Erythrocyte Na+/Li+ countertransport and Na+/K+–2Cl− co-transport measurement in essential hypertension: useful diagnostic tools or failure? A meta-analysis of 17 years of literature

Tepper, T.; Sluiter, Willem; Huisman, Roel M.; Zeeuw, de Dick

doi:10.1042/cs0950649

Cited by 9 publications

(11 citation statements)

References 14 publications

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“…Similar to most previous studies, 5 there is much overlap in Na/Li CT parameters (Figure 1), but the effect of thiol alkylation with NEM on K m was the clearest discriminator in the EHT-FH patients. It was unaffected by plasma triglyceride levels.…”

Section: Discussionsupporting

confidence: 71%

“…It is clear that in the present study the EHT-FH patients with the abnormal Na/Li CT kinetic parameters that were due to the abnormal thiol protein were very poorly discriminated by the single Na/Li CT flux rate assay. A recent meta-analysis of data from the latter assay concluded that the difference assessed by Na/Li CT flux rate between patients with EHT and NCs was weak but observed that kinetic parameters may be more useful, 5 and this is clearly shown in the present study.…”

Section: Discussionsupporting

confidence: 68%

“…4 An activity Ͼ0.4 mmol/hϫL red blood cell (rbc) was considered abnormal, but although this was initially promising, a recent meta-analysis of many studies has shown that discrimination between EHT and normal is poor. 5 However, Na/Li CT activity is increased not only by the familial factor related to EHT but also by metabolic factors associated with dyslipidemia, 6,7 and values Ͼ0.4 have been much less common in successive studies, even from the same laboratory. 8 This is probably due to improved management of plasma lipids.…”

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confidence: 99%

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Thiol Protein Defect in Sodium-Lithium Countertransport in Subset of Essential Hypertension

1999

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Abstract-There is probably a heterogeneous etiology for essential hypertension (EHT), and abnormal erythrocyte sodium-lithium countertransport (Na/Li CT) is common in a subgroup of patients with a strong family history of hypertension and cardiovascular disease (EHT-FH patients). The aim of this study was to test the hypothesis that altering a membrane thiol protein could mimic the abnormal Na/Li CT observed in the patients and that a more refined understanding of the mechanism of abnormal Na/Li CT would facilitate a clearer identification of a subgroup of patients with a homogeneous biochemical abnormality. Na/Li CT kinetics were determined in untreated erythrocytes and after thiol group alkylation with N-ethylmaleimide (NEM). Compared with normal control erythrocytes, untreated erythrocytes from EHT-FH patients had a low K m of Na/Li CT, with a high ratio of maximum velocity to K m . This kinetic pattern was reproduced in normal erythrocytes by treatment with NEM in sodium-free medium. The same treatment in EHT-FH erythrocytes caused a markedly abnormal effect with an increase in maximum velocity, indicating an increase in transporter turnover in contrast to the increase in sodium affinity seen in normal control erythrocytes. Frequency distributions of these kinetic changes showed a subgroup of Ϸ75% of EHT-FH patients with abnormal kinetic changes with NEM. Therefore, the key Na/Li CT thiol group that is very reactive to NEM and causes the abnormal Na/Li CT in a subgroup of hypertensive patients may be a useful intermediate phenotype for a disease group within the syndrome of EHT. The single flux assay of Na/Li CT at 140 mmol/L sodium poorly discriminates this group. Identification of the thiol protein involved may lead to a molecular explanation of the altered membrane function in this subgroup of patients. Key Words: erythrocytes Ⅲ hypertension, essential Ⅲ kinetics Ⅲ sodium-lithium countertransport E ssential hypertension (EHT) is common in developed Western societies and is a major risk factor for cardiovascular disease. EHT is not a single disease, and because blood pressure is normally distributed in populations, EHT is difficult to define even as a clinical syndrome and has a wide range of severity. Current guidelines are therefore to treat all patients with sustained blood pressure above a particular level, which varies in different countries. Because it is not possible to predict which patients will develop a complication, many treated patients would never have suffered a complication if left untreated. A trial of the treatment of mild hypertension (diastolic blood pressure up to 110 mm Hg) found that 850 patient years of treatment prevented one stroke and did not alter the occurrence of myocardial infarction. 1 Approximately 95% of hypertensive patients are classified as having EHT. It seems unlikely that this large group will be homogeneous, and there are probably multiple etiologic factors. However, in patients with relatively severe hypertension and with a strong family history of hypertension and...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 68%

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confidence: 99%

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Thiol Protein Defect in Sodium-Lithium Countertransport in Subset of Essential Hypertension

1999

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“…It was felt that a simple measurement on red blood cells from individuals in at-risk groups might inform clinicians about appropriate therapeutic strategies or lifestyle advice. However, larger studies failed to find a clear correlation [102], suggesting that measurements of red blood cell Na + -K + -2Cl − cotransport rate had no diagnostic value in essential hypertension. We are now in a position to understand why a connection between hypertension and red blood cell NKCC activity might exist.…”

Section: Wnks Cccs and Bpmentioning

confidence: 85%

Cotransporters, WNKs and hypertension: important leads from the study of monogenetic disorders of blood pressure regulation

Flatman

2007

Clinical Science

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Major advances are being made in identifying the structure and behaviour of regulatory cascades that control the activity of cation-Cl(-) cotransporters and certain Na(+), K(+) and Cl(-) channels. These transporters play key roles in regulating arterial blood pressure as they are not only responsible for NaCl reabsorption in the thick ascending limb and distal tubule of the kidney, but are also involved in regulating smooth muscle Ca(2+) levels. It is now apparent that defects in these transporters, and particularly in the regulatory cascades, cause some monogenetic forms of hypertension and may contribute to essential hypertension and problems with K(+) homoeostasis. Two families of kinases are prominent in these processes: the Ste-20-related kinases [OSR1 (oxidative stress-responsive kinase 1) and SPAK (Ste20/SPS1-related proline/alanine-rich kinase)] and the WNKs [with no lysine kinases]. These kinases affect the behaviour of their targets through both phosphorylation and by acting as scaffolding proteins, bringing together regulatory complexes. This review analyses how these kinases affect transport by activating or inhibiting individual transporters at the cell surface, or by changing the surface density of transporters by altering the rate of insertion or removal of transporters from the cell surface, and perhaps through controlling the rate of transporter degradation. This new knowledge should not only help us target antihypertensive therapy more appropriately, but could also provide the basis for developing new therapeutic approaches to essential hypertension.

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“…Na/LiCT has a major inherited component, but is also affected by environmental/metabolic factors, notably circulating plasma lipid concentrations [2]. Hence it has not been a clear marker of disease or disease susceptibility and some studies have shown poor discrimination from NC (normal controls) [3,4]. However, the consistent finding of abnormal Na/LiCT in some groups of patients with EH justifies attempts to understand the molecular mechanism for the association with disease.…”

Section: Introductionmentioning

confidence: 96%

Sodium–lithium countertransport and the Gly460→Trp α-adducin polymorphism in essential hypertension

et al. 2005

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A polymorphism of the alpha-subunit of adducin, Gly460-->Trp, may affect membrane ion transport and be associated with human EH (essential hypertension). The alpha-adducin Gly460-->Trp polymorphism was determined in 242 NC (normal controls) and 73 patients with EH and was related to the membrane ion transport marker in EH, erythrocyte Na/LiCT (sodium-lithium countertransport), in a subgroup of these subjects. The Km for external sodium was lower in patients with EH than NC. The Km of the Trp allele was lower than with the Gly/Gly genotype [NC, 105+/-6 compared with 88+/-5 mmol Na/l respectively (P=0.05); patients with EH, 76+/-5 compared with 64+/-4 mmol Na/l respectively (P=0.06)]. The Km was lower in patients with EH than NC for any adducin genotype. Thiol alkylation with NEM (N-ethylmaleimide) caused a decrease in Km in NC, but not in patients with EH. With a Trp allele, NEM lowered Km less in NC (-20 compared with -35) and increased it in patients with EH (+24 compared with +3; P=0.007 for genotype effect). Thiol alkylation with NEM caused an increase in Vmax in patients with EH but not in NC. With a Trp allele, NEM increased Vmax substantially in patients with EH (+0.12 compared with +0.03) but did not cause a decrease in NC (+0.02 compared with -0.06; P=0.007 for genotype effect). In conclusion, the Gly460-->Trp polymorphism of alpha-adducin modifies the kinetics of Na/LiCT. The effect of this genotype is different in patients with EH compared with NC and it does not explain the abnormal kinetics in patients with EH. The Trp allele was not associated with disease in the population studied. Several cytoskeletal proteins may interact with adducin in the overall phenotype of EH.

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Erythrocyte Na+/Li+ countertransport and Na+/K+–2Cl− co-transport measurement in essential hypertension: useful diagnostic tools or failure? A meta-analysis of 17 years of literature

Cited by 9 publications

References 14 publications

Thiol Protein Defect in Sodium-Lithium Countertransport in Subset of Essential Hypertension

Thiol Protein Defect in Sodium-Lithium Countertransport in Subset of Essential Hypertension

Cotransporters, WNKs and hypertension: important leads from the study of monogenetic disorders of blood pressure regulation

Sodium–lithium countertransport and the Gly460→Trp α-adducin polymorphism in essential hypertension

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