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

The "reverse genetic" approach to essential hypertension is complicated by the fact that blood pressure is a heterogeneous, quantitative, complex trait. One strategy is to use "intermediate phenotypes" that are not only associated with hypertension but that also have a simple mode of inheritance, compatible with the action of a single gene. Red cell sodium-lithium countertransport (SLC) is one of the best characterized intermediate phenotypes for hypertension. The similarity in stoichiometry and kinetics between SLC and Na+/H+ exchange has led to the proposal that the gene encoding the Na+/H+ antiporter (APNH) may be responsible for the individual variance in SLC. We have tested this hypothesis by both an association study and Haseman and Elston's sib pair method of linkage analysis, by using a polymorphism at the APNH locus detected by denaturing gradient gel electrophoresis. Both analytical techniques were performed before and after correction of SLC values for known covariates. There was no significant association between mean SLC values and any of the three possible genotypes of the APNH locus either before or after regressing out covariates (F = 0.64 and P greater than 0.52; F = 0.63 and P greater than 0.53, respectively). Linkage analysis similarly failed to demonstrate a relationship between the squared difference in SLC values and the identity by descent status for APNH as well as other loci that map close to APNH (D1S57, RH, and ALPL). Taking these results together, we conclude that mutations at the APNH locus are not responsible for the observed variation in SLC values.
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PMID:Assessing the role of APNH, a gene encoding for a human amiloride-sensitive Na+/H+ antiporter, on the interindividual variation in red cell Na+/Li+ countertransport. 166 Nov 90

The primary abnormalities that contribute to the pathogenesis of human essential hypertension are unknown. The known genetic contribution to this disorder suggests the possible use of genetic linkage analysis to test whether specific candidate genes contribute to the pathogenesis of either essential hypertension or intermediate phenotypes. Among such phenotypes, elevated erythrocyte Na(+)-Li+ countertransport (SLC) is the best known, supporting major gene inheritance by pedigree analysis. Striking similarities between SLC and Na(+)-H+ exchange suggest that mutations at the Na(+)-H+ antiporter gene locus (APNH) might result in elevated SLC and contribute to the subsequent pathogenesis of hypertension. We have tested these hypotheses by genetic linkage analysis, with APNH as a candidate gene. By determining genotypes at APNH and flanking loci in pedigrees that support major gene segregation of elevated SLC, we have excluded linkage of APNH and the major SLC locus with a LOD score of -5.91, an odds ratio of almost 1,000,000:1 against linkage. In the analysis of 93 hypertensive sibling pairs, we have further demonstrated that APNH explains none of the variance in SLC in hypertensive individuals (r2 = 6 x 10(-7), p greater than 0.99). Finally, we have directly tested for linkage of APNH to genes predisposing toward hypertension by linkage in hypertensive sibling pairs. Mean allele sharing at APNH is not greater than expected from random assortment in hypertensive siblings (0.92 versus 1.0, p greater than 0.80), and the upper 95% confidence limit of this value (1.04) indicates that mutations at APNH rarely if ever contribute to the pathogenesis of hypertension in this population.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Exclusion of the Na(+)-H+ antiporter as a candidate gene in human essential hypertension. 184 21

The Na+/H+ antiporter is a ubiquitous membrane-associated protein that plays an important role in the regulation of intracellular pH. APNH, a gene encoding the antiporter, has been cloned and mapped to the short arm of chromosome 1 by in situ hybridization. Using the polymerase chain reaction, we have amplified a 376 base pair fragment corresponding to the 5' end of APNH. We have detected a polymorphism within this fragment by denaturing gradient gel electrophoresis. Using polymorphisms at other 1p loci (ALPL, the gene for alkaline phosphatase, RH and D1S57), we have been able to map APNH telomeric to D1S57 and close to RH and ALPL by genetic linkage. APNH is a plausible candidate gene for human essential hypertension; the APNH polymorphism combined with a knowledge of its genetic map location allow this candidate to be tested in hypertensive kindreds and sib-pairs.
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PMID:The Na+/H+ antiporter: a "melt" polymorphism allows regional mapping to the short arm of chromosome 1. 197 10

In both essential hypertension and diabetic nephropathy (DN), the ubiquitous cellular Na+/H+ exchanger (NHE) exhibits altered kinetics with increased transport activity. The mechanism for this phenotype and its dependence on the presence of serum are unknown, but increased lymphoblast NHE activity in DN has been attributed to a defect in post-translational processing of NHE-1 rather than an increased cellular exchanger number. Phosphorylation of NHE-1 has been proposed to play a role in its activation in a variety of cell models. We have examined, therefore, the role of NHE-1 phosphorylation and the effect of serum in determining the increased NHE-1 activity in lymphoblasts from patients with DN. Cells from these patients exhibited increased NHE activity in the presence and absence of fetal calf serum (range 42-59%, P < 0.005, analysis of variance) and an increased proliferation rate (P < 0.01) when compared with cells from both normoalbuminuric diabetic patients and non-diabetic control subjects. However, NHE-1 abundance was very similar among all groups in the presence and absence of serum, indicating that increased NHE activity in cells of nephropathy patients was due to an increased turnover number. This nephropathy phenotype was not accompanied by an increased net phosphorylation of NHE-1 in the presence or absence of serum. Our findings suggest that increased NHE-1 activity in cells of DN patients is independent of the presence of serum and is not attributable to altered NHE-1 phosphorylation. Additional post-translational mechanisms for activation of NHE-1, therefore, may be involved.
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PMID:Phosphorylation and activity of Na+/H+ exchanger isoform 1 of immortalized lymphoblasts in diabetic nephropathy. 755 55

Increased activity of the cellular Na(+)-H+ exchanger (NHE) has been documented in various cell types in essential hypertension and in vascular myocytes of the spontaneously hypertensive rat (SHR). The mechanism underlying this abnormality is unclear. Because the NHE can be activated by phosphorylation, we examined phosphorylation of the Na(+)-H+ exchanger isoform 1 (NHE-1) as one possible mechanism for its increased turnover number in cultured vascular myocytes of the SHR. A polyclonal rabbit antibody against a fusion protein consisting of beta-galactosidase and the C-terminus of NHE-1 was used to immunoprecipitate 32P-labeled NHE-1 from cell extracts of SHR and Wistar-Kyoto (WKY) rat vascular myocytes in the absence and presence of 10% fetal calf serum. Immunoprecipitates were separated by SDS-PAGE, and 32P-labeled NHE-1 was quantified from autoradiographs. Similar amounts of NHE-1 protein were detected on Western blots of the cultured vascular myocytes from SHR and WKY rats. In quiescent cells, NHE-1 was significantly more phosphorylated in SHR myocytes than in WKY myocytes (2.17 +/- 0.06-fold enhancement [mean +/- SEM]; P < .001, n = 8). The addition of fetal calf serum to quiescent cells had no significant effect on the phosphorylation of NHE-1 in SHR myocytes. However, NHE-1 phosphorylation fell transiently in serum-treated WKY myocytes, with recovery to control levels after 20 minutes. Measurement of NHE activity using fluorometry confirmed elevated activity in the quiescent SHR myocytes compared with WKY myocytes. Fetal calf serum led to further enhancement of NHE activity in both cell types. These findings suggest that the increased NHE activity in quiescent SHR myocytes may be correlated with enhanced NHE-1 phosphorylation and that serum stimulates NHE activity in both cell types without a further increase in total NHE-1 phosphorylation, indicating a role for non-phosphorylation-dependent regulatory mechanisms.
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PMID:Na(+)-H+ exchanger isoform 1 phosphorylation in normal Wistar-Kyoto and spontaneously hypertensive rats. 772 99

It has been demonstrated that the activity of the sodium-proton exchanger (NHE-1 isoform) is increased in lymphocytes and other blood cells from patients with essential hypertension. In the present study, we investigated whether an increased level of NHE-1-specific mRNA in lymphocytes from patients with essential hypertension would explain the enhanced transport activity. Twenty-two hypertensive patients and 21 normotensive subjects were studied. Basal cytosolic pH was measured by the pH-sensitive fluorescent probe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Maximal sodium-proton exchange activity was determined by acidifying cell pH and measuring the initial rate of the net sodium-dependent proton efflux driven by an outward proton gradient. The transcript level of NHE-1 was measured by reverse transcription-polymerase chain reaction in comparison with a constitutively expressed reference gene (beta-actin). Intracellular pH was lower in hypertensive patients than normotensive subjects (7.34 +/- 0.01 versus 7.39 +/- 0.01, mean +/- SEM, P < .001). The maximal activity of the sodium-proton exchanger was higher in hypertensive patients than in normotensive subjects (1262 +/- 100 versus 881 +/- 56 mmol/L cells per hour, P < .01). NHE-1 mRNA was increased in hypertensive patients compared with normotensive subjects (ratio of NHE-1 mRNA to beta-actin mRNA, 0.16 +/- 0.01 versus 0.12 +/- 0.02, P < .05). These data suggest that the increased sodium-proton exchange activity in essential hypertension may be related to the de novo synthesis of exchanger protein.
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PMID:Enhanced Na(+)-H+ exchanger activity and NHE-1 mRNA expression in lymphocytes from patients with essential hypertension. 787 60

The plasma membrane Na/H exchanger plays an essential role in regulating intracellular pH and Na+ concentration and has been implicated in several pathophysiological conditions, including essential hypertension and congenital secretory diarrhea. Four isoforms of the Na/H exchanger encoded by separate genes have recently been identified by cDNA cloning. To map their locations in the human and rat genomes, rat isoform-specific cDNA probes were hybridized to Southern filters containing panels of somatic cell hybrids that segregate either human or rat chromosomes. The rat Nhe1 gene was assigned to Chromosome (Chr)5, extending the homology with human chromosome 1p that has previously been shown to contain the human NHE1 gene. The genes encoding the NHE-2 and NHE-4 isoforms were syntenic in the two species and assigned to rat Chr 9 and human Chr 2. A single Nhe3 gene was detected in rat and assigned to Chr 1. In contrast, although evidence to date has suggested a single human NHE3 gene on Chr 5, two NHE3 genes, NHE3A and NHE3B, were identified and assigned to Chrs 10 and 5, respectively. Interestingly, rat Chr 1 has recently been found to carry a gene controlling systolic blood pressure upon sodium loading in stroke-prone, spontaneously hypertensive rats. Thus, this and other evidence implicates rat Nhe3 as a possible candidate gene in this disease process.
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PMID:Chromosomal assignment of four genes encoding Na/H exchanger isoforms in human and rat. 819 3

An enhancement of sodium-proton exchange activity is a frequently observed ion transport abnormality in essential hypertension. The cellular basis for this has not yet been elucidated. Due to the lack of a specific cell culture system it has been impossible to distinguish between intrinsic cellular abnormalities and influences exerted by the hypertensive neurohumoral milieu. Using Epstein-Barr virus we have immortalized lymphocytes from controls and from patients with essential hypertension that exhibited enhanced sodium-proton exchanger activity. Sodium-proton exchanger activity was determined in cells loaded with the fluorescent cytosolic pH indicator 2'7'-biscarboxyethyl-5,6-carboxyfluorescein acetoxymethylester (BCECF) after pretreatment with 250 nM of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate for 10 min. Cell lines from hypertensive patients displayed higher Vmax values of sodium-proton exchange than those from normotensive controls (129.6 +/- 30.0 vs. 77.1 +/- 13.2 mmol H+/min.; P < 0.001). Hill coefficients for H+ were distinctly lower in hypertension compared to normotension (1.12 +/- 0.12 vs. 1.50 +/- 0.14; P < 0.0001). The enhanced antiporter activity in cell lines from hypertensive patients was not accompanied by a corresponding increase in steady-state NHE-1 mRNA transcript levels, which argues against overexpression of antiporter protein in hypertension. The cells from hypertensive patients with high sodium-proton exchange activity proliferated distinctly faster than those from normotensive controls. These human cell lines represent a novel model to study the mutual interaction between sodium-proton exchange and cell proliferation, and may provide insights into the alterations in ion transport observed in a group of patients with essential hypertension.
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PMID:Hypertensive sodium-proton exchanger phenotype persists in immortalized lymphoblasts from essential hypertensive patients. A cell culture model for human hypertension. 822 69

This review focuses on the mechanisms whereby the cytosolic Ca2+ regulates the ubiquitous Na+/ H+ exchanger (NHE-1) and how these regulatory processes might modify the behavior of NHE-1 in essential hypertension. The pH setpoint for activation of the Na+/H+ exchanger is controlled by two interrelated and Ca(2+)-dependent pathways, namely, the protein kinase/ phosphatase cascade and Ca2+/calmodulin. The cytoplasmic domain of NHE-1 contains elements responsive to serine/theorine kinases and a high affinity binding site to Ca2+/calmodulin. Phosphorylation of NHE-1 or the binding of the Ca2+/calmodulin complex to its binding site promotes an alkaline shift in the pH setpoint for the exchanger. It is suggested that, in essential hypertension, an increased cellular Ca2+ load or an enhanced external Ca2+ entry stimulate the NHE-1 through protein kinase/phosphatase and Ca2+/calmodulin systems, thereby increasing its activity.
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PMID:The links between cellular Ca2+ and Na+/H+ exchange in the pathophysiology of essential hypertension. 880 85

In this study, we investigated whether antihypertensive treatment with the angiotensin converting enzyme inhibitor quinapril modifies Na+/H+ exchanger activity or NHE-1 (isoform of the exchanger) mRNA expression in lymphocytes from patients with essential hypertension. Thirty-three hypertensive patients and 27 normotensive subjects were studied. Maximal sodium-proton exchange activity was determined by acidifying cell pH and measuring the initial rate of the net sodium-dependent proton efflux driven by an outward proton gradient. The transcript level of NHE-1 was measured by reverse transcription-polymerase chain reaction in comparison with a constitutively expressed reference gene (beta-actin). With the 100% confidence (upper) limit of the normotensive population as a cutoff point, a subgroup of 11 hypertensive patients had an abnormally high lymphocyte Na+/H+ exchange activity (group A). The activity of the exchanger was within the normal range in the remaining patients (group B). After 6 months of quinapril treatment the activity of the exchanger decreased to normal values (P < .001) in patients from group A, but remained unchanged in patients from group B. The NHE-1 mRNA expression was not modified with treatment neither in patients from the group A, nor in patients from the group B. These results suggest that chronic angiotensin enzyme inhibition with quinapril abolishes Na+/H+ exchange overactivity present in lymphocytes from a subgroup of hypertensive patients. This effect appears to be independent of changes in the expression of the mRNA encoding for the NHE-1 isoform of the exchanger.
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PMID:Angiotensin converting enzyme inhibition corrects Na+/H+ exchanger overactivity in essential hypertension. 900 52


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