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

Although it has been recognized for almost 70 years that there is a substantial genetic component to the pathogenesis of hypertension, only recently have systematic efforts been made to identify the responsible genetically determined mechanisms. In the case of several rare syndromes, spectacular progress has been made in identifying the underlying molecular mechanisms responsible for the clinical expression. Glucocorticoid-suppressible aldosteronism and Liddle's syndrome, each inherited as an autosomal-dominant condition, complete the list. In the case of randomly selected patients and families with essential hypertension, inheritance involves many genes and progress has been far more modest. Probably the most promising lead has involved the genes governing the structure of angiotensinogen, the substrate in the renin reaction. Linkage has been established and confirmed. At the moment, however, neither the relation of the genetic abnormality to the underlying mechanisms, nor the contribution of this abnormality to hypertension in the individual patient, has been defined. We know less about other candidate genes, with the exception of studies that rigorously ruled out a contribution. The development of the concept of the "intermediate phenotype," a physiological feature that makes it possible to identify a homogeneous subpopulation, should help to sort out many of these issues. Unfortunately, the identification and characterization of intermediate phenotypes is substantially more difficult at the moment than are the genetic studies, and so progress is likely to be slow. The field is complicated by the reporting of claims made on the basis of small patient samples. In the case of polymorphisms in the angiotensin-converting enzyme gene as a risk factor for tissue injury, for example, substantial follow-up studies have systematically failed to confirm the original report, which was based on a small patient sample. The fact that the same DNA collection is likely to be examined many times for multiple gene candidates creates a setting in which type I errors are likely, and so we are likely to see many more examples. Caveat lector. Again, the development of relevant intermediate phenotypes will make the spurious association less likely.
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PMID:Genes, hypertension, and intermediate phenotypes. 888 70

In 1963 Liddle et al. described a disorder that simulated primary aldosteronism, characterized by severe hypertension and hypokalemia but with negligible secretion of aldosterone. They theoried that this was a disorder in which the renal tubules transport ions with such abnormal facility that the end result simulates that of a mineralcorticoid excess. Later, it was postulated that this disorder could be related to the abnormality of amiloride sensitive Na channel. The activity of amiloride-sensitive Na channels constitutes the rate limiting step for Na reabsorption in Na transporting epithelia. Recently, the primary sequence of the rat amiloride-sensitive epithelial Na+ channel (rENaC) was determined by functional expression cloning and shown to be composed of three homologous subunits: alpha, beta, and gamma. Its expression of all three subunits in Xenopus oocytes markedly increased the magnitude of these currents. Analysis of subjects with Liddle's syndrome demonstrates the mutation of carboxy-terminal domain in alpha, beta, and gamma subunits. The mutations are either premature termination, frameshift mutation, or missense mutations.
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PMID:[Liddle syndrome]. 890 41

Primary dysregulation of the epithelial sodium channel, manifested by continuing Na+ channel activity despite dietary salt excess, would cause inappropriate renal sodium reabsorption, blunted sodium excretion, and low-renin hypertension. There are now well-characterized genetic causes of hypertension in human pedigrees, which are explained by inappropriate and/or constitutive activation of the epithelial Na+ channel. Although Liddle's syndrome has been the most thoroughly investigated, the incidence of such activating mutations in the subunits of the Na+ channel appears to be relatively rare. Of continuing interest is the possibility that polymorphisms in the channel subunits could result in activation of the channel in response to normal regulatory influences. One such example is provided by a provocative report by Su et al. In this issue of the journal (J Am Soc Nephrol 1996;7:2543-2549). Despite several important technical limitations of the findings presented in the article, the suggestion that polymorphisms found in defined human populations would affect the regulation of sodium channel activity in response to environmental variables is worthy of serious consideration, and serves as a further stimulus to defining the functional significance of the various polymorphisms described in the subunits of the amiloride-sensitive sodium channel.
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PMID:Polymorphism in the beta subunit and Na+ transport. 898 26

The amiloride-sensitive, epithelial sodium channel (ENaC) is composed of at least three subunits (alpha, beta, and gamma). This study demonstrates that the ENaC beta subunit gene is expressed in human B cell lines, peripheral blood lymphocytes, and lymph node at the mRNA level. Further, this study shows that both wild-type and mutated alleles of the ENaC beta subunit gene are transcribed in human B lymphocytes derived from an individual affected with Liddle's syndrome, an autosomal dominant form of human hypertension.
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PMID:Expression of the amiloride-sensitive sodium channel beta subunit gene in human B lymphocytes. 901 57

The 14-year follow-up of a female patient with Liddle's syndrome (LS), a rare disease characterized by hypertension, hypokalemic alkalosis, and negligible aldosterone secretion due to renin suppression, is described. The disease was diagnosed at the age of 10 months (youngest identification). The patient was repeatedly investigated during follow-up for plasma renin activity (PRA), plasma aldosterone concentration (PA), serum sodium and potassium (K) concentration, blood pressure (BP), somatic anthropometry, and mental development. Noteworthy results included: persistent low circulating K, PRA, and PA and high BP, coinciding with unauthorized withdrawal of the triamterene therapy. These findings are in keeping with the hypothesis that LS results from a pathogenetic disorder which is not correctable with age. The triamterene therapy was effective in correcting the endocrine and metabolic disorders as well as arterial hypertension, but did not prevent a deficit in mental and physical development. However, the information derived from this study allows further clarification of the clinical picture of the disease.
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PMID:Liddle's syndrome: a 14-year follow-up of the youngest diagnosed case. 903 63

The pathophysiological basis of Liddle's syndrome, a rare autosomal dominant form of arterial hypertension, has been found to rest on missense mutations or truncations of the beta- and gamma-subunits of the epithelial sodium channel. The hypothesis has been advanced that molecular variants of these genes might also contribute to the common polygenic forms of hypertension. We tested this hypothesis by performing a cosegregation study in a reciprocal cross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and a Wistar-Kyoto rat (WKY-1HD) reference strain. We carried out genetic mapping and chromosomal assignment of the alpha-, beta-, and gamma-subunits of the epithelial sodium channel using both linkage analysis and fluorescent in situ hybridization techniques. We demonstrate that in the rat, the beta- and gamma-subunits, as in humans, are in close linkage; they map to rat chromosome 1 and cosegregate with systolic pressure after dietary NaCl (logarithm of the odds [LOD] score, 3.7), although the peak LOD score of 5.0 for this quantitative trait locus was detected 4.4 cM away from the beta-/gamma-subunit locus. The alpha-subunit was mapped to chromosome 4 and exhibited no linkage to blood pressure phenotype. Comparative analysis of the complete coding sequences of all three subunits in the SHRSPHD and WKY-1HD strains revealed no biologically relevant mutations. Furthermore, Northern blot comparison of mRNA levels for all three subunits in the kidney showed no differences between SHRSPHD and WKY-1HD. Our results fail to support a material contribution of the epithelial sodium channel genes to blood pressure regulation in this model of polygenic hypertension.
Hypertension 1997 Jan
PMID:Role of the alpha-, beta-, and gamma-subunits of epithelial sodium channel in a model of polygenic hypertension. 903 92

Secondary hypertension accounts for a minority of all cases of hypertension. Certain clues in the patient's medical history and laboratory parameters may help identify the rare patient with secondary hypertension. The association of hypertension with hypokalemia and renal potassium wasting should raise one's suspicion for a state of mineralocorticoid excess. The clinical syndrome of hypertension and hypokalemia may be related either to a high renin state, such as renovascular disease, or to a low renin state, such as primary hyperaldosteronism, adrenal enzyme defects, certain familial syndromes, and licorice ingestion. Over the past decade, a genetic basis has been identified for apparent mineralocorticoid excess (AME) syndrome, Liddle's syndrome, and glucocorticoid remediable aldosteronism (GRA). This brief review focuses on a few of the unusual conditions which cause a true or apparent mineralocorticoid excess state, and summarizes the clinical presentation, pathogenetic mechanism, and treatment of these diseases.
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PMID:Hypertension and hypokalemia: unusual syndromes. 906 95

Liddle's syndrome is an autosomal dominant form of hypertension that resembles primary hyperaldosteronism, is characterized by the early onset of hypertension with hypokalemia and suppression of both PRA and aldosterone, and is caused by mutations in the carboxyl-terminus of the beta- or gamma-subunits of the renal epithelial sodium channel. We describe a kindred (K176) whose distinguishing clinical features were mild hypertension and decreased aldosterone secretion. The index case was a 16-yr-old girl with intermittent mild hypertension and hypokalemia and subnormal PRA, aldosterone, 18-hydroxy-corticosterone, and deoxycortisol levels, but normal cortisol/cortisone metabolite ratio and cortisol half-life. A frameshift mutation in the carboxyl-terminus of the beta-subunit of the epithelial sodium channel was identified in the index case, establishing the diagnosis of Liddle's syndrome. Sixteen at-risk relatives of the index case were tested. Seven new subjects were heterozygous for the mutation found in the index case, and two deceased obligate carriers were identified. All genetically affected adult subjects had a history of mild hypertension, and four had a history of hypokalemia. Basal and postcosyntropin plasma aldosterone and urinary aldosterone levels were significantly suppressed in those positive for the mutation. The family demonstrates variability in the severity of hypertension and hypokalemia in this disease, raising the possibility that this disease may be underdiagnosed among patients with essential hypertension.
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PMID:Liddle's syndrome: prospective genetic screening and suppressed aldosterone secretion in an extended kindred. 910 May 75

In the most exciting genetic advances in the diagnosis of essential hypertension, genes responsible for three distinct forms of low-renin hypertension have been identified. Two of these forms are dominant: glucocorticoid remediable hypertension (a new gene created by the fusion of the 11 beta-hydroxylase and aldosterone synthase genes) and Liddle's syndrome (a defect in the epithelial sodium channel). One of the forms is recessive: the syndrome of apparent mineralocorticoid excess (a defect in renal 11 beta-hydroxysteroid dehydrogenase). The role of more than 20 other genes in causing hypertension has been assessed with variable findings. The most convincing evidence supports a role for the angiotensinogen gene, where linkage has been documented and an association with an intermediate phenotype of hypertension (nonmodulation) has been reported.
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PMID:Genetic approach to diagnostic and therapeutic decisions in human hypertension. 914 79

This review, covering work from the Baker Institute and elsewhere, is divided into four sections. In the first a summary account of two areas-mineralocorticoid receptors and the enzyme 11 beta hyderoxysteroid dehydrogenase-will be given as background. Next is a brief consideration of the three single-gene causes of human hypertension described to date-glucocorticoid-remediable aldosteronism. Liddle's syndrome, and apparent mineralocorticoid excess-in all of which abnormal sodium handling is a feature. Third, the sequelae of aldosterone occupancy of nonepithelial mineralocorticoid receptors will be analyzed in some detail by reviewing studies on experimental mineralocorticoid hypertension and cardiac fibrosis from this laboratory and elsewhere. Finally, three recent studies from this laboratory will be presented: on putative 11-ketosteroid receptors in epithelial tissue, on glucose-PKC potentiation of mineralocorticoid effects on heart cells, and on the necessity for factors/ processes other than the conversion of cortisol to cortisone (or, in the rat, corticosterone to 11-dehydrocorticosterone) to ensure aldosterone-specific effects in mineralocorticoid target tissues.
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PMID:Mineralocorticoid receptors, salt, and hypertension. 923 55


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