucleotide-dependent dehydrogenase activity (transformation of tritiated corticosterone into tritiated-11 dehydrocorticosterone, as measured by high-pressure liquid chromatography). Hypertensive patients exhibited significantly lower 11-beta hydroxysteroid dehydrogenase type 2 activity (9.7+/-4.7 femtomoles per 3 mm length of duct and per 10 minutes incubation, median+/-SD) than did normotensive subjects (15.9+/-2.6). Such defect was undetectable using the classical urinary corticosteroid metabolism indexes, probably because of compensatory mechanisms. Relations between these findings and blood pressure levels should benefit from direct enzyme measurements in the vasculature. In conclusion, this cross-sectional study points to partial 11-beta hydroxysteroid dehydrogenase type 2 deficiency as a novel feature of essential hypertension, which should stimulate search for new signaling pathways and therapeutical targets.
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PMID:Impaired 11-beta hydroxysteroid dehydrogenase type 2 activity in sweat gland ducts in human essential hypertension. 1498 Oct 55

Aldosterone blockade has been shown to be effective in reducing total mortality as well as hospitalization for heart failure in patients with systolic left ventricular dysfunction (SLVD) due to chronic heart failure and in patients with SLVD post acute myocardial infarction. The evidence for the effectiveness of aldosterone blockade in chronic heart failure comes from the randomized aldactone evaluation study (RALES) while that for patients post infarction from the eplerenone post acute myocardial infarction efficacy and survival study (EPHESUS). These studies suggest that mineralocorticoid receptor activation remains important despite the use of an angiotensin converting enzyme-inhibitor/angiotensin receptor blocking (ARB) agent and a beta blocker. Increasing evidence suggest that aldosterone blockade has important effects not only on the kidney but on ventricular remodeling, myocardial fibrosis, autonomic balance, fibrinolysis, oxidative stress, and activation of the NF-kappaB and AP-1 signaling pathways. The results of these studies in patients with SLVD has important implications not only for patients with chronic heart failure and post infarction but also for the therapy of patients with essential hypertension and other cardiovascular diseases.
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PMID:Effect of aldosterone blockade in patients with systolic left ventricular dysfunction: implications of the RALES and EPHESUS studies. 1513 1

The two major outcome trials on the combination of angiotensin-converting enzyme (ACE) inhibitors and mineralocorticoid receptor (MR) antagonists in heart failure are RALES (Randomized Aldactone Evaluation Study) and EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). There have also been studies in essential hypertension, and in diabetic hypertensive patients, on the cardiac and renal effects of ACE inhibitors and MR antagonists, individually and in combination. In the clinical studies on heart failure, in outcome trials and the smaller studies using surrogate end points, a combination of ACE inhibition and MR blockade is superior to ACE inhibition alone, and in the hypertension studies to either agent alone. Some insight into their distinct sites of protective action may be gained from studies on experimental animal preparations. The principal caveat in the use of combination therapy is the possibility of hyperkalemia, which should be minimal in patients with creatine clearance greater than 30 mL/min and with the low doses of MR antagonist shown to be effective in outcome trials.
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PMID:ACE inhibitors and mineralocorticoid receptor blockade in patients with congestive heart failure. 1566 15

Spirolactones harboring various C7 substituents are aldosterone antagonists, and some of them are used in the treatment of essential hypertension. They bind to the human mineralocorticoid receptor and render it transcriptionally inactive. Structural analysis using a three-dimensional homology model of the ligand-binding domain of the receptor has revealed that the Met852 residue of the ligand-binding cavity faces the C7 substituent of spirolactones. We therefore tested the binding capacities of C7-substituted spirolactones in an in vitro system expressing either the mutant receptor, in which Met852 was replaced by alanine, or the wild-type receptor. The M852A mutation had almost no effect on the binding of C7-substituted spirolactones to mineralocorticoid receptor but dramatically reduced the capacity of the receptor to bind steroids with no C7 substituent (aldosterone, cortisol, deoxycorticosterone, and canrenone). cis-trans Cotransfection assays revealed that two spirolactones characterized by having a propyl group [7 alpha-propyl-17 alpha-hydroxy-3-oxo-preg-4-ene-21-carboxylic acid gamma-lactone (RU26752)] or a thioacetyl group (spironolactone) at the C7 position acquired agonist properties when bound to the mutant receptor. In contrast, mexrenone and eplerenone, both of which harbor an acetyl group at the C7 position, retained antagonist properties when bound to the mutant receptor. Overall, these findings indicate that Met852 acts as an organizer residue that plays two major roles: 1) it allows steroids with no substituent at the C7 position to be accommodated within the ligand-binding cavity; and 2) it is involved in the steric hindrance that prevents C7-substituted spirolactones from folding the receptor in its active state.
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PMID:The Met852 residue is a key organizer of the ligand-binding cavity of the human mineralocorticoid receptor. 1571 62

Antihypertensive medications belong to different pharmacological classes. Besides blood pressure lowering properties, many substances, particularly ACE inhibitors and AT1-receptor antagonists but also in part calcium antagonists and aldosterone receptor antagonists, exert additional anti-inflammatory and antifibrotic effects as well as protective effects on endothelium. Delay of disease progression in chronic kidney disorders by inhibition of the renin-angiotensin system also as the result of blood pressure independent effects has been documented in clinical trials. On the other hand, in patients with essential hypertension without end-organ damage, it remains unclear whether the clinically proven blood pressure independent effects of antihypertensive agents are also clinically relevant. However, in clinical studies ACE inhibitors and AT1-receptor antagonists reduce the de novo occurrence of the diabetic metabolic state. Inhibition of the renin-angiotensin system decreases the incidence of diabetic nephropathy. This contribution presents currently available data on possible blood pressure independent effects of antihypertensive agents.
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PMID:[Blood pressure independent effects of antihypertensive agents]. 1580 Jul 76

Several monogenic hypertensive disorders are caused by genetic mutations leading to the deranged function and/or regulation of renal tubular NaCl transport, such as mutations of the renal epithelial Na+ channel (ENaC) in Liddle syndrome, of the kinase WNK1 (with no K) in Gordon syndrome, and of the mineralocorticoid receptor, or of 11beta-hydroxysteroid dehydrogenase. Moreover, excessive formation of aldosterone in glucocorticoid-remediable hypertension leads to severe hypertension. Conversely, impaired function of the Na+,K+,2Cl- cotransporter (NKCC2), the renal outer medullary K+ channel (ROMK1), and the renal epithelial Cl- channel ClCKb/Barttin causes Bartter syndrome and defective Na+,Cl+ cotransporter (NCCT) Gitelman syndrome, salt-wasting disorders with hypotension. These monogenic disorders are rare, but illustrate the significance of renal tubular transport in blood pressure regulation. There is little doubt, however, that deranged renal salt reabsorption significantly contributes to essential hypertension polymorphisms of several genes participating in the regulation of renal Na+ transport have been shown to be associated with blood pressure and prevalence of hypertension. Two common genes will be discussed in more detail. The first encodes the renal Cl- channel ClCKb. A gain-of-function mutation of ClCKb, increasing channel activity by 7- to 20-fold is found in approximately 20% of unselected Caucasians and 40% of an unselected African population. The second common gene variant (prevalence, 3%-5% in unselected Caucasians), to be discussed in more detail, affects the serum and glucocorticoid inducible kinase SGK1, a kinase upregulated by mineralocorticoids and enhancing the activity of ENaC, ROMK, and Na+/K+ATPase. Both gene variants are associated with slightly increased blood pressure. SGK1 further stimulates the glucose transporter SGLT1, and the SGK1 gene variant correlates, in addition, with increased body mass index.
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PMID:Renal tubular transport and the genetic basis of hypertensive disease. 1598 Sep 41


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