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)

The predisposition of African Americans to the salt sensitive form of essential hypertension may result from increased freely exchangeable Ca in intracellular Ca stores and a higher cellular Ca turnover (i.e., enhanced Ca entry into and accelerated Ca extrusion from the cytosol). These alterations entail higher activities of Ca extrusion transport systems, including the Na+/Ca2+ exchanger (NCE), which extrudes Ca in exchange for external Na+, and plasma membrane Ca-ATPase (PMCA) that extrudes Ca in exchange for external protons. The higher activity of PMCA, coupled with a higher metabolic activity resulting from a rise in freely exchangeable Ca, increase cellular acid load. Adaptive cellular mechanisms must evolve under these conditions, whereby increased activity of the Na/H exchanger (NHE-1) maintains normal cytosolic pH by enhancing the extrusion of cytosolic protons in exchange for extracellular Na. Cells with increased cellular Ca stores and enhanced Ca turnover may be particularly vulnerable to the factors that inhibit the Na-pump. By inhibiting the Na-pump, these factors diminish the transmembrane Na gradient and consequently inhibit the forward mode of the NCE. Since cells from African Americans show increased Ca turnover, they should retain more Ca upon exposure to Na-pump inhibitors; a heightened sensitivity to Na-pump inhibitors could therefore underlie the propensity of African Americans and other individuals with accelerated cellular Ca turnover rate to the salt sensitive form of essential hypertension. Accelerated cellular Ca turnover in African Americans also explains their better response to Ca antagonists compared with other antihypertensive drugs.
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PMID:Cellular calcium and sodium regulation, salt-sensitivity and essential hypertension in African Americans. 939 72

Both Na+/Li+ countertransport and electrochemical proton gradient (delta mu(H+))-induced Na+ and H+ fluxes are increased in erythrocytes from patients with essential hypertension. It was assumed that these abnormalities are related to ubiquitous (housekeeping) forms of the Na+/H+ exchanger (NHE-1). To examine this hypothesis, we compared kinetic and regulatory properties of erythrocyte Na+/Li+ countertransport and delta mu(H+)-induced Na+ and H+ fluxes with data obtained for cloned isoforms of the Na+/H+ exchanger. In human erythrocytes, Na+/Li+ countertransport exhibited a hyperbolic dependence on [Na+]0 with a K0.5 of approximately 30 to 40 mmol/L. The activity of this carrier was increased by two-fold in the fraction of erythrocytes enriched with the old cells, was inhibited by 0.1 mmol/L phloretin, and was insensitive to both 1 mmol/L amiloride and ATP depletion. In contrast, delta mu(H+)-induced 22Na influx was exponentially increased at [Na+]0 > 60 mmol/L, was insensitive to phloretin, was partly decreased by both 1 mmol/L amiloride and ATP depletion, and was the same in total erythrocytes and in the old cells. The values of Na+/Li+ countertransport and delta mu(H+)-induced Na+ influx in erythrocytes from different species were not correlating and their ratio in human, rat, and rabbit erythrocytes was 10:1:170 and 1:5:1 for Na+/ Li+ countertransport and delta mu(H+)-induced Na+ influx, respectively. In contrast to the majority of nonepithelial cells and cells transfected with an ubiquitous isoform of Na+/H+ exchanger, both delta mu(H+)-induced Na+ influx and Na+/Li+ countertransport in human erythrocytes were completely insensitive to ethylisopropyl amiloride (20 micromol/L) and cell shrinkage. Thus, our data strongly suggest that human erythrocyte Na+/Li+ countertransport and delta mu(H+)-induced Na+/H+ exchange are mediated by the distinct transporters. Moreover, because the properties of these erythrocyte transporters and NHE-1 are different, it complicates the use of erythrocytes for the identification of the mechanism for activating the ubiquitous form of Na+/H+ exchanger in primary hypertension.
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PMID:Can we use erythrocytes for the study of the activity of the ubiquitous Na+/H+ exchanger (NHE-1) in essential hypertension? 968 37

Erythrocyte Na+-Li+ countertransport shows an increased activity in essential hypertension and diabetic nephropathy, but its nature remains unknown. This amiloride-insensitive membrane transport may not be a mode of operation of the amiloride-sensitive NHE1, the only Na+-H+ exchange isoform found in human erythrocytes. Whether an independent, although unknown, amiloride-insensitive isoform mediates Na+-Li+ countertransport is unclear. Na+-H+ exchange activity was measured in acid-loaded erythrocytes. Dimethylamiloride, a specific inhibitor of Na+-H+ exchange and phloretin, a known inhibitor of Na+-Li+ countertransport, gave a reduction in H+-driven Na+ influx (by 31 and 37%, respectively). This effect was additive, and a 66% reduction in H+-driven Na+ influx was found in the presence of both inhibitors. Internal acidification, a stimulus for Na+-H+ exchange, enhanced Na+-Li+ countertransport activity (from 287 +/- 55 to 1213 +/- 165 micromol x Lcell(-1) h(-1), mean +/- SEM, P = 0.003). This transport remained sensitive to phloretin under both conditions. Conversely, external acidification decreased Na+-Li+ countertransport activity (as expected for a Na+-H+ exchanger). Competition between internal H+ and Li+ or Na+ for a common binding site was present. Finally, similar kinetic parameters for external Na+ characterized Na+-Li+ countertransport and the phloretin-sensitive component of H+-driven Na+ influx. These findings suggest that both Na+-Li+ countertransport and the amiloride-insensitive, phloretin-sensitive component of H+-driven Na+ influx can be mediated by a previously unrecognized novel amiloride-insensitive Na+-H+ exchange isoform in human erythrocytes.
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PMID:Amiloride-insensitive Na+-H+ exchange: a candidate mediator of erythrocyte Na+-Li+ countertransport. 984 74

The Na+/H+ exchangers (NHEs) are membrane-bound transporters that catalyze the electro-neutral movement of extracellular Na+ for intracellular H+. NHE genes play a critical role in pH homeostasis and cellular volume regulation and can be considered candidate genes for essential hypertension and renal disease. This study was performed to determine whether the NHE genes contributed to genetic susceptibility in end-stage renal disease (ESRD). To date, 5 isoforms of NHE have been cloned in mammals (NHE1 to NHE5). The complementary DNA (cDNA) sequences of NHE1 to NHE3 and NHE5 are known in humans. Because the chromosomal structure of the NHE genes is unknown, we used cDNA sequences to design polymerase chain reaction primers for use in radiation hybrid mapping. Radiation hybrid mapping of NHE genes identified nearby polymorphic markers for NHE1 to NHE3 (NHE1: D1S197, D1S2677; NHE2: D2S373, D2S1789; and NHE3: D5S678, D5S2005). We used these markers, and other previously identified polymorphic markers for NHE5, in linkage and association analyses of ESRD. The NHE1 to NHE3 and NHE5 loci did not demonstrate evidence for linkage to ESRD. However, NHE5 showed significant evidence for association (P</=1.0x10(-4)). The strongest evidence for association was observed with allele 6 of NHE5 (P</=0.001 to 0. 01). Allele 6 appeared to have a renoprotective effect, with a frequency of 0.15 in the control population and 0.06 to 0.09 in patients with ESRD. The combined approach of designing primers from cDNA and radiation hybrid mapping has proven successful in identifying polymorphisms for human genes of which only cDNA sequences were previously available. The NHE primers and associated polymorphic loci identified in this study can be used in genomic, linkage, and association analysis of NHE genes in future genetic studies of hypertension and renal failure. Given the allelic association, further evaluation of the role of NHE5 in ESRD susceptibility appears warranted.
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PMID:Human Na+/H+ exchanger genes : identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease. 1064 88

Enhanced Na(+)/H(+) exchange, measured as amiloride derivative-sensitive Na(+) and H(+) fluxes in cells with a preliminary acidified cytoplasm (Deltamu(H+)-induced Na(+)/H(+) exchange), is one of the most prominent intermediate phenotypes of altered vascular smooth muscle cell (VSMC) function in spontaneously hypertensive rats (SHR). Analysis of Na(+)/H(+) exchange in F(2) hybrids of SHR and normotensive rats seems to be the most appropriate approach in the search for the genetic determinants of abnormal activity of this carrier. However, the measurement of Deltamu(H+)-induced Na(+)/H(+) exchange is hardly appropriate for precise analysis of the carrier's activity in VSMC derived from several hundred F(2) hybrids. To overcome this problem, we compared the rate of (22)Na influx under baseline conditions and in Na(+)-loaded (ouabain-treated) VSMC. The dose-dependency of the rate of Deltamu(H+)-induced H(+) efflux as well as of (22)Na influx in control and ouabain-treated cells on ethylisopropylamiloride (EIPA) concentration were not different (K(0.5) approximately 0.3 microM), suggesting that these ion transport pathways are mediated by the same carrier. EIPA-sensitive (22)Na influx in Na(+)-loaded cells was approximately 6-fold higher than in ouabain-untreated VSMC and was increased by 50-70% in two different substrains of SHR. About the same increment of EIPA-sensitive (22)Na influx in Na(+)-loaded VSMC was observed in 5- to 6-week-old SHR (an age at which hypertension has not yet developed) as well as in stroke-prone SHR (SHRSP) with severe hypertension, indicating that the heightened activity of Na(+)/H(+) exchange is not a consequence of long-term blood pressure elevation. To examine whether or not the augmented activity of Na(+)/H(+) exchange in SHR is caused by mutation of NHE1, i.e. the only isoform of this carrier expressed in VSMC, we undertook single-stranded conformational polymorphism analysis of 23 NHE1 cDNA fragments from SHR and SHRSP and sequencing of the 456-2421 NHE1 cDNA fragment. This study did not reveal any mutation in the entire coding region of NHE1. The lack of mutation in the coding region of NHE1 indicates that the augmented activity of the ubiquitous Na(+)/H(+) exchanger in primary hypertension is caused by altered regulation of carrier turnover number or/and its plasma membrane content.
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PMID:Increased Na(+)/H(+) exchanger isoform 1 activity in spontaneously hypertensive rats: lack of mutations within the coding region of NHE1. 1065 86

Sodium/proton antiporters or exchangers (NHE) are integral membrane proteins present in most, if not all, living organisms. In mammals, these transporters chiefly catalyze the electroneutral exchange of Na(+) and H(+) down their respective concentration gradients and are crucial for numerous physiological processes, ranging from the fine control of intracellular pH and cell volume to systemic electrolyte, acid-base and fluid volume homeostasis. NHE activity also facilitates the progression of other cellular events such as adhesion, migration, and proliferation. Thus far, eight distinct NHE genes (NHE1/SLC9A1-NHE8/SLC9A8) and several pseudogenes have been identified in the human genome. The functional genes encode proteins of varying primary sequence identity (25-70%), but share a common predicted secondary structure comprising 12 conserved membrane-spanning segments at the amino-terminus and a more divergent, cytoplasmically-oriented, carboxy-terminus. They show considerable heterogeneity in their patterns of tissue/cell expression and membrane localization. Functional studies have revealed further differences in their kinetic properties, sensitivity to pharmacological antagonists, and regulation by diverse hormonal and mechanical stimuli. Altered NHE activity has been linked to the pathogenesis of several diseases, including essential hypertension, congenital secretory diarrhea, diabetes, and tissue damage caused by ischemia/reperfusion. Further characterization of their functional properties should lead to a better understanding of their unique contributions to human health and disease.
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PMID:Diversity of the mammalian sodium/proton exchanger SLC9 gene family. 1284 33

The C825T polymorphism of the beta-3 subunit of the protein G (GNB3) has been related to an increased activity of the Na+/H+ exchanger (NHE-1) through the synthesis of an anomalous hyperactive protein. Because of the important role of this system in essential hypertension (EH), we analysed the distribution of the different genotypes of this polymorphism in normotensive subjects (NS) and essential hypertensive patients (EHP), their relationship with the condition of salt sensitivity, plasma sodium and potassium concentrations and plasma renin activity (PRA) in EHP. 144 subjects (78 EHP and 76 NS) were studied. Salt sensitivity was assessed by the rapid protocol of Weinberger and genotype determination for GNB3 C825T polymorphism was performed by PCR. The distribution of the different genotypes was similar among EHP (CC 37.2%; CT 41.1%; TT 16.7%) and NS (CC 32.9%; CT 55.3%; TT 11.8%). In regard to general characteristics of EHP (including blood pressure levels) and the condition of salt sensitivity, there were no differences among the different genotypes. Plasma sodium concentration was higher and plasma potassium was lower in TT patients (141.0+/-1.7 and 3.7+/-0.1) than in CC patients (139.1+/-1.9 and 4.0+/-0.3) p<0.05. CT patients had intermediate values (139.9+/-1.9 and 3.9+/-0.2). PRA values were similar in the three genotypes as were the rest of analytical parameters studied. Our data demonstrate an association between the C825T polymorphism of the GNB3 and plasma sodium and potassium concentrations in EHP, as expression of an increase in NHE-1 activity, without modifications in PRA nor relationship with salt sensitivity.
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PMID:G-protein beta-3 subunit gene C825 T polymorphism: influence on plasma sodium and potassium concentrations in essential hypertensive patients. 1600 97

Human NHA2 is a poorly characterized Na(+)/H(+) antiporter recently implicated in essential hypertension. We used a range of computational tools and evolutionary conservation analysis to build and validate a three-dimensional model of NHA2 based on the crystal structure of a distantly related bacterial transporter, NhaA. The model guided mutagenic evaluation of transport function, ion selectivity, and pH dependence of NHA2 by phenotype screening in yeast. We describe a cluster of essential, highly conserved titratable residues located in an assembly region made of two discontinuous helices of inverted topology, each interrupted by an extended chain. Whereas in NhaA, oppositely charged residues compensate for partial dipoles generated within this assembly, in NHA2, polar but uncharged residues suffice. Our findings led to a model for transport mechanism that was compared to the well-known electroneutral NHE1 and electrogenic NhaA subtypes. This study establishes NHA2 as a prototype for the poorly understood, yet ubiquitous, CPA2 antiporter family recently recognized in plants and metazoans and illustrates a structure-driven approach to derive functional information on a newly discovered transporter.
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PMID:Model-guided mutagenesis drives functional studies of human NHA2, implicated in hypertension. 2005 53

Previously, we have shown that an increased cGMP-activated protein Kinase (PKG) activity after phosphodiesterase 5 (PDE5) inhibition by Sildenafil (SIL), leads to myocardial Na+/H+ exchanger (NHE1) inhibition preserving its basal homeostatic function. Since NHE1 is hyperactive in the hypertrophied myocardium of spontaneous hypertensive rats (SHR), while its inhibition was shown to prevent and revert this pathology, the current study was aimed to evaluate the potential antihypertrophic effect of SIL on adult SHR myocardium. We initially tested the inhibitory capability of SIL on NHE1 in isolated cardiomyocytes of SHR by comparing H+ efflux during the recovery from an acid load. After confirmed that effect, eight-month-old SHR were chronically treated for one month with SIL through drinking water. Compared to their littermate controls, SIL-treated rats presented a decreased NHE1 activity, which correlated with a reduction in its phosphorylation level assigned to activation of a PKG-p38 MAP kinase-PP2A signaling pathway. Moreover, treated animals showed a decreased oxidative stress that appears to be a consequence of a decreased mitochondrial NHE1 phosphorylation. Treated SHR showed a significant reduction in the pro-hypertrophic phosphatase calcineurin, despite slight tendency to decrease hypertrophy was detected. When SIL treatment was prolonged to three months, a significant decrease in myocardial hypertrophy and interstitial fibrosis that correlated with a lower myocardial stiffness was observed. In conclusion, the current study provides evidence concerning the ability of SIL to revert established cardiac hypertrophy in SHR, a clinically relevant animal model that resembles human essential hypertension.
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PMID:PDE5 inhibition improves cardiac morphology and function in SHR by reducing NHE1 activity: Repurposing Sildenafil for the treatment of hypertensive cardiac hypertrophy. 3315 35


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