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

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na-Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelman's syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.
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PMID:Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. 852 45

GENETIC DISEASE MODELS: A certain proportion of hypertension cases are due to renal disease. Recent advances in genetics has improved our knowledge of the pathophysiological mechanisms involved in certain rare diseases including apparent overproduction of mineralocorticoids, Liddle syndrome and Gitelman syndrome, and to hypothesize on the mechanism of primary hypertension. EFFECT ON PROGNOSIS: Onset of renal disease in hypertensive patients, whether expressed by proteinuria or the early stages of renal failure, worsens cardiovascular prognosis. FREQUENCY OF RENAL DISEASE: Renal disease is relatively rare in hypertensive patients, but as the general hypertensive population becomes older, there is a considerable rise in the prevalence of hypertensive renal disease as the underlying cause leading to dialysis. The risk of progressing to renal failure appears to be related to the level of the blood pressure, especially systolic pressure, at disease onset. Hypertension black subjects have a higher risk of developing chronic renal failure. THERAPEUTIC BENEFIT: Several studies have shown that lowering blood pressure with antihypertensive drugs lowers the risk progressing with primary hypertension.
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PMID:[Renal involvement in essential arterial hypertension]. 920 91

Fifteen patients with Bartter's syndrome (hyponatremic hypochloremic hypokalemic metabolic alkalosis) were compared with 15 healthy volunteers. Red blood cell Na+/H+ and Cl-/HCO3- exchanges were enhanced in all patients with Bartter's syndrome. In calciuric normomagnesemic patients, sensitive to nonsteroidal anti-inflammatory drugs (classic Bartter's syndrome), red blood cell Na+,K+,2Cl- cotransport was markedly reduced, calcium-dependent K+ permeability was moderately increased, and up to 60% of sodium permeability was represented by cAMP-activated fraction (presumably human analog of beta-isoform of Na+/H+ exchange). In noncalciuric hypomagnesemic patients insensitive to indomethacin (Gitelman's syndrome), Na+,K+,2Cl- cotransport was enhanced, Na+ permeability was increased due to calmodulin-dependent fraction, and calcium-dependent K+ permeability was markedly enhanced. A new subtype of Bartter-like syndrome ("variant Bartter's syndrome") has been described in which calciuria, hypomagnesemia, and insensitivity to nonsteroidal anti-inflammatory drugs were associated with decreased Na+,K+,2Cl- cotransport, enhanced calmodulin-activated fraction of Na+ influx, and reduced calcium-dependent K+ permeability.
Hypertension 1997 Dec
PMID:Membrane ion transport in Bartter's syndrome: evidence for a new syndrome subtype. 940 50

Advances in the molecular genetics of inherited renal tubulopathies have allowed some insight into the normal mechanisms of tubular cation and anion reabsorption. It is now possible to view Bartter's syndrome, Gitelman's syndrome and pseudohypoaldosteronism type 1 as having genetic abnormalities which produce tubular defects that are similar to those induced by the pharmacological actions of loop diuretics, thiazide diuretics or potassium-sparing diuretics, respectively. Although these rare monogenic disorders with dramatic phenotypes seem to have little relevance to everyday clinical practice, it is possible that subtle abnormalities of the regulation of the ENaCs may play a role in low-renin forms of 'essential' hypertension. Similarly, subtle abnormalities in the function of the electroneutral sodium-(potassium)-chloride cotransporters (NKCC2 and NCCT) and the renal CLC-type chloride channels (CLC5) may be major determinants of urinary calcium excretion with roles in the pathogenesis of 'idiopathic' hypercalciuria and osteoporosis. Because of the intricate and diverse molecular mechanisms by which tubular reabsorption of water and solutes takes place in each different nephron segment, it is likely that other renal channels and transporters will be implicated in the pathogenesis of further monogenic disorders, and that these will allow additional insights into tubular functioning. Recent studies have demonstrated that in addition to abnormalities in the NKCC2 and ROMK1 genes, mutations at a third genetic locus can also cause Bartter's syndrome. Linkage studies, followed by mutational analyses have found deletions and point mutations in the gene encoding one of the TAL-specific chloride channels, CLCKB, in 17 Bartter's families. This chloride channel is similar in structure to CLC5, and is located on the long arm of chromosome 1. Importantly, there appears to be a phenotypic difference between subjects with Bartter's syndrome due to CLCKB abnormalities and those with NKCC2 or ROMK1 mutations. Despite the fact that all of these Bartter's patients had significant hypercalciuria, nephrocalcinosis was not found in any of the 17 subjects with CLCKB mutations, compared to 19 of 20 patients with NKCC2 or ROMK1 mutations. These findings have also demonstrated a key role for CLCKB as a major basolateral chloride channel involved in mTAL sodium and chloride reabsorption (Figure 2).
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PMID:Straightening out the renal tubule: advances in the molecular basis of the inherited tubulopathies. 951 7

-Hydrochlorothiazide and indapamide are thought to exert their hypotensive efficacy through a combined vasodilator and diuretic effect, but in vivo evidence for a direct vascular effect is lacking. The presence and mechanism of a direct vascular action of hydrochlorothiazide in vivo in humans were examined and compared with those of the thiazide-like drug indapamide. Forearm vasodilator responses to infusion of placebo and increasing doses of hydrochlorothiazide (8, 25, and 75 microg. min-1. dL-1) into the brachial artery were recorded by venous occlusion plethysmography. Dose-response curves were repeated after local tetraethylammonium (TEA) administration to determine the role of potassium channel activation and, in patients with the Gitelman syndrome, to determine the role of the thiazide-sensitive Na-Cl cotransporter in the vasodilator effect of hydrochlorothiazide. Vascular effects of hydrochlorothiazide were compared with those of indapamide in both normotensive (mean arterial pressure, 85+/-7 mm Hg) and hypertensive (mean arterial pressure, 124+/-16 mm Hg) subjects. At the highest infusion rate, local plasma concentrations of hydrochlorothiazide averaged 11.0+/-1.6 microg/mL, and those of indapamide averaged 7. 2+/-1.5 microg/mL. In contrast to indapamide, hydrochlorothiazide showed a direct vascular effect (maximal vasodilation, 55+/-14%; P=0. 013), which was inhibited by TEA (maximal vasodilation after TEA, 13+/-10%; P=0.02). The response was not dependent on blood pressure and was similar in patients with Gitelman syndrome, indicating that absence of the Na-Cl cotransporter does not alter the vasodilatory effect of hydrochlorothiazide. The vasodilator effect of hydrochlorothiazide in the human forearm is small and only occurs at high concentrations. The mechanism of action is not mediated by inhibition of vascular Na-Cl cotransport but involves vascular potassium channel activation. In contrast, indapamide does not exert any direct vasoactivity in the forearm vascular bed.
Hypertension 1998 Dec
PMID:Thiazide-induced vasodilation in humans is mediated by potassium channel activation. 985 76

Blood pressure homeostasis in humans reflects the coordinate interactions of cardiac output, peripheral vascular resistance, renal volume control, and CNS integration in response to short- and long-term environmental stimuli. Variations in mean arterial pressure within the population include a significant hereditary component. The clearest examples of this genetic contribution occur in rare forms of monogenic hypertension (glucocorticoid remediable aldosteronism, apparent mineralocoid excess, Liddle's syndrome) or hypotension (pseudohypoaldosteronism type I, Bartter's syndrome, Gitelman's syndrome). Primary hypertension, which comprises approximately 95% of hypertensives and is a major risk factor for coronary heart disease, stroke, and renal disease in the U.S., represents a multifactorial and polygenic disease with incremental contributions from genetic and environmental determinants. Efforts to date have identified several candidate genes involved in primary hypertension, including angiotensinogen (AGT), a vasoactive peptide; alpha-adducin, a protein that regulates sodium transport; and the G protein beta 3 subunit, a protein involved in intracellular signal transduction. Advances in knowledge and technology associated with the Human Genome Project, combined with continuing basic research on the physiologic and biochemical causes of hypertension, offer promise for improved diagnosis and therapy of this prevalent disease.
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PMID:Genetic determinants of blood pressure regulation. 1038 72

Recent studies using molecular biological methods have enabled us to identify the genetic abnormality in renal electrolyte metabolism. In renal tubules, diuretic sensitive Na transporter systems are present, and key molecules have been cloned. Thiazide-sensitive Na-Cl contransporter (TSC) is one of the molecules localized in the distal convoluted tubule, whose genetic abnormality causes Gitelman's syndrome (a variant of Bartter's syndrome characterized by dehydration, hypokalemic metabolic alkalosis, secondary aldosteronism lacking hypertension, hypomagnesemia, and hypocalciuria). We identified a mutation in TSC (Leu to Pro change at 623 amino acid position, L623P) in familial Gitelman's syndrome, and we confirmed the loss of TSC function by this mutation in a functional expression system using mammalian cells. This L623P mutation has been found in other patients with Gitelman's syndrome living in the northern part of Japan.
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PMID:[Renal sodium transport abnormality: Gitelman's syndrome and renal sodium transporter]. 1063 22

Sodium and water homeostasis are key to the survival of organisms. Reabsorption of sodium and water occurs throughout the tubule structure of the nephron, the basic functional unit of the kidney, by various transport mechanisms. Altered transport protein function can lead to renal tubular disorders resulting in metabolic alkalosis, hypokalemia, hypertension, and decreased capacity to concentrate urine, for instance. However, recent advances in molecular physiology, molecular genetics and expression cloning systems have aided in unraveling the molecular basis of some renal tubular disorders. This review will examine the molecular basis of Bartter's syndrome, Gitelman's syndrome, Liddle's syndrome, and autosomal nephrogenic diabetes insipidus. An understanding of the molecular basis of these disorders of the human kidney can give us a better understanding of basic renal function of lower mammals and other vertebrates.
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PMID:The molecular basis of renal tubular transport disorders. 1096 27

Gitelman's syndrome is an autosomal recessive disorder characterized by electrolyte disturbances and low blood pressure. The disease is caused by homozygous or compound heterozygous inactivating mutations in the thiazide-sensitive NaCl-cotransporter gene leading to reduced renal sodium reabsorption. We report 4 patients with Gitelman's syndrome from southern Sweden, all in whom we identified compound heterozygous mutations in the thiazide-sensitive NaCl-cotransporter gene (Gly439Ser, Gly731Arg, Gly741Arg, Thr304Pro, and 2745insAGCA), of which the latter 2 have not been described before. We hypothesized that such mutations in their heterozygous form protect against primary hypertension in the general population and that the gene may also harbor activating mutations that increase the risk for primary hypertension. Accordingly, the gene was screened for mutations in 20 patients with primary hypertension and in 20 normotensive subjects by single-strand conformation polymorphism and direct DNA sequencing. The Arg904Gln, Gly264Ala, and C1420T variants, found in the mutation screening of subjects without Gitelman's syndrome, were studied further. Population genotype frequencies were determined in 292 unrelated patients with primary hypertension and 264 unrelated normotensive subjects from southern Sweden. Gln904 homozygotes were overrepresented in hypertensive patients compared with normotensive subjects (5 of 292 versus 0 of 264; P:=0.03). In conclusion, we confirm that Gitelman's syndrome is caused by mutations in the thiazide-sensitive NaCl-cotransporter gene. Our results further suggest that subjects homozygous for the Gln904 variant have an increased risk for development of primary hypertension.
Hypertension 2000 Sep
PMID:Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. 1098 70

The relationship between salt homeostasis and blood pressure has remained difficult to establish from epidemiological studies of the general population. Recently, mendelian forms of hypertension have demonstrated that mutations that increase renal salt balance lead to higher blood pressure, suggesting that mutations that decrease the net salt balance might have the converse effect. Gitelman's syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inherited hypokalemic alkalosis with so-called "normal" blood pressure. We hypothesized that the mild salt wasting of Gitelman's syndrome results in reduced blood pressure and protection from hypertension. We have formally addressed this question through the study of 199 members of a large Amish kindred with Gitelman's syndrome. Through genetic testing, family members were identified as inheriting 0 (n=60), 1 (n=113), or 2 (n=26) mutations in NCCT, permitting an unbiased assessment of the clinical consequences of inheriting these mutations by comparison of the phenotypes of relatives with contrasting genotypes. The results demonstrate high penetrance of hypokalemic alkalosis, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant NCCT alleles. In addition, the NCCT genotype was a significant predictor of blood pressure, with homozygous mutant family members having significantly lower age- and gender-adjusted systolic and diastolic blood pressures than those of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na(+) than did wild-type subjects, reflecting a self-selected higher salt intake. Finally, heterozygous children, but not adults, had significantly lower blood pressures than those of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood pressure in humans.
Hypertension 2001 Jun
PMID:Mutations in the Na-Cl cotransporter reduce blood pressure in humans. 1140 95


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