Sodium-lithium countertransport

West, Ian; Rutherford, Peter; Thomas, T.H.

doi:10.1097/00004872-199816010-00002

Cited by 86 publications

(39 citation statements)

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“…A genetic study founded on the hypothesis that the Na ϩ -H ϩ exchanger NHE1 was mediating Na/Li CT excluded NHE1 from linkage with EHT with very high confidence. 26 However, because rat erythrocytes have very high NHE1 activity but no Na/Li CT activity, 3 this hypothesis was unlikely to be true. No other candidate proteins have been suggested in relation to Na/Li CT. We conclude that an abnormal thiol protein could be responsible for the abnormal Na/Li CT kinetics in a subgroup of EHT patients who may have a common biochemical pathology.…”

Section: Discussionmentioning

confidence: 99%

“…2 In vivo, in the absence of lithium, this transporter must give equimolar sodium-sodium exchange, and its physiological role is obscure. 3 The initial measurement of sodium-lithium countertransport (Na/Li CT) was as a lithium flux rate from lithium-loaded erythrocytes with 140 mmol/L external sodium. 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.…”

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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: Discussionmentioning

confidence: 99%

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

1999

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“…S o d i u m -l i t h i u m countertransport (Na-Li CT) is a membrane transport system involving a one-to-one exchange of sodium for lithium, usually measured as sodium-dependent lithium efflux in lithiumloaded red blood cells (RBCs). Na-Li CT affinity for lithium is approximately 15-to 18-fold greater than that for sodium (30,31). Patients treated with lithium for a bipolar disorder typically have serum sodium and lithium concentrations of approximately 140 mEq/L and 0.6 to 1.5 mEq/L, respectively (30,31).…”

Section: Discussionmentioning

confidence: 99%

Winter Sale on Lithium Levels: The Impact of Seasonality

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et al. 2013

Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychophar

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Amaç: Lityum duygudurum bozukluklarının koruma tedavisinde etkili bir ilaç olarak tüm dünyada tanınmaktadır. Lityumun bipolar bozukluk profilaksisindeki etkinliği yetmişli yılların başından beri kanıtlanmıştır. Lityum bipolar bozuklukta akut duygudurum epizodları farmakoterapisi, döngülerin önlenmesi, önleyici tedavi ve intiharın önlenmesinde dayanak noktası olmuş ve olmaya devam etmektedir. Bazı ülkelerde lityum düzeylerinin mevsimsel değişiklikleri olduğu şeklinde yayınlar mevcuttur. Winter sale on lithium levels: the impact of seasonality Objective: Lithium is recognized worldwide as an effective prophylactic agent in mood disorders. Prophylactic efficacy of lithium in mood disorders has been established since the early seventies. Lithium has been and continues to be the mainstay of bipolar disorder (BD) pharmacotherapy for acute mood episodes, switch prevention, and suicide prevention. There are reports of seasonal variation in lithium levels from a few countries. Variability in the lithium level can lead to a lack of efficacy or to toxicity, making seasonal variation clinically relevant. We aimed to compare lithium levels of bipolar patients between summer and winter. Methods: Euthymic bipolar patients who were followed in the Raşit Tahsin Mood Clinic of the Bakırköy Research and Training Hospital for Psychiatry, Neurology and Neurosurgery were recruited for the study, and lithium levels were measured in the second part of winter and summer (15 th of June to 1st of September and 15 th of January to 1 st of March). A prospective case sheet audit was performed for 32 BD patients for recording plasma lithium level, age and gender for one year. Bipolar patients whose treatment dosage of lithium was changed for any reason during the study follow-up were excluded. Situations of lithium use other than for bipolar disorder were excluded. The presence of concomitant diagnoses of mental retardation or drug dependence constituted exclusion criteria, as did medication non-compliance detected by persistently low lithium plasma levels. The use of antihypertensive drugs, nonsteroidal anti-inflammatory drugs, theophylline, some antibiotics, topiramate, and diuretics that could cause an increase in plasma concentrations of lithium, and of theophylline that could reduce lithium concentrations constituted exclusion criteria. Sodium levels were also monitored due to their propable effect on lithium levels. Lithium levels were compared using the paired sample t-test. Correlation analysis was done for the parameters that could affect lithium levels. Results: The mean age of the patients was 35.75±9.59 years, the mean age of onset was 21.97±6.17 and the mean duration of disorder was 13.90±9.41 year. 15 out of 32 patients were male. The overall average dose of lithium taken by the patients was 1190.6±249.0 mg/day. The mean lithium plasma level was 0.75±0.12 mEq/L in winter, and the mean lithium plasma level was 0.83±0.12 mEq/L in summer (p=0.003). The overall serum sodium levels were 139.1±2.2 mEq/L in summer and 137.1±2.3 mEq/L i...

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“…Thiol group(s) regulate the activity of the SLC in erythrocytes. 1,2,[32][33][34] In these cells, thiol group alkylation with maleimide primarily appears to increase the activity of the SLC by lowering the Km for Li ϩ , ie, increasing the affinity of the transporter to Li ϩ . 35 Indeed, NEM increased the activity of the SLC in EBV-immortalized lymphoblasts.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 The activity of SLC is modified by thiol alkylating agents, such as maleimide, which increases the affinity of the SLC to Li ϩ . 1,2 Although the kinetics of the SLC are well characterized, the nature of the transporter and the genes contributing to its expression are unknown. Evidently, functional properties of the SLC 3 and its gene(s) 4,5 are different from those of the ubiquitous Na ϩ /H ϩ -antiport (NHE-1).…”

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Genomic Association/Linkage of Sodium Lithium Countertransport in CEPH Pedigrees

et al. 2002

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Abstract-Little is known about genetic determinants explaining variation in the erythrocyte sodium-lithium countertransport (SLC), an intermediate phenotype of essential hypertension. We characterized the SLC in immortalized lymphoblasts and showed that its behavior is similar to that of erythrocyte SLC. We then performed association and linkage analyses of the SLC in immortalized lymphoblasts from 5 large pedigrees from the Center d'Etude du Polymorphisme Humain (CEPH) genomics repository. The results of these analyses showed that a number of genomic regions harboring genes involved in glutathione metabolism might explain variations in SLC activity. The activity of SLC is modified by thiol alkylating agents, such as maleimide, which increases the affinity of the SLC to Li ϩ . 1,2 Although the kinetics of the SLC are well characterized, the nature of the transporter and the genes contributing to its expression are unknown. Evidently, functional properties of the SLC 3 and its gene(s) 4,5 are different from those of the ubiquitous Na ϩ /H ϩ -antiport (NHE-1). Thus, a search for genes that explain variation in SLC activity is in order. The discovery of these genes may have clinical relevance because the SLC is one of the most studied intermediate phenotypes of essential hypertension. The National Library of Medicine lists Ͼ500 peerreviewed papers that have explored the epidemiology and physiology of the SLC in the context of essential hypertension and related cardiovascular diseases. The activity of the SLC, as expressed in erythrocytes in vivo, has been shown to correlate with a host of cardiovascular risk factors that relate to essential hypertension, including insulin resistance and dyslipidemia. 6 -9 In addition, the activity of the SLC is lower in blacks than in whites 10 -12 (for review, see Aviv and Lasker 13 ) and is lower in white women than in white men. 14,15 Importantly, the activity of the SLC reflects both genetic and environmental factors. 14 -16 In the present study, we describe a novel strategy for dissecting the genetic basis of the SLC by shielding it from influences owing to different environmental conditions that exist in vivo, and by taking advantage of the vast amount of publicly available genotype data. We accomplished this by studying the SLC in Epstein-Barr virus (EBV)-immortalized lymphoblasts of large reference Center d'Etude du Polymorphisme Humain (CEPH) pedigrees. The CEPH collection provides a considerable advantage in that extensive genotype data are already available for some of the pedigrees in the CEPH (http://landru.cephb.fr) and the companion Coriell Cell Repositories (http://locus.umdnj.edu/nigms/ceph/ceph.html). By screening cell lines from CEPH pedigrees for variations in the SLC, we were able to rapidly use this enormous amount of genotype data. Materials and Methods Accessing the CEPH PedigreesLymphoblasts from the members of 5 CEPH pedigrees were obtained from the CEPH and the Coriell Cell Repositories. These repositories contain information on Ͼ12 000 DNA microsatell...

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Sodium-lithium countertransport

Cited by 86 publications

References 102 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

Winter Sale on Lithium Levels: The Impact of Seasonality

Genomic Association/Linkage of Sodium Lithium Countertransport in CEPH Pedigrees

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