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

Abnormal renal sodium transport causing excess reabsorption of sodium may be one mechanism that causes high blood pressure. For example, increased activity of epithelial sodium channels in the distal tubule is the cause of high blood pressure in Liddle's syndrome, a rare familial form of hypertension. We have shown that the increase in sodium channel activity can be detected in the nose using transepithelial potential difference measurements in 1 family with Liddle's syndrome. We therefore used nasal potential difference measurements to look for increased sodium channel activity in white patients with essential hypertension. Transnasal potential difference was measured in 42 white hypertensive (HT) subjects and 38 white normotensive (NT) subjects before and after topical application of 10(-4) mol/L of amiloride. There was no difference in maximum potential between HT and NT subjects (HT, -18.8+/-0.9 mV; NT, -18.2+/-1.0 mV) (values mean+/-SEM; lumen-negative with respect to the submucosa). However, the postamiloride potential was significantly higher (HT, -12.6+/-0.7 mV; NT, -10.5+/-0.7 mV; P=0. 015) and the change in potential in response to amiloride significantly lower (HT, 6.2+/-0.5 mV, 33.1+/-2.0%; NT, 7.7+/-0.6 mV, 41.9+/-2.0%; P=0.046 and 0.003, respectively) in HT than in NT subjects. These results suggest that sodium channel activity is not increased in whites with essential hypertension and indicate that sodium channel overactivity similar to that seen in Liddle's syndrome is unlikely to be the cause of high blood pressure in this group. Increased postamiloride potential may reflect increased activity of chloride channels or amiloride-insensitive sodium channels.
Hypertension 1999 Apr
PMID:Epithelial sodium channel activity is not increased in hypertension in whites. 1020 43

Aldosterone participates in blood volume and serum potassium homeostasis, which in turn regulate aldosterone secretion by the zona glomerulosa of the adrenal cortex. Autonomous aldosterone hypersecretion leads to hypertension and hypokalemia. Improved screening techniques have led to a re-evaluation of the frequency of primary aldosteronism among adults with hypertension, recognizing that normokalemic cases are more frequent than was previously appreciated. The genetic basis of glucocorticoid remediable aldosteronism has been elucidated and adequately explains most of the pathophysiologic features of this disorder. A new form of familial aldosteronism has been described, familial hyperaldosteronism type II; linkage analysis 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 features of aldosterone hypersecretion may be due to non-aldosterone-mediated mineralocorticoid excess. These include two causes of congenital adrenal hyperplasia (11 beta-hydroxylase deficiency and 17 alpha-hydroxylase deficiency), the syndrome of apparent mineralocorticoid excess (AME) due to 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) deficiency, primary glucocorticoid resistance, Liddle's syndrome due to activating mutations of the renal epithelial sodium channel, and exogenous sources of mineralocorticoid, such as licorice, or drugs, such as carbenoxolone. The features of mineralocorticoid excess are also often seen in Cushing's syndrome. Hypoaldosteronism may lead to hypotension and hyperkalemia. Hypoaldosteronism may be due to inadequate stimulation of aldosterone secretion (hyporeninemic hypoaldosteronism), defects in adrenal synthesis of aldosterone, or resistance to the ion transport effects of aldosterone, such as are seen in pseudohypoaldosteronism type I (PHA I). PHA I is frequently due to mutations involving the amiloride sensitive epithelial sodium channel. Gordon's syndrome (PHA type II) is due to resistance to the kaliuretic but not sodium reabsorptive effects of aldosterone for which the genetic basis is still unknown. This review aims to provide a survey of the clinical disorders of aldosterone excess and deficiency and their clinical management, with a focus on primary aldosteronism and isolated aldosterone deficiency.
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PMID:Hyper- and hypoaldosteronism. 1023 50

The objective was to test the hypothesis that the effects of the sodium channel blockers lignocaine and tetrodotoxin are modified in the presence of hypertension-induced hypertrophy. We describe the effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles isolated from 6-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The upstroke velocity, amplitude, and overshoot of the action potential were reduced; action potentials were prolonged; and the contractions were reduced on the hypertrophied left ventricles of the SHRs. Lignocaine and tetrodotoxin reduced the upstroke velocity, amplitude, and overshoot and prolonged the left ventricular action potentials. These effects of lignocaine and tetrodotoxin on the SHR were less than those on the WKY left ventricle, possibly because the action potential was already modified by hypertrophy. Lignocaine also reduced the left ventricular contractions and the concentrations producing this reduction were lower for the hypertrophied than those for the normal left ventricle. Tetrodotoxin at 3 x 10(-6)-10(-5) M caused similar attenuation of the WKY and SHR left ventricle contractions. Our study shows that the effects of lignocaine on contraction are enhanced in the hypertrophied left ventricle of the SHR, which suggests that the binding is increased or the access of lignocaine to the receptor is enhanced in hypertrophy. In contrast, the effects of tetrodotoxin on contractions are similar, and thus the binding or access of tetrodotoxin to the receptor is not altered in the hypertrophied left ventricle of the SHR.
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PMID:The effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles from normo- and hypertensive rats. 1032 83

Previous studies of hypertension in humans and experimental animal models have identified a number of candidate genes that have since been implicated as possibly contributing to essential hypertension. Among them are the genes encoding angiotensinogen, renin, the beta- and gamma-subunits of the epithelial sodium channel (beta/gamma-ENaC), alpha-adducin, and kallikrein (KLK). To examine the role of possible contribution of these genes in ethnic Chinese, as well as the epistatic interaction among them, we studied a large cohort of hypertensive sib pairs from China. DNA samples from 310 concordant affected sibling pairs with hypertension were tested for linkage with the use of excess allele-sharing algorithms based on genotyping with highly informative GT-repeat microsatellite markers localized in the immediate vicinity of the genes encoding angiotensinogen, renin, beta- and gamma-ENaC, alpha-adducin, and KLK. Affected sib pair analysis conducted according to 3 different methods (Statistical Analysis for Genetic Epidemiology [S.A.G.E. ]/SIBPAL, MAPMAKER/SIBS, and affected pedigree member [APM] methods) revealed no evidence for linkage of any of these genes to primary hypertension in the population studied. Moreover, 2-locus sib pair linkage analyses to test for gene-gene interactions among each possible pair of candidate genes failed to yield any statistically significant results. Our findings provide no support for a significant contribution of the angiotensinogen, renin, beta/gamma-ENaC, alpha-adducin, or KLK genes, alone or in concert, to the pathogenesis of essential hypertension among Chinese. Our results emphasize the possible role of ethnic differences for complex disease genetics, as well as the need for large, well-characterized investigations.
Hypertension 1999 Jun
PMID:Linkage analysis of candidate genes and gene-gene interactions in chinese hypertensive sib pairs. 1037 11

Arterial blood pressure is critically dependent on sodium balance. The kidney is the key player in maintaining sodium homeostasis. Aldosterone-dependent epithelial sodium transport in the distal nephron is mediated by the highly selective, amiloride-sensitive epithelial sodium channel (ENaC). Direct evidence that dysfunction of ENaC participates in blood pressure regulation has come from the molecular analysis of two human genetic diseases, Liddle's syndrome and pseudohypoaldosteronism type 1 (PHA-1). Both, increased sodium reabsorption despite low aldosterone levels in Liddle's patients and decreased sodium reabsorption despite high aldosterone levels in PHA-1 patients, demonstrated that ENaC is an effector for aldosterone action. Gene-targeting and classical transgenic technology enable the generation of mouse models for these diseases and the analysis of the involvement of the epithelial sodium channel (ENaC) in the progress of these diseases. A first mouse model using alphaENaC transgenic knockout mice [alphaENaC(-/-)Tg] mimicked several clinical features of PHA-1, like salt-wasting, metabolic acidosis, high aldosterone levels, growth retardation and increased early mortality. Such mouse models will be necessary in testing the involvement of genetic and/or environmental factors like salt-intake in hypertension.
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PMID:Implication of ENaC in salt-sensitive hypertension. 1041 16

The monogenic forms of human hypertension have yielded to the power of modern genetic techniques in the last several years. With the successful expression cloning of the subunits of the epithelial sodium channel, a whole era has evolved in our basic understanding of the low renin forms of human hypertension. Of note, all of these hypertensive syndromes (Liddle's syndrome, glucocorticoid-remediable aldosteronism, and the apparent mineralocorticoid excess syndrome) share an underlying dysregulation of the activity of the epithelial sodium channel in the cortical collecting tubule. Loss of function defects due to mutations in the channel subunits themselves, or in the mineralocorticoid receptor (pseudohypoaldosteronism, type I) also affect blood pressure regulation consequent to renal salt wasting and dysregulation of the epithelial sodium channel in the cortical collecting tubule.
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PMID:Hypertension. 1043 75

Renin and aldosterone secretion is often lower in blacks than in whites, characteristics that resemble a milder form of Liddle syndrome in which a mutation in the amiloride-sensitive epithelial sodium channel (ENaC) of the kidney results in enhanced resorption of sodium. In the present study, we looked for evidence that the intrinsic level of ENaC activity is indeed higher in blacks than in whites. In overnight urine samples collected from young people (249 white and 181 black subjects, mean age 13.4 years), the urinary aldosterone/potassium ratio, which is typically very low in Liddle syndrome, was lower in blacks than in whites: 0.421+/-0.024 (mean+/-SE) versus 0.582+/-0.016 nmol/mmol (P<0.0001). In addition, all but 1 of 5 molecular variants in ENaC were much more common in blacks than in whites. G442V in the beta-subunit, present in 16% of the blacks and in only 1 white, was associated with parameters reflective of a greater Na retention and potentially a higher ENaC activity: a lower plasma aldosterone concentration (P=0.070), a lower urinary aldosterone excretion rate (P=0.052), a higher potassium excretion rate (P=0.048), and a lower urinary aldosterone/potassium ratio (P=0.027). In a second cohort consisting of 126 black and 161 white normotensive subjects and 232 black and 188 white hypertensive subjects, betaG442V did not show a significant association with hypertension (P=0.089). On the other hand, a variant that was twice as common in whites, alphaT663A, was associated with being normotensive both in blacks (P=0.018) and in whites (P=0.034). Expression of either betaG442V or alphaT663A in Xenopus oocytes did not result in a change in basal Na current, consistent with the variants being in linkage disequilibrium with alleles at active loci. In conclusion, several lines of evidence are presented to suggest that ENaC activity is higher in blacks than in whites, which could contribute to racial differences in Na retention and the risk for hypertension.
Hypertension 1999 Oct
PMID:Genetic variants in the epithelial sodium channel in relation to aldosterone and potassium excretion and risk for hypertension. 1052 38

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

With the expression cloning of the subunits of the epithelial sodium channel, a new era has evolved in our basic understanding of the low-renin forms of human hypertension. The monogenic hypertensive syndromes manifest dysregulation of the epithelial sodium channel in the cortical collecting tubule. These rare syndromes provide a schema for organizing our thinking about the more common form(s) of low renin hypertension, and raise the possibility that dysregulation of sodium channel activity and consequent salt retention and volume expansion provide a basic pathophysiological mechanism for low-renin hypertension. What are needed are more specific agents to interrupt the mineralocorticoid response pathways, and clinically relevant approaches to measuring sodium channel activity at the level of the collecting tubule in the individual patient. The combined use of aldosterone antagonists and angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists could have a beneficial effect on "progression" of renal disease associated with glomerular and interstitial fibrosis, especially if the effects of hyperkalemia on the heart and aldosterone secretion can be minimized.
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PMID:Low renin hypertension in the next millennium. 1065 Dec 17

The role of the endothelin-B receptor (ET(B)) in vascular homeostasis is controversial because the receptor has both pressor and depressor effects in vivo. Spotting lethal (sl) rats carry a naturally occurring deletion in the ET(B) gene that completely abrogates functional receptor expression. Rats homozygous for this mutation die shortly after birth due to congenital distal intestinal aganglionosis. Genetic rescue of ET(B)(sl/sl) rats from this developmental defect using a dopamine--hydroxylase (DBH)-ET(B) transgene results in ET(B)-deficient adult rats. On a sodium-deficient diet, DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats both exhibit a normal arterial blood pressure, but on a high-sodium diet, the former are severely hypertensive. We find no difference in plasma renin activity or plasma aldosterone concentration between salt-fed wild-type, DBH-ET(B);ET(B)(+/+) or DBH-ET(B);ET(B)(sl/sl) rats, and acute responses to intravenous L-NAME and indomethacin are similar between DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats. Irrespective of diet, DBH-ET(B);ET(B)(sl/sl) rats exhibit increased circulating ET-1, and, on a high-sodium diet, they show increased but incomplete hypotensive responses to acute treatment an ET(A)-antagonist. Normal pressure is restored in salt-fed DBH-ET(B);ET(B)(sl/sl) rats when the epithelial sodium channel is blocked with amiloride. We conclude that DBH-ET(B);ET(B)(sl/sl) rats are a novel single-locus genetic model of severe salt-sensitive hypertension. Our results suggest that DBH-ET(B);ET(B)(sl/sl) rats are hypertensive because they lack the normal tonic inhibition of the renal epithelial sodium channel.
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PMID:Salt-sensitive hypertension in endothelin-B receptor-deficient rats. 1074 72


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