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Increased Sodium-Lithium Countertransport in Red Cells of Patients with Essential Hypertension
Abstract
This paper describes experiments showing that one of the pathways of sodium transport across the red-cell membrane, sodium-lithium countertransport, is faster in patients with essential hypertension than in control subjects. This transport system accepts only sodium or lithium and is not inhibited by ouabain. The maximum rate of transport shows inherited differences. The mean maximum rate of sodium-lithium countertransport was found to be 0.55 +/- 0.02 (mean +/- S.E.M.) mmol (liter of red cells X hour)(-1) in a group of 36 patients with essential hypertension and 0.24 +/- 0.02 in 26 control subjects (P less than 0.001). The first-degree relatives of eight patients with essential hypertension and 10 control subjects had mean maximum rates of sodium-lithium countertransport of 0.54 +/- 0.05 and 0.23 +/- 0.02, respectively. Five patients with secondary hypertension had normal mean maximum rates of sodium-lithium countertransport. The relation between heritability of red-cell sodium-lithium countertransport and essential hypertension should be investigated further.
... A single plasma sample at the midpoint of urine collection was deemed adequate for calculating the clearance of lithium by the kidneys [12]. The activity of erythrocyte SLC-T was measured by Canessa et al.'s [13] method. ...
... Sequentially, lithium accumulation caused renal damage as seen on biopsy: tubular cysts, tubular dilatation, and interstitial fibrosis (see Fig. 1a-c). This pathology is consistent with biopsy findings reported by Markowitz et al. [19] that often seen in chronic lithium use with progressive glomerular and tubulointerstitial nephropathy [13]. ...
... Classic findings upon renal biopsy of lithium nephrotoxicity[12] and Ig-N[13] Pathology of lithium nephrotoxicity and IgA-N (in adults)Lithium nephrotoxicity (chronic interstitial nephritis)IgA-N Tubular lesions (i.e., dilatation of tubules in the distal segments and collecting ducts)Mehandru et al.: IgA Nephropathy and Lithium Toxicity www.karger.com/cnd ...
Lithium is one of the first-line agents for treating bipolar disorder. Although this agent is highly effective in treating mood disorders, renal toxicity is a frequent side effect. Lithium metabolism is affected by sodium-lithium counter-transporter (SLC-T) in erythrocytes. The high activity of SLC-T can result in decreased urinary lithium clearance and may lead to accumulation of lithium in the distal renal tubular cells, causing lithium toxicity. SLC-T is a genetic marker in primary hypertension (HTN), HTN in pregnancy, diabetic nephropathy, and IgA nephropathy (IgA-N) with HTN. Patients with IgA-N have been reported to have enhanced SLC-T activity and are likely to have considerably lower renal fractional clearance of lithium. Therefore, patients taking lithium for bipolar disorder with coexisting IgA-N can have severe lithium-induced nephropathy and nephrotoxicity even at therapeutic serum levels. Serum lithium levels reflect only extracellular lithium concentration. However, lithium exerts its effects once it has moved to the intracellular compartment. This phenomenon illustrates the reason why patients with significantly elevated serum levels might be asymptomatic. Creatinine clearance is inversely related to the duration of lithium therapy. The degree of interstitial fibrosis on renal biopsy has been known to be associated with the duration of lithium therapy and cumulative dose. We present a case with a past medical history of bipolar disorder treated with lithium for almost 20 years. His family history was significant for HTN. The patient was diagnosed with renal insufficiency of unknown causes, for which he underwent renal biopsy. The renal biopsy showed a typical lithium-induced tubulointerstitial nephritis and a coincidental finding of IgA-N. We suspect a high activity of SLC-T seen in IgA-N, and the adverse effects of lithium on SLC-T activity might cause reduction of urinary lithium clearance and accumulation of lithium in distal renal tubular cells, contributing to nephrotoxicity. There is a lack of the literature on the coexistence of IgA-N and lithium nephrotoxicity. We recommend in patients with concomitant IgA-N, taking lithium, more frequent monitoring of renal functions, and dose adjustments may reduce the risk of lithium-induced nephrotoxicity.
... Хорошо известно, что большая скорость Na + -Li + -ПТ в мембране эритроцита (более 390 мкМ Li на 1 л клеток в час) -маркёр так называемых мембранных нарушений, составляющих основу такого широко распространённого заболевания современного человека, как гипертоническая болезнь [7,14]. В клетках при этом накапливается избыток Ca 2+ , и возникает (вторично Рис. 1. Схема основных патогенетических механизмов и функциональных нарушений, вариабельно способствующих микрососудистой дисфункции у пациентов с кардиальным синдромом Х (адаптировано из [40]). ...
... Также был проведён сравнительный анализ результатов, полученных в исследовании A. Gaspardone, с распределением скоростей Na + -Li + -ПТ в популяции у здоровых людей и у пациентов, страдающих артериальной гипертензией, согласно данным клинического исследования M. Canessa [14] и популяционного исследования В.Н. Ослопова [6] (рис. ...
... Рис. 4. Сопоставление величин скорости Na + -Li + -противотранспорта (Na + -Li + -ПТ) в эритроцитах у больных с кардиальным синдромом Х, артериальной гипертензией (АГ) и людей с нормальным артериальным давлением (NАД) (адаптировано из [6,14,28]). ...
There are numerous pathophysiological mechanisms unequally responsible for the cardiac syndrome X development. The most important is endothelium and smooth muscle cells dysfunction that can intensify vasoconstriction and depress both endothelium-dependant and endothelium-independent vasodilatation, finally leading to coronary micro vascular dysfunction as the basis of the cardiac syndrome X pathogenesis. Together with other possible mechanisms of pathogenesis, studying the importance of increased cell membrane Na+-Li+-countertransport activity seems promising. If was found that a significant number of patients with cardiac syndrome X have increased Na+-Li+-countertransport activity, which is an in vitro marker of Na+-H+-antiporter. Therefore, it is important to measure Na+-Li+-countertransport speed in patients with coronary heart disease, because its high levels increases the chance for cardiac syndrome X, which is a coronary heart disease with no anatomic signs of coronary arteries involvement.
... However, adult RBCs possess an amiloride-insensitive Na/HX and Na/Li countertransport (CT) (329,359) under physiological conditions, although manipulations of Ca, Na, and H gradients brings about amiloride-sensitivity (360,361). Since the finding of an increased Na/LiCT in erythrocytes from essential hypertensive and diabetic nephropathy patients (362)(363)(364)(365)(366)(367)(368) in the 1980s there has been a long-standing controversy about its relationship to the NHE isoforms due to lack of inhibition by amiloride of the Na/LiCT activity or as determined by statistical tests (369)(370)(371)(372)(373)(374)(375). This controversy has been unequivocally eliminated by Zerbini and coworkers, who demonstrated that the erythrocyte NHE is lacking the amiloride binding site of the transporter (376). ...
... To a large extent this was due to its insensitivity to amiloride and derivatives that, prior, to the readily available cDNA cloning and sequencing techniques, was considered as a proof of evidence of the exchanger. Although abnormalities in Na transport in hypertensive rats existed (see references in (362)), the first report of an increase in Na/LiCT in RBCs of essential but not secondary hypertensive patients was provided by our group in 1980 (362). Numerous reports followed, some confirming the finding of an abnormal Na/LiCT in essential hypertension (329,363,365,367,406,(409)(410)(411)(412)(413)(414)(415)(416)(417)(418), others disproving it (365,373,374,(419)(420)(421). ...
... Simultaneous studies of Na/LiCT and NKCC designed to solve this puzzle produced surprising results in that, depending on the geographical location, Na/LiCT was either normal or elevated. In contrast, NKCC was either decreased or elevated and this variation in NKCC was found later on to be caused by both genetic diversity and dietary differences (362,363,409,412,(424)(425)(426)(427)(428)(429) leading to the conclusion that the two systems were separate entities and raising new questions about their heritability (362,363,424,425). ...
... [8] Sodium/lithium countertransporter activity is a highly heritable trait associated with diabetes mellitus and arterial hypertension in humans. [10,11] At the outset of our studies, the physiological role and molecular function of NHA2 was unknown and the pharmacology of NHA2 unexplored. In this review, we will summarize the results of our studies performed within the NCCR TransCure to deorphanize NHA2, including our efforts to identify and characterize compounds targeting NHA2 and to set up a high-resolution kinetic transport assay. ...
... As shown in Fig. 3B, CJnh064 caused a dose-dependent inhibition of insulin se-2.2 NHA2 is Critical for Insulin Secretion in β-Cells of the Endocrine Pancreas Given the possible association of NHA2 with diabetes in humans, [8,10,11,17,18] we investigated the role of NHA2 in systemic glucose homeostasis. We discovered that NHA2 is expressed in human as well as rodent β-cells and β-cell lines. ...
NHA2, also known as SLC9B2, is an orphan intracellular Na+/H+ exchanger (NHE) that has been associated with arterial hypertension and diabetes mellitus in humans. The objective of this NCCR TransCure project was to define the physiological and molecular function of NHA2, to develop a high resolution kinetic transport assay for NHA2 and to identify specific and potent compounds targeting NHA2. In this review, we summarize the results of this highly interdisciplinary and interfaculty effort, led by the groups of Proffs. Jean-Louis Reymond, Christoph von Ballmoos and Daniel Fuster.
... Based on genomic localization, tissue distribution pattern and inhibitor characteristics (tolerance to amiloride but sensitivity to phloretin), NHA2 was proposed as a possible candidate for the elusive sodium-lithium countertransporter (SLC) (Xiang et al., 2007). An increased activity of this countertransporter in erythrocytes and fibroblasts is a heritable trait that has been linked to the pathogenesis of arterial hypertension and diabetes mellitus (Canessa et al., 1980;Mangili et al., 1988;Laurenzi et al., 1997;Strazzullo et al., 1998;Vaccaro et al., 2005). ...
... Similar to the role of NHA2 in the endocrine pancreas, NHA2 has been suggested to have a physiological role in renal tubular function and blood pressure homeostasis. Strong reasons for this proposition are the localization of the NHA2 gene within a certain region of the fourth chromosome associated with the sodium-lithium countertransporter, its inhibitory characteristics (phloretin-sensitive and amiloride-insensitive), as well as distal tubular localization, a tubular segment important for sodium and blood pressure homeostasis (Canessa et al., 1980;Mangili et al., 1988;Carr et al., 1990;Meneton et al., 2004;Meneton et al., 2005;Ye et al., 2006;Xiang et al., 2007;Kondapalli et al., 2012). Localization of NHA2 to the distal nephron has already been reported upon initial description of the protein (Fuster et al., 2008), and recently further detailed and validated in mice, as well as humans (Kondapalli et al., 2017;Anderegg et al., 2021). ...
The SLC9 gene family encodes Na + /H + exchangers (NHEs), a group of membrane transport proteins critically involved in the regulation of cytoplasmic and organellar pH, cell volume, as well as systemic acid-base and volume homeostasis. NHEs of the SLC9A subfamily (NHE 1-9) are well-known for their roles in human physiology and disease. Much less is known about the two members of the SLC9B subfamily, NHA1 and NHA2, which share higher similarity to prokaryotic NHEs than the SLC9A paralogs. NHA2 (also known as SLC9B2) is ubiquitously expressed and has recently been shown to participate in renal blood pressure and electrolyte regulation, insulin secretion and systemic glucose homeostasis. In addition, NHA2 has been proposed to contribute to the pathogenesis of polycystic kidney disease, the most common inherited kidney disease in humans. NHA1 (also known as SLC9B1) is mainly expressed in testis and is important for sperm motility and thus male fertility, but has not been associated with human disease thus far. In this review, we present a summary of the structure, function and regulation of expression of the SLC9B subfamily members, focusing primarily on the better-studied SLC9B paralog, NHA2. Furthermore, we will review the potential of the SLC9B subfamily as drug targets.
... В качестве естественной модели для исследования проницаемости биологических мембран наиболее удобна мембрана эритроцита (МЭ), так как, вопервых, эритроцитфактически идеальная изолированная («чис тая») мембрана, вовторых, была доказана корреляция между свойствами МЭ и других клеток [4,6]. Na + Li + противотранспорт (Na + Li + ПТ) в МЭ может быть использован как модель in vitro для определения биодос тупности различных веществ и лекарственных препаратов. ...
... Определение скорости Na + Li + ПТ в МЭ (в мкМ лития на 1 л клеток в час) проводили по методу M. Canessa и соавт. [6]: определяли обмен внутриклеточного лития в загруженных этим ионом клетках на внеклеточный натрий из среды инкубации. Концентрацию лития регистрировали методом атомной абсорбционной спектрофотометрии в эмиссионном режиме. ...
Aim. To assess the effect of newly synthesized quaternary phosphonium salts with highest alkyl substituents (C10, C12, C14, C16, C18) on the permeability of cell membranes for sodium ions in vitro. Methods. In vitro studied was the effect of different concentrations of new quaternary phosphonium salts with highest alkyl substituents on the cell membrane permeability to sodium ions according to the rate of Na+-Li+-countertransport in the erythrocyte membrane. Results. Low concentration (0.001 mM) of substance C10 increased the rate of Na+-Li+-countertransport in the erythrocyte membrane by 11.9%, substance C12 - by 11.8%, substance C14 - by 12.7%, substance C16 - by 13%, substance C18 - by 12.3%. Higher concentrations of substances (0.01-0.05 mM) had no significant effect on the cell membrane permeability to sodium ions. Conclusion. An increase in the rate of Na+-Li+-countertransport in the erythrocyte membrane is influenced by minimal concentrations of a substance, under the influence of other concentrations the rate of Na+-Li+-countertransport doe not change.
... В клинической практике можно оценивать про-ницаемость клеточной мембраны по Na + , изучая так называемую облегчённую диффузию Na + , осуществляемую белком-переносчиком, -Na + -Li + -противотранспорт (Na + -Li + -ПТ) по методике M. Canessa и соавт. (1980) [10]. В последние годы обнаружена различная эффективность лекарственных препаратов в зависимости от скорости Na + -Li + -ПТ в мембране эритроцита [6,7,9]. ...
... Определение скорости Na + -Li + -ПТ в мембране эритроцита (в микромолях лития на 1 л клеток в час) проводили по методу M. Canessa и соавт. [10], при котором изучают (путём определения концентрации ионов) обмен внутриклеточного лития в загруженных этим ионом клетках на внеклеточный натрий и магний из среды инкубации. Концентрацию лития регистрировали методом атомной абсорб-ционной спектрофотометрии в эмиссионном режиме (СА-455). ...
Aim. To study the influence of triphenyltetradecylphosphonium bromide [(PPh)3P+C14H29] Br- on the cell membranes permeability to Na+ by determining the rate of Na+-Li+-counter transport in erythrocyte membrane depending on it’s variable initial condition. Methods. Blood samples of 10 healthy volunteers with different Na+-Li+-counter transport rate distribution in erythrocyte membrane were analyzed: I quartile (5 subjects) - low permeability, III quartile (5 subjects) - moderately high permeability. Results. Na+-Li+-counter transport rate change in erythrocyte membrane under the influence of triphenyltetradecylphosphonium bromide depends on genetically determined initial membrane permeability. In subjects belonging to III quartile of Na+-Li+-counter transport the initial membrane permeability is high, and after administration of 0.001 and 0.005 μM concentrations of [(PPh)3P+C14H29] Br- membrane permeability to Na+ increased. In subjects belonging to I quartile of Na+-Li+-counter transport (low initial permeability) [(PPh)3P+C14H29] Br- did not alter membrane permeability to Na+. Conclusion. Triphenyltetradecylphosphonium bromide increases erythrocyte membrane permeability to Na+ in subjects belonging to III quartile of Na+-Li+-counter transport and dose not influence subjects belonging to I quartile of Na+-Li+-counter transport.
... Согласно литературным данным, наиболее дезадаптивными являются высокие значения скорости ПТИ [36][37][38][39][40][41][42][43][44][45][46]. В лабораторных условиях для определения скорости ПТИ используется метод определения скорости натрий-литиевого противотранспорта (НЛП) в мембране эритроцита [47], где эритроцит используется как легкодоступная исследованию модель, отражающая ионотранспортные функции всех клеток индивидуума. ...
... Всем пациентам на каждом этапе наблюдения проводился стандартный неврологический осмотр. Скорость НЛП в мембране эритроцита на этапе включения в исследование определялась по методу M.L. Canessa 1980 г. [47]. Метод заключается в измерении скорости обмена внутриклеточного лития, в загруженных этим ионом клетках, на внеклеточный натрий и магний из среды инкубации. ...
The efficacy and tolerability of donepezil (Alzepil) in the treatment of undifferentiated dementia in 52 patients (mean age 77 ± 8,2 years at the time of inclusion) with cerebrovascular disease (CVD) were investigated. Patients were divided into groups based on the genetically determined factor - the rate of passive transmembrane ion transport (PTIT) which determines both the severity of the disease and its response to therapy. PTIT rate was determined by the rate of Na-Li countertransport (NLC) in the erythrocyte membrane. Patients with high NLC rates had more severe dementia and better responded to treatment. Therefore, evaluation of NLC rate is a promising research method in terms of predicting the disease severity and response to treatment. In general, donepezil (Alzepil) demonstrated good efficacy and tolerability in patients with dementia and CVD regardless of the neuropsychological profile, justifying its use in any type of dementia.
... Высокая скорость НЛП (>390 мкмоль Li/клеток в час), по данным литературы, являются маркером так называемых мембранных нарушений, лежащих в основе АГ. При этом в клетках происходит избыточное накопление свободного кальция, что приводит к повышению тонуса микрососудов и чувствительности к сосудосуживающим стимулам [16,24,27,28]. ...
... Скорость НЛП в мембране эритроцита на этапе включения в исследование определяли по методу M. Canessa [27]. Метод заключается в измерении обмена внутриклеточного лития, в загруженных этим ионом клетках, на внеклеточный натрий и магний из среды инкубации. ...
Objective: to provide a dynamic assessment of cognitive functions in hypertensive patients in relation to the cerebral perfusion reserve and passive transmembrane ion transport velocity.Patients and methods. The investigation enrolled 79 hypertensive patients (the mean age at the start of examination was 54 years), including 44 women (mean age, 58±16.2 years) and 35 men (mean age, 60±9.8 years). During a screening, the mean duration of hypertension was more than 5 years in 60% of the patients and less than 5 years in 40%. 55% of the patients had adequate antihypertensive therapy and normal blood pressure (BP) (<140/90 mm Hg), 45% were not on this therapy and they failed to achieve normal BP. The investigators evaluated a variety of factors, such as gender, age, BP, duration of hypertension, indicators of cerebrovascular reactivity (CVR), and levels of passive transmembrane ion transport, by using a model of Na+-Li+ countertransport (NLCT) in the erythrocyte membrane as an example.Results. Some risk factors were ascertained to influence cognitive functions in hypertension, but to a greater extent on CVR values in different vascular beds. A correlation was found between CVR and genetically determined NLCT velocity.Conclusion. The indicators CVR and NLCT may be used as predictors for the development and progression of vascular cognitive impairment.
... 4 SLC activity analysis requires the accurate determination of lithium efflux rate. [2][3][4][5] Traditionally, lithium efflux rates have been determined by linear regression of repeat (duplicate or triplicate) measurements of lithium concentrations at three time points. 4 -6 This approach ensures that any outlying values, which can sometimes be extreme, do not significantly affect the final estimates of efflux. ...
... Based on chromosomal localization, transport characteristics and inhibitor sensitivity, NHA2 was proposed to be the long sought mediator of Na + /Li + counter-transport (SLC) 3 . SLC activity is a highly heritable trait, associated with abnormalities in Na + homeostasis, diabetes mellitus and arterial hypertension in humans [4][5][6][7][8][9] . We previously demonstrated that NHA2 resides in endosomes of β-cells and is critical for insulin secretion 10,11 . ...
NHA2 is a sodium/proton exchanger associated with arterial hypertension in humans, but
the role of NHA2 in kidney function and blood pressure homeostasis is currently
unknown. Here we show that NHA2 localizes almost exclusively to distal convoluted
tubules in the kidney. NHA2 knock-out mice displayed reduced blood pressure,
normocalcemic hypocalciuria and an attenuated response to the thiazide diuretic
hydrochlorothiazide. Phosphorylation of the thiazide-sensitive sodium/chloride
cotransporter NCC and its upstream activating kinase Ste20/SPS1-related proline/alanine
rich kinase (SPAK), as well as the abundance of with no lysine kinase 4 (WNK4), were
significantly reduced in the kidneys of NHA2 knock-out mice. In vitro experiments
recapitulated these findings and revealed increased WNK4 ubiquitylation and enhanced
proteasomal WNK4 degradation upon loss of NHA2. The effect of NHA2 on WNK4
stability was dependent from the ubiquitylation pathway protein Kelch-like 3 (KLHL3) .
More specifically, loss of NHA2 selectively attenuated KLHL3 phosphorylation and
blunted protein kinase A- and protein kinase C-mediated decrease of WNK4 degradation.
Phenotype analysis of NHA2/NCC double knock-out mice supported the notion that
NHA2 affects blood pressure homeostasis by a kidney-specific and NCC-dependent
mechanism. Thus, our data show that NHA2 as a critical component of the WNK4-NCC
pathway and is a novel regulator of blood pressure homeostasis in the kidney.
... Furthermore, patients with diabetic nephropathy (Krolewski et al. 1988;Mangüi et al. 1988;Walker et al. 1990) and their parents (Walker et al. 1990) have been found to have increased sodium lithium countertransport activity, which is believed to be a genetic marker of hypertension (Hasstedt et al. 1988;Canessa et al. 1980). ...
The relation of blood pressure to the renal and retinal complications of insulin dependent diabetes was examined in a cross-sectional analysis of 3250 clinic- attending patients from 31 centres in Europe (the EURODIAB IDDM Complications Study). In addition, the hypothesis that susceptibility to diabetic nephropathy can be identified by a parental history of hypertension was examined. The relation between blood pressure and albumin excretion differed strikingly between patients with and without retinopathy. This original finding has not been reported before. In patients without retinopathy, albumin excretion was low even when blood pressure was high and glycaemic control poor. In patients with retinopathy, albumin excretion increased steeply with blood pressure above the median (120/75 mmHg). Thus albumin excretion tended to be high only in patients with both raised blood pressure and retinopathy. The prevalence of retinopathy increased with blood pressure, but the association was prominent only in patients with raised albumin excretion, in whom proliferative retinopathy was two to three times more frequent when blood pressure was above 105/65 mmHg than below this level. Both blood pressure and albumin excretion were higher in patients reporting a parental history of hypertension than in patients reporting no parental hypertension. However, parental hypertension made no contribution to the relation between blood pressure and albumin excretion independent of blood pressure in the offspring. These data suggest that patients with retinopathy are particularly vulnerable to the effect of raised blood pressure on the kidney. This offers a plausible explanation for the well known observation that nephropathy without retinopathy is rare, while retinopathy without nephropathy is common. The hypothesis that susceptibility to diabetic nephropathy is determined by a genetic disposition to hypertension is not supported by this study. Rather, it is suggested that patients at high risk of nephropathy can be distinguished by the presence of both retinopathy and raised (above median) blood pressure, irrespective of parental hypertension.
... Определение скорости Na + -Li + -ПТ в мембране проводили по методу M. Canessa и соавт. [13], при котором изучают (путём определения концентрации ионов) обмен внутриклеточного лития в загруженных этим ионом клетках на внеклеточный натрий и магний из среды инкубации. Концентрацию лития регистрировали методом атомной абсорбционной спектрофотометрии в эмиссионном режиме (СА-455 ПО КОМЗ). ...
Aim. Comparative analysis of effects of novel biologically active agents: triphenyltetradecylphosphonium bromide and tributylhexadecylphosphonium bromide on cell membrane permeability for sodium by determination of of Na +-Li +-countertransport speed in erythrocyte membrane at patients with genetically determined high membrane permeability for sodium. Methods. Blood samples of 8 healthy volunteers who were classified as persons belonging to IV population quartile according to Na +-Li +-counter-transport speed in erythrocyte membrane, i.e. persons with high membrane permeability, were studied. Effects of different concentrations of triphenyltetradecylphosphonium bromide and tributylhexadecylphosphonium bromide (known by antibacterial and antifungal action) on Na +-Li +-counter-transport speed in erythrocyte membrane in vitro according to the method proposed by M. Canessa et al. Results. Effect of triphenyltetradecylphosphonium bromide (С 14) and tributylhexadecylphosphonium bromide (С 16) on cell membrane permeability for sodium depends on the genetically determined baseline cell membrane state. С 14reduced the erythrocyte membrane permeability for sodium in studied patients belonging to IV quartile of Na +-Li +-counter-transport speed if administered in a concentration of 0.05 μm. C 16increased membrane permeability for sodium in the same group if administered in concentrations of 0.001 and 0.005 μm. Thus, tributylhexadecylphosphonium bromide is better suitable for designing a drug with antibacterial and antifungal action for patients belonging to IV quartile of Na +-Li +-counter-transport speed, if Na +-Li +-counter-transport speed reduction is wanted. If Na +-Li +-counter-transport speed increase is wanted, triphenyltetradecylphosphonium bromide is better suitable. Conclusion. Cand Csubstances affect cell membrane permeability for sodium in patients with genetically determined high membrane permeability for sodium.
... В 1980 г. группой ученых Гарвардского уни-верситета было обнаружено, что у больных ги-пертонической болезнью увеличена скорость Na + /Na + обмена, регистрируемая по Na + о -зависи-мой компоненты скорости выхода Li + из ýритро-цитов, предварительно нагруженных ýтим кати-оном [37]. В англоязычной литературе ýтот вид транспорта получил название Na + /Li + exchange или Na + /Li + counter transport. ...
The review summarizes the history of the discovery in the mid-70s of the impaired ion transport across the plasma membrane of cells during primary arterial hypertension. A half-century’s history of studies on the molecular nature of the ionic transporters underlying these disorders and the mechanisms mediated by them leading to the development of hypertension and complications caused by a long-term increase in blood pressure is analyzed.
... NHA2 resides at the apical membrane of certain epithelial cells, as well as in that of endosomes [112,113]. It has been proposed that NHA2 acts as a Na + /Li + counter transporter, which had been related to arterial hypertension and diabetes [114,115]. ...
In the male reproductive tract, ionic equilibrium is essential to maintain normal spermatozoa production and, hence, the reproductive potential. Among the several ions, HCO3⁻ and H⁺ have a central role, mainly due to their role on pH homeostasis. In the male reproductive tract, the major players in pH regulation and homeodynamics are carbonic anhydrases (CAs), HCO3⁻ membrane transporters (solute carrier 4—SLC4 and solute carrier 26—SLC26 family transporters), Na⁺–H⁺ exchangers (NHEs), monocarboxylate transporters (MCTs) and voltage-gated proton channels (Hv1). CAs and these membrane transporters are widely distributed throughout the male reproductive tract, where they play essential roles in the ionic balance of tubular fluids. CAs are the enzymes responsible for the production of HCO3⁻ which is then transported by membrane transporters to ensure the maturation, storage, and capacitation of the spermatozoa. The transport of H⁺ is carried out by NHEs, Hv1, and MCTs and is essential for the electrochemical balance and for the maintenance of the pH within the physiological limits along the male reproductive tract. Alterations in HCO3⁻ production and transport of ions have been associated with some male reproductive dysfunctions. Herein, we present an up-to-date review on the distribution and role of the main intervenient on pH homeodynamics in the fluids throughout the male reproductive tract. In addition, we discuss their relevance for the establishment of the male reproductive potential.
... У всех пациентов была исследована скорость пассивного трансмембранного ионотранспорта с помощью метода M. Canessa и соавт. [16], заключающегося в определении скорости пассивного натрий-литиевого противотранспорта (Na + -Li + countertransport, NLC) в мембране эритроцита. В данном случае эритроцит является легко доступным для исследования объектом, при этом простота метода позволяет изучать функциональные свойства плазматической мембраны без помех, накладываемых внутриклеточными органеллами и сократительной активностью клеток. ...
Objective: to study the clinical phenomenology of vascular cognitive impairment (VCI) in individuals with different rates of passive transmembrane ion transport. Patients and methods. Cognitive functions were evaluated in 372 patients with different clinical variants of moderate VCI after 1, 5, and 10 years of follow-up. Quantile analysis was used to group patients into quartiles according to the ranges in the rate of passive transmembrane ion transport reflecting the genetically determined properties of cell membranes and identified by the study of Na+-Li+ countertransport (NLC) in the erythrocyte membrane Results. There was initially a monofunctional non-amnestic type in 11.0% of the patients, a monofunctional amnestic type in 16.1%, a multifunctional non-amnestic type in 34.9%, and a multifunctional amnestic type in 37.9%. At the same type, in the patients with high-speed NLC, the number of amnestic VCI types statistically dominated: 77.1% of the patients belonging to IV quartile. After 1 year and 5 years of follow-up there was an increase in the number of patients with severe cognitive impairment, reaching the degree of dementia (33.2% of all the examinees following 1 year). The patients with high-speed NLC showed a significant predominance of not only the total number of dementias (86.7% of the patients in IV quartile; p<0.001), but also a more unfavorable mixed (disregulatory + Alzheimer's disease) type of dementia (74.7% of the patients in IV quartile; p<0.001). The dysregulatory type of dementia was more common in patients with low-and moderate-speed NLC. 70% of all dementias formed from the multifunctional amnestic type of mild cognitive impairment (MCI). Different types of MCI were observed to be transformed to the prognostically unfavorable multifunctional amnestic type of MCI. The study conducted 10 years later noted the same trends. Conclusion. The NLC speed has been shown to be associated with the VCI profile, which makes this indicator promising for predicting the course of VCI in the early stage of the disease and for choosing a treatment policy.
... Lithium efflux from cells is also sodium dependent, as evidenced by observations that lower concentrations of extracellular sodium cause a reduction in lithium efflux in red blood cells (Canessa et al. 1980) and neurons (Szentistvanyi et al. 1979). Experiments on lymphoid cells in which both intracellular and extracellular concentrations are varied suggest that one component of the sodium-dependent lithium efflux is from a sodium-lithium countertransport system in which both sodium and lithium can go both ways (Yurinskaya et al. 2014). ...
Lithium has literally been everywhere forever, since it is one of the three elements created in the Big Bang. Lithium concentration in rocks, soil, and fresh water is highly variable from place to place, and has varied widely in specific regions over evolutionary and geologic time. The biological effects of lithium are many and varied. Based on experiments in which animals are deprived of lithium, lithium is an essential nutrient. At the other extreme, at lithium ingestion sufficient to raise blood concentration significantly over 1 mM/, lithium is acutely toxic. There is no consensus regarding optimum levels of lithium intake for populations or individuals—with the single exception that lithium is a generally accepted first-line therapy for bipolar disorder, and specific dosage guidelines for sufferers of that condition are generally agreed on. Epidemiological evidence correlating various markers of social dysfunction and disease vs. lithium level in drinking water suggest benefits of moderately elevated lithium compared to average levels of lithium intake. In contrast to other biologically significant ions, lithium is unusual in not having its concentration in fluids of multicellular animals closely regulated. For hydrogen ions, sodium ions, potassium ions, calcium ions, chloride ions, and magnesium ions, blood and extracellular fluid concentrations are closely and necessarily regulated by systems of highly selective channels, and primary and secondary active transporters. Lithium, while having strong biological activity, is tolerated over body fluid concentrations ranging over many orders of magnitude. The lack of biological regulation of lithium appears due to lack of lithium-specific binding sites and selectivity filters. Rather lithium exerts its myriad physiological and biochemical effects by competing for macromolecular sites that are relatively specific for other cations, most especially for sodium and magnesium. This review will consider what is known about the nature of this competition and suggest using and extending this knowledge towards the goal of a unified understanding of lithium in biology and the application of that understanding in medicine and nutrition.
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... У 147 пациентов (77 основной группы и 70 группы сравнения) была определена скорость пассивного трансмембранного ионотранспорта. для этого использовали метод выявления максимальной скорости натрий-литиевого противотранспорта (НЛП) в эритроцитах [18]. Лабораторный анализ проводили на базе кафедры пропедевтики внутренних болезней Казанского государственного медицинского университета. ...
The objective: to identify the risk factors of seizures in patients with chronic cerebral ischemia using clinical, functional, neuroimaging research methods. Materials and methods. The results of complex examination of 304 patients suffering from chronic cerebral ischemia (174 patients with epileptic seizures and 130 without seizures) are presented. In addition to the analysis of clinical and neuroimaging features the assessment of the rate of sodium lithium countertransport (the marker of genetically determined transport mechanisms of cell membranes) in patients with chronic cerebral ischemia with and without epileptic seizures was carried out. Results. The focal seizures were common (88,5%) for patients with brain ischemia. The clinical manifestation of seizures was between the ages 60 and 69. The cortical and subcortical localization of vascular lesions, the higher degree of MRI white matter changes was revealed in patients with seizures than in patients without them. The correlation of epilepsy with high rate of sodium lithium countertransport was confirmed - there were significantly more cases with rate of sodium lithium countertransport more than 346 umol/L RBC/hr among patients with seizures. Conclusion. The study showed that high rate of sodium lithium countertransport, especially in association with other clinical and neuroimaging features (age from 60 to 69, cortical and subcortical localization of vascular lesions, white matter changes) can be risk factor of epilepsy in patients with chronic cerebral ischemia.
... Elevation in SLC activity is a secondary biochemical indication of an abnormality in sodium homeostasis and has been extensively documented in erythrocytes and fibroblasts [3,13,30]. Numerous studies have reported a relationship between hypertension, SLC activity, and sodium levels in several ethnic groups, including Caucasians and Asians [4,7,8,13]. In addition to the correlation with essential hypertension, SLC activity and intracellular Na + concentrations are highly heritable [8,13]. ...
Increased renal reabsorption of sodium is a significant risk factor in hypertension. An established clinical marker for essential hypertension is elevated sodium lithium countertransport (SLC) activity. NHA2 is a newly identified Na⁺(Li⁺)/H⁺ antiporter with potential genetic links to hypertension, which has been shown to mediate SLC activity and H⁺-coupled Na⁺(Li⁺) efflux in kidney-derived MDCK cells. To evaluate a putative role in sodium homeostasis, we determined the effect of dietary salt on NHA2. In murine kidney sections, NHA2 localized apically to distal convoluted (both DCT1 and 2) and connecting tubules, partially overlapping in distribution with V-ATPase, AQP2, and NCC1 transporters. Mice fed a diet high in sodium chloride showed elevated transcripts and expression of NHA2 protein. We propose a model in which NHA2 plays a dual role in salt reabsorption or secretion, depending on the coupling ion (sodium or protons). The identified novel regulation of Na⁺/H⁺ antiporter in the kidney suggests new roles in salt homeostasis and disease.
... зивные потомки больных эссенциальной гипертензией с высокими значениями скорости Na + -Li + -ПТ также имели повышенную скорость Na + -Li + -ПТ [5, 8]. В настоящем исследовании нами проведен анализ ассоциации I/D полиморфизма гена АПФ с риском развития ГБ во взаимосвязи с величинами скорости Na + -Li + -ПТ в мембране эритроцита — с квартилями популяционного распределения величин скорости Na + -Li + -ПТ: I КВ — 38-203, II КВ — 204-271, III КВ — 272-345, IV КВ –346-730 мкМ Li. ...
Изучен I/D полиморфизм гена ангиотензин-превращающего фермента (АПФ) в группах больных гипертонической болезнью (ГБ) и условно здоровых лиц, представляющих общую популяцию населения Республики Татарстан, в общем и в зависимости от скорости Na+-Li+-противотранспорта (Na+-Li+-ПТ). Показано отсутствие значимых различий в распределении частот аллелей и генотипов, однако в группе больных ГБ отмечено повышение частоты гетерозиготного генотипа I/D и, реже, гомозиготного генотипа I/I. Обнаружен уникальный для каждого квартиля скорости Na+-Li+-ПТ характер распределения аллелей и генотипов гена АСЕ: у больных ГБ во II квартиле скорости Na+-Li+-ПТ доминирует генотип DD, в IV квартиле — генотип II.
Ключевые слова: полиморфизм гена АПФ, скорость Na+-Li+-противотранспорта, гипертоническая болезнь.
The Na+/H+ exchanger SLC9B2, also known as NHA2, correlates with the long-sought-after Na+/Li+ exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite the functional importance of NHA2, structural information and the molecular basis for its ion-exchange mechanism have been lacking. Here we report the cryo-EM structures of bison NHA2 in detergent and in nanodiscs, at 3.0 and 3.5 Å resolution, respectively. The bison NHA2 structure, together with solid-state membrane-based electrophysiology, establishes the molecular basis for electroneutral ion exchange. NHA2 consists of 14 transmembrane (TM) segments, rather than the 13 TMs previously observed in mammalian Na+/H+ exchangers (NHEs) and related bacterial antiporters. The additional N-terminal helix in NHA2 forms a unique homodimer interface with a large intracellular gap between the protomers, which closes in the presence of phosphoinositol lipids. We propose that the additional N-terminal helix has evolved as a lipid-mediated remodeling switch for the regulation of NHA2 activity. NHA2 exchanges sodium ions for protons across cell membranes, and its activity is linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Drew et al. report the cryo-EM structure of NHA2 in detergent and nanodiscs.
High-throughput techniques allow us to measure a wide-range of phospholipids which can provide insight into the mechanisms of hypertension. We aimed to conduct an in-depth multi-omics study of various phospholipids with systolic blood pressure (SBP) and diastolic blood pressure (DBP). The associations of blood pressure and 151 plasma phospholipids measured by electrospray ionization tandem mass spectrometry were performed by linear regression in five European cohorts (n = 2786 in discovery and n = 1185 in replication). We further explored the blood pressure-related phospholipids in Erasmus Rucphen Family (ERF) study by associating them with multiple cardiometabolic traits (linear regression) and predicting incident hypertension (Cox regression). Mendelian Randomization (MR) and phenome-wide association study (Phewas) were also explored to further investigate these association results. We identified six phosphatidylethanolamines (PE 38:3, PE 38:4, PE 38:6, PE 40:4, PE 40:5 and PE 40:6) and two phosphatidylcholines (PC 32:1 and PC 40:5) which together predicted incident hypertension with an area under the ROC curve (AUC) of 0.61. The identified eight phospholipids are strongly associated with triglycerides, obesity related traits (e.g. waist, waist-hip ratio, total fat percentage, body mass index, lipid-lowering medication, and leptin), diabetes related traits (e.g. glucose, insulin resistance and insulin) and prevalent type 2 diabetes. The genetic determinants of these phospholipids also associated with many lipoproteins, heart rate, pulse rate and blood cell counts. No significant association was identified by bi-directional MR approach. We identified eight blood pressure-related circulating phospholipids that have a predictive value for incident hypertension. Our cross-omics analyses show that phospholipid metabolites in the circulation may yield insight into blood pressure regulation and raise a number of testable hypothesis for future research.
Thermotopography and Sherbacks thermoregulation reflex have been stuided in 60 healthy people, chosen with consideration of genetic membrane characteristics and types of vegetative reaction. In the course of quartile analysis correlation of thermoregulation indices with the defined values of Na/Li countertransport velocity in erythrocytes membranes has been established. Thermometric studies in healthy people with vegetative reaction disadaptive types have shown specific disorders of thermotopography and functional thermoregulation test, mostly associated with high values of membrane transport velocity; at the same time at low values of membrane transport indices characteristics of vegetative and thermotopographic pattern appeared to be in the limits of normal variations.
Types of vegetative responding were studied with evaluation of initial vegetative reactions and vegetative activity in healthy people, aged from 7-42, in association with one of the markers of genetically determined structural and functional status of cell membranes - velocity of Na+/Li+ countransport in erythrocyte membranes. It was found that level of intensity of vegetative effects with transition of adaptation reactions to orthostasis is most characterestic of high values of transmembrane monotransport velocity.
Personal characteristics in combination of vegetative homeostasis were studied, and also type of morphoconstitution in association with one of genetic marker - velocity of Na+/ Li+ countertransport in erythrocyte membranes of 192 healthy people, aged from 17 to 42 y.o. Trends to increase the anxiety level in patients of both sex in all age groupes were determined at the velocity range of Na + /Li+ countertransport in erythrocytes: from 162 to 278 mс Mol Li/1 c h, which were most expressed in asthenic morphoconstitution people with sympathicotonic type of vegetative effects, this being combined with disadaptive forms of vegetative reactions.
Treatment and rehabilitation of patients with acute cerebrovascular accidents and their consequences are the most important medical and social tasks. Movement disorders, along with speech disorders, are the main organic defects in patients after a stroke, causing a high degree of disability.
Background High-throughput techniques allow us to measure a wide-range of phospholipids which can provide insight into the mechanisms of hypertension. We aimed to conduct an in depth multi-omics study of various phospholipids with systolic blood pressure (SBP) and diastolic blood pressure (DBP).
Methods The associations of blood pressure and 151 plasma phospholipids measured by electrospray ionization tandem mass spectrometry were performed by linear regression in five European cohorts (n = 2,786 in discovery and n = 1,185 in replication). We further explored the blood pressure-related phospholipids in Erasmus Rucphen Family (ERF) study by associating them with multiple cardiometabolic traits (linear regression) and predicting incident hypertension (Cox regression). Mendelian Randomization (MR) and phenome-wide association study (pheWAS) were also explored to further investigate these association results.
Results We identified six phosphatidylethanolamines (PE 38:3, PE 38:4, PE 38:6, PE 40:4, PE 40:5 and PE 40:6) and two phosphatidylcholines (PC 32:1 and PC 40:5) which together predicted incident hypertension with an area under the curve (AUC) of 0.61. The identified eight phospholipids are strongly associated with triglycerides, obesity related traits (e.g. waist, waist hip ratio, total fat percentage, body mass index, lipid-lowering medication, and leptin), diabetes related traits (e.g. glucose, insulin resistance and insulin) and prevalent type 2 diabetes. The genetic determinants of these phospholipids also associated with many lipoproteins, heart rate, pulse rate and blood cell counts. No significant association was identified by bi-directional MR approach.
Conclusion We identified eight blood pressure-related circulating phospholipids that have a predictive value for incident hypertension. Our cross-omics analyses show that phospholipid metabolites in the circulation may yield insight into blood pressure regulation and raise a number of testable hypothesis for future research.
Cation/proton antiporters (CPAs), which include Na⁺/H⁺ exchangers, are evolutionarily ancient transporters present in most species from prokaryotes to higher eukaryotes. Many of them are expressed in epithelial cells or various organs, where they utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. In the intestinal and renal epithelia, NHEs are critical for vectorial transport of Na⁺, HCO3⁻ and water, and consequently for the systemic volume and acid–base homeostasis. They also contribute to nutrient absorption, cellular proliferation, migration, and apoptosis, and modulate extracellular milieu, e.g., to regulate the intestinal microbial microenvironment. Their dysregulation, or in some instances, mutations, contributes to the human disease pathogenesis and some of the well-characterized Na⁺/H⁺ exchangers have been considered as attractive targets for pharmacological inhibition. In this chapter, we provide an overview of the members of the CPA superfamily of cation/proton antiporters, with particular focus on their roles in epithelial cells, their expression patterns, intracellular localization, regulation, and function, primarily as determined by gene targeting studies.
Background: There is increasing evidence that nephrolithiasis is a systemic disease, as opposed to an isolated urinary metabolic problem, after considerable links were found between nephrolithiasis and systemic diseases such as hypertension, obesity, dyslipidemia, and insulin resistance. The interplay between these four factors defines metabolic syndrome (MetS). In this review we aim to clarify the associations of MetS and its components to kidney stone incident.
Methods: Online databases of EMBASE, MEDLINE, and Google Scholar were searched from January 1998 up to October 2020 to identify observational studies examining the association between metabolic syndrome components and kidney stone incident. Bayesian random-effects meta-analysis and meta-regression were performed to observe the association. Linear dose-response analysis was conducted to shape the direction of the association. Data analysis was performed using STATA, and R statistics.
Results: A total of 25 potentially relevant studies (n = 934,588 participants) were eventually identified. The pooled results suggested that metabolic syndrome was associated with an increased risk of nephrolithiasis with an odds ratio (OR) of 1.769 (95% CI: 1.386 – 2.309). The summary OR of hypertension and dyslipidemia for developing nephrolithiasis were 1.613 (95% CI: 1.213 – 2.169) and 1.586 (95% CI: 1.007 – 2.502) respectively. The presence of diabetes mellitus and obesity had an OR of 1.552 (95% CI: 1.027 – 2.344) and 1.531 (95% CI: 1.099 – 2.109) respectively. Our results revealed that the increasing number of MetS traits will increase the risk of developing nephrolithiasis, the higher the fasting plasma glucose, and body mass index, the higher the risk of kidney stones incident.
Conclusions: Our results suggest that hypertension, diabetes, obesity and dyslipidemia are associated with increased risk of developing nephrolithiasis. Linear significant association between MetS components and nephrolithiasis were revealed in our study which reinforced the notion that should be considered a systemic disorder.
Despite increasing research efforts, there is not yet a final cure for diabetes, whether insulin‐ or non‐insulin‐dependent. On the other hand, the most intensive treatment programs to correct hyperglycemia can decrease the incidence of diabetic nephropathy (DN), but are not easy to put into practice. Tight metabolic control is particularly difficult to achieve in type 2 diabetes, and therefore the current epidemic of type 2 diabetes, paralleled by obesity, is likely to generate in perspective a steep increase of cases of DN. As a consequence of the above, DN has rapidly and progressively become the first reason of end‐stage renal failure on a worldwide basis. Based on these premises, this chapter is aimed to describe the clinical protocols presently applied to treat DN and the research studies meant to identify new ways to prevent, cure, and, ideally, induce the regression of this life‐threatening complication of diabetes.
Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. They belong to an ancient family of highly evolutionarily conserved proteins, and they play essential physiological roles in all phyla. In this review, we focus on the mammalian Na+/H+ exchangers (NHEs), the solute carrier (SLC) 9 family. This family of electroneutral transporters constitutes three branches: SLC9A, -B, and -C. Within these, each isoform exhibits distinct tissue expression profiles, regulation, and physiological roles. Some of these transporters are highly studied, with hundreds of original articles, and some are still only rudimentarily understood. In this review, we present and discuss the pioneering original work as well as the current state-of-the-art research on mammalian NHEs. We aim to provide the reader with a comprehensive view of core knowledge and recent insights into each family member, from gene organization over protein structure and regulation to physiological and pathophysiological roles. Particular attention is given to the integrated physiology of NHEs in the main organ systems. We provide several novel analyses and useful overviews, and we pinpoint main remaining enigmas, which we hope will inspire novel research on these highly versatile proteins.
Twenty-one patients with coronary heart disease, functional classes I-II angina pectoris concurrent with moderate arterial hypertension were examined. Magnesium preparations were studied for their effect on blood pressure values, ECG parameters, and exercise tolerance during a bicycle ergometric test, as well as serum lipid profile and some membranous ion-transporting systems in the red blood cells. Exogenous magnesium was not found to have any effect on blood pressure. The administration of magnesium preparations promotes a decrease in urinary excretion of magnesium and an increase in its intracellular concentration, positively affects its homeostasis and the metabolism of other elements related to the development of vascular abnormalities.
An increase in Ca-content of erythrocytes can induce the characteristic changes, such as reduced osmotic fragility and increased rigidity of the membrane. These phenomena are induced by the binding of the intracellular Ca to the cytoskeleton proteins (contractile proteins) distributed in the erythrocyte membrane.
To investigate the Ca-sensitivity of the erythrocyte membrane, the changes of the osmotic fragility of erythrocytes by Ca-loading were observed. Samples from essential hypertension (WHO I and II) and spontaneously hypertensive rats (SHR, Okamoto & Aoki) were examined in comparison with age-matched normotensive subjects and Wistar Kyoto rats (WKY), respectively. Treatment of washed erythrocytes with Ca-ionophore (A 23187) and Ca in the bathing medium caused the reduction of the osmotic fragility dose-dependently on Ca-concentration. The degree in alteration of the osmotic fragility by Ca-loading was significantly greater in hypertension than normotensive controls. However, in the presence of Ca-antagonists (verapamil, diltiazem) or calmodulin antagonist (trifluoperazine) in the medium, the reduction of the osmotic fragility by Ca-loading was inhibited, and the differences between the hypertensives and the controls were abolished by Ca-antagonists and a calmodulin antagonist.
These results suggest that greater changes of the osmotic fragility of erythrocytes by Ca-loading in hypertension might be due to a genetic abnormality of the Ca-handling of the cell membranes, and it would be corrected by Ca-inhibitors.
An increased level of sodium-lithium countertransport (SLC) activity has been associated with salt-sensitive hypertension. Previous findings have suggested that dysregulation of the renin-angiotensin-aldosterone system (RAAS) may be involved in the mechanism linking elevated SLC activity and hypertension. Therefore, baboons with different levels of SLC activity were given two diets differing in sodium content, with and without an angiotensin II (ANG II) infusion, to investigate the relationship between SLC activity, the RAAS, and physiological regulation by sodium. Although we anticipated that high SLC (HSLC) activity would be associated with inappropriate function of the RAAS and greater arterial pressure sensitivity to dietary sodium and ANG II and that low SLC (LSLC) activity would be associated with the least BP sensitivity, we found that the LSLC phenotype correlated with BP sensitivity similar to the HSLC phenotype, and the normal SLC (NSLC) phenotype showed the least BP sensitivity to dietary sodium and ANG II.
The corollary to the conception of high blood pressure as a risk factor is that reduction of raised blood pressure will be of benefit in preventing or reversing cardiovascular disease, and that the means — mostly pharmacologic — lowering high blood pressure must not necessarily be specific, i.e. interfering with the causes of hypertension, but they must simply reduce arterial pressure significantly.
During the last decade mechanisms of ion transport across the cell membrane have been studied by many investigators interested in arterial hypertension [1–4], because ion transport is fundamental in the regulation of body fluids, renal function, hormone secretion and activity, nerve activity, etc. So far, many abnormalities of various ion transport systems have been described in hypertensive rats and in men with “hereditary” forms of hypertension. Such abnormalities regarding Na-K co-transport [5–7], Na/Li countertransport [6,8–10], Na/H countertransport [11,12], Na-K pump [13], passive permeability or leak [14], Ca pump [15], Ca channels [16] etc. have been reported in the literature. Therefore, theoretically, an abnormality of ion transport might be involved in the pathogenesis of “hereditary” or “primary” forms of hypertension.
Despite the evidence that both type 1 and type 2 diabetes are presently treated with up-to-date therapeutic protocols, complete normalization of glycemic control for both diseases appears to be still out of reach. The gap existing between the “ideal” cure still to come and the present pharmacological treatment of diabetes is the cause of the development of microvascular diabetic complications such as nephropathy and retinopathy.
The transmembranal Na⁺/H⁺ antiporters transport sodium (or several other monovalent cations) in exchange for H⁺ across lipid bilayers in all kingdoms of life. They are critical in pH homeostasis of the cytoplasm and/or organelles. A particularly notable example is the SLC9 gene family, which encodes Na⁺/H⁺ exchangers (NHEs) in many species from prokaryotes to eukaryotes. In humans, these proteins are associated with the pathophysiology of various diseases. Yet, the most extensively studied Na⁺/H⁺ antiporter is Ec-NhaA, the main Na⁺/H⁺ antiporter of Escherichia coli.
In this chapter, we review the mechanism of action of lithium salts from a chemical perspective. A description on how lithium salts are used to treat mental illnesses, in particular bipolar disorder, and other disease states is provided. Emphasis is not placed on the genetics and the psychopharmacology of the ailments for which lithium salts have proven to be beneficial. Rather we highlight the application of chemical methodologies for the characterization of the cellular targets of lithium salts and their distribution in tissues.
Der biologisch wirksame Bestandteil von Lithiumsalzen ist das Lithiumion. Es kommt im Körper normalerweise nur in geringen Spuren vor. Das Lithiumion ähnelt chemisch sowohl den einwertigen Alkalimetallionen Na⁺ und K⁺ wie auch den zweiwertigen Erdalkalimetallionen Ca+ + und Mg+ +. Seine biologische Wirksamkeit beruht wahrscheinlich auf einer Konkurrenz mit einem oder mehreren dieser biologisch wichtigen Ionen an ihren Bindungsstellen. Damit könnte die Fülle der verschiedenen biochemischen Effekte von Lithiumionen erklärt werden. Insbesondere wird derzeit die mögliche Konkurrenz von Lithium mit Kalziumionen intensiv diskutiert.
Several years ago, it was reported that red blood cells of patients with essential hypertension contain an increased sodium concentration [1]. It could be demonstrated that the passive Na+ influx into these erythrocytes was augmented in contrast to other types of hypertension [2]. Recently, results of a new test have been published by Garay and Meyer [3] showing abnormal net Na+ and K+ fluxes in erythrocytes of essential hypertensive patients. In Na+-loaded/K+-depleted red cells of these patients, a constant increase in net K+ influx and a reduced ratio of Na+/K+ net fluxes were observed; this was not seen in hypertensives of renal origin. Wambach et al [4] reported an increased Na+/K+-ATPase activity in erythrocyte ghosts of patients with essential hypertension. In our earlier studies [5], we could not confirm these findings. We did, however, measure an increased number of 3H-ouabain binding sites and of Na+/K+-ATPase activity in erythrocytes of patients with hypokalemia due to chronic diuretic treatment. Canessa et al [6] reported an increased sodium-lithium countertransport in red cells of patients with essential hypertension, apparently without overlap with normotensive people.
We are exploring the role of major genes in the pathogenesis of common diseases [1]. The role of heredity in control of blood pressure is evidenced by familial aggregations of blood pressure levels [2]. Correlations of systolic (S) and diastolic (D) blood pressure in identical twins (S: .55, D: .58) are significantly higher than among unidentical twins (S: .25, D: .27) [3]. Adoption studies suggest more resemblance between biologic sibs and their parents than between adopted sibs and their adoptive parents, suggesting that genetic factors rather than a common environment alone account for the familial aggregation of blood pressure levels [4].
A number of recent findings have pointed to possible molecular mechanisms that could account for the long-suspected association between sodium intake and the development of essential hypertension.
The ionic leak across human red cell membranes is very small and close to the ground permeability of an artificial lipid bilayer [1]. Transmembrane ionic movements are allowed by genetically coded transport systems. Regarding Na+ and K+ transport, most of the carrier-mediated fluxes are catalyzed by the Na+/K+ pump [2]. This system catalyzes the exchange of intracellular Na+ by extracellular K+ coupled to the hydrolysis of ATP, thus generating electrochemical gradients of Na+ and K+ across the cell membrane (Fig. 1).
In the past decade, two major developments have focused research interest on the cell membrane for the role it may play in the pathogenesis of hypertension. One development is based on the finding that the sensitivity of vascular smooth muscle increases in experimental hypertension. This increase is due to an altered membrane function of this tissue [1], It may be responsible for the increase in total peripheral resistance that causes the arterial pressure elevation. The second development is the evidence that the membrane abnormality in hypertension is present in many tissues [2, 3]. The membrane of the red blood cell has been mostly studied as a readily available marker for the disease and as a tool for study of the characteristics of the membrane malfunction.
Recent studies have revealed a number of functional alterations of the erythrocyte membrane in essential hypertension and its experimental analogue — spontaneous hypertension of rats (SHR, Kyoto-Wistar). In particular, it was demonstrated in both forms of primary hypertension that permeability of the erythrocyte membrane for monovalent cations is increased [1–3], and the calcium-binding ability of the inner part of the membrane is decreased [4, 5]. It is natural to suggest that such abnormalities in the erythrocyte membrane function in hypertension are due to certain changes of the membrane structure.
Results presented in 1980 seem to indicate that the Na+/Li+ exchange activity in erythrocytes of essential hypertensive patients is two to three times greater than in red cells of nonessential hypertensive individuals. Relatively no overlap was observed between the two groups [1]. Furthermore, the idea has been put forward that measurement of red cell Na+/Li+ exchange may be a useful tool in differentiating between essential and secondary hypertension and in identifying those normotensive individuals who are predisposed to developing essential hypertension later in life [1–3].
Der unimodale Verteilungsmodus des arteriellen Blutdrucks weist auf ein polygenes Vererbungsmuster der arteriellen Hypertonie hin. Die beteiligten Gene vermitteln die Funktionsstörung Hypertonie über sogenannte intermediäre Phänotypen. Als solche werden derzeit neben Funktionsänderungen neurohumoraler Systeme (z. B. verschiedene Neurotransmitter und deren Rezeptoren, Renin, Kallikrein etc.) insbesondere auch quantitative und qualitative Alterationen von Membrantransportproteinen diskutiert. Unabhängig oder auch durch Interaktion mit exogenen Faktoren bewirken solche intermediäre Phänotypen dann die Ausbildung der arteriellen Blutdrucksteigerung. Diese Anschauung ist vereinbar mit dem Konzept der multifaktoriellen Pathogenese der essentiellen Hypertonie, wie es erstmals von Page 1949 formuliert wurde.
This paper compares the transport of Li(+) and Na(+) in erythrocytes from a patient with mania and from members of his family to that in erythrocytes from normal humans. In normal human erythrocytes, Li(+) is transported by at least three operationally distinct pathways: one inhibited by ouabain (ouabain-sensitive), one by phloretin (phloretin-sensitive), and one not inhibited by either compound (insensitive). Li(+) can be driven up its electrochemical potential gradient by an oppositely directed electrochemical potential gradient for Na(+)-i.e., Li(+)/Na(+) counterflow can occur-through the phloretin-sensitive pathway but not through the other two pathways. Because ouabain-sensitive Li(+) transport is negligible under physiological conditions, Li(+) distribution between erythrocytes and plasma in vivo depends mainly on the balance between Li(+)/Na(+) counterflow and the insensitive pathway(s) of Li(+) transport. The steady-state ratio of Li(+) concentration in the erythrocytes to that in the plasma of the patient was between 2 and 3 times higher than the comparable ratio in normal persons. The phloretin-sensitive Li(+)/Na(+) counterflow system was almost absent in the erythrocytes of the patient. Furthermore, unlike those from normal individuals, the patient's erythrocytes showed no external Li(+)-stimulated, phloretin-sensitive, ouabain-insensitive Na(+) efflux. The magnitudes of the ouabain-sensitive and insensitive pathways for Li(+) transport in the patient's erythrocytes were within normal limits. The decreased Li(+)/Na(+) counterflow in the patient's erythrocytes was probably not due to the presence of an inhibitor in the plasma of the patient but rather to an intrinsic defect in the erythrocytes. Because the father and several siblings of the patient showed a similar abnormality in erythrocyte Li(+)/Na(+) transport, it is probable that this defect is inherited.
The influxes of Na(+) and K(+) into the human red cell appear to be interrelated. This relationship was investigated under conditions in which either Na(+) or K(+) concentration outside the cell was varied or one cation was replaced by Mg(2+), choline(+), or Li(+). The effects of furosemide on Na(+) and K(+) movements were studied in the presence of ouabain. When ouabain was present, Na(+) influx was higher with K(+) ions externally than with other cations externally. Furosemide inhibited this K(+)-stimulated Na(+) influx, but it had little effect when K(+) was absent. Ouabain-insensitive K(+) influx was stimulated two-fold by external Na(+) compared with other cations. Furosemide also inhibited this stimulation, but it had little effect when Mg(2+) or choline(+) replaced external Na(+). Thus it was confirmed that synergism exists between the ouabain-insensitive influxes of Na(+) and K(+) and it was demostrated that furosemide inhibits this cooperative effect. The ouabain-insensitive influx of both K(+) and Na(+) showed a hyperbolic "saturating" dependence on the external concentration of the transported cation. Furosemide therefore eliminates a saturable component of influx of each cation. The net uptake of Na(+) in the presence of ouabain was stimulated by K(+) ions. A similar effect was observed with red cells, in which Li(+) replaced nearly all the internal Na(+) plus K(+) ions. In these cells, net Na(+) uptake was stimulated by external K(+), and net K(+) uptake was stimulated by external Na(+). Furosemide inhibited this mutual stimulation of net cation entries. The inhibitory action of furosemide was not limited to inward flux and net movement of Na(+) and K(+). Furosemide also inhibited the efflux of Na(+) into Na(+)-free media and the efflux of K(+) into K(+)-free media. It appeared, therefore, that the action of furosemide was not explained by inhibition of exchange diffusion. These data are consistent with an ouabain-insensitive transport process that facilitates the inward cotransport of Na(+) plus K(+)-ions, and that can produce a net movement of both ions. Although this process under some conditions mediates an equal bidirectional flux of both Na(+) and K(+), it cannot be defined as exchange diffusion. The contransport process is inhibited by furosemide.
A new and simple laboratory test for measuring net Na+ and K+ fluxes in Na+- loaded/K+-depleted human erythrocytes was developed and applied to hypertension. Moderate essential hypertension (10 patients) was characterised by a constant increase in net K+ influx, possibly related to higher Na+, K+-pump activity. In more severe cases (8 patients) net Na+ efflux from erythrocytes dropped. The ratio of Na+/K+ net fluxes was therefore reduced in all essential hypertensive patients. Conversely, Na+ and K+ erythrocyte fluxes were normal in hypertension of renal origin (5 patients). Erythrocyte K+ influx was normal in young normotensive people born of normotensive parents (17 cases), but was increased in 5 of 8 young normotensive people born of essential hypertensive parents, in families where blood-pressure has been recorded for three generations. This result, which seems to indicate genetic transmission, suggests that measurement of Na+ and K+ erythrocyte fluxes may help to detect subjects liable to high blood-pressure.
Li+ net-transfer across cell membranes was studied on human erythrocytes and ghosts preloaded with 1–2 mM Li+ and incubated in saline media of varying composition at initial thermodynamic equilibrium for Li+. The following results were obtained:
1.
Li+ is extruded from glycolyzing erythrocytes against an electrochemical gradient until a steadystate Li+ distribution is established after 24–28 h.
2.
The initial rate of Li+ extrusion is not altered by ouabain or by reduction of ATP levels to less than 25% of the normal value.
3.
Replacement of external Na+ by K+ or choline+ abolishes the establishment of an electrochemical Li+ gradient.
4.
The Li+ distribution ratio Li
e
+
/Li
i
+
increases proportional to the ratio Na
e
+
/Na
i
+
at constant extracellular K+ concentrations.
5.
In ghost suspension an uphill Li+ transport is driven by an oppositely directed Na+ gradient. The direction of the Li+ uphill transport can be reversed by reversing the Na+ gradient.
From the results it is concluded that the Li+ uphill transport across human red cell membranes is mediated by a Na+-dependent Li+ counter-transport system. This system is not inhibited by ouabain and does not appear to be identical to the Na+–Na+ exchange system described by Garrahan and Glynn [24].
Red blood cells (RBC) of patients with essential hypertension differ from those of normotensive individuals by their higher passive permeability for sodium ions (the rate constant of steady-state Na/Na exchange in RBC is 1.52±0.12 vs 0.70±0.12 · 10−5 mole/min · l of cells).
Calcium depletion of the RBC by EDTA results in the removal of more calcium ions from the outer part of the RBC membrane in the case of hypertensive patients (60±5 vs 41±3 μeq/l of RBC); this may be considered as evidence of alteration of calcium binding in the outer RBC membrane in essential hypertension.
By varying the total concentration of intracellular calcium (Cat) in reconstituted RBC (resealed cells, RRBC from 0–500 μmole/l [various concentrations of free calcium (Ca2+f), up to 41 μmole/l, being maintained by a Ca2+-ATP buffer] a lower level of Na-K-ATPase activity in hypertensive patients is observed: when [Ca2+]f=3 μmole/l, the activity was 0.77±0.04 vs 0.93±0.02 μmole of orthophosphate per hour per ml of RRBC, for hypertensive and normotensive individuals respectively. The differences in the kinetics of inhibition of Na−K-ATPase activity when the Ca/ATP ratio in the RBC is decreased was apparently caused by the alteration of calcium binding ability of the inner part of the RBC membrane.
It is suggested that the alteration of the RBC membrane function may be a manifestation of a more wide-spread defect of cell membrane in essential hypertension. The alteration of calcium binding in the membrane is probably one of the patterns of this defect.
An attempt is made to elucidate the cellular mechanisms which may account for the well-documented correlation between sodium metabolism and peripheral vascular resistance. As a starting point, the evidence that the Na electrochemical gradient across the vascular smooth muscle cell plasma membrane (sarcolemma) plays an important role in cell calcium regulation is reviewed. Because there is significant resting tension ("tone") in most resistance vessels, the ionized Ca2+ level ([Ca2+]1) in the smooth muscle fibers in these vessels must be maintained above the contraction threshold. Consequently, the Ca transport system in the sarcolemma, presumably an Na-Ca exchange mechanism, must be set so as to hold [Ca2+]1 at this suprathreshold level. Any change in the Na gradient will then be reflected as a change in [Ca2+]1 and, therefore, in steady vessel wall tension and peripheral resistance. The correlation between Na metabolism and hypertension could then be accounted for if a circulating agent, perhaps the "natriuretic hormone," affects the Na gradient (across the sarcolemma) and, therefore, [Ca2+]1 and tension.
The in vivo RBC/plasma Li+ ratio is determined by the equilibrium between Li+ influx (ouabain-sensitive Na+-K+ pump and ouabain-insensitive leakage pathways) and Li+ efflux (phloretin-sensitive Li+-Na+ counterflow). A study of RBC Li+ transport via these pathways showed that a deficiency of Li+-Na+ counterflow was responsible for the high in vivo ratio (1:1) observed in a manic patient. This defect was related to an alteration in the membrane Na+ exchange system and was under genetic control. The level of counterflow before lithium therapy was an excellent predictor (r = .88) of the in vivo Li+ ratio and was deficient in approximately one-fourth of manic-depressive patients but not in controls, schizophrenics, or unipolar depressed patients.
Unidirectional and net Na+ fluxes modified by changes in internal Na+ concentration ([Na+]i) were studied in human red blood cells incubated in K+-free solutions containing 10-minus 4 m ouabain. An increase in [Na+]i brought about (a) a reduction in net Na+ gain, (b) no change in Na+ influx, (c) a reduction in the rate constant for Na+ effux and (d) an increase in Na+ efflux. Similar reductions in net Na+ gain were observed when the changes in [Na+]i were carried out at constant [K+]i. In addition, the rate constant for 42K+ efflux was not affected by changes in [Na+]i. The electrical membrane potential (as determined from the chloride distribution ratio) was also constnat. Furosemide (10-minus 3 M) increased the net Na+ gain in concentration reduced Na+ efflux and increased Na+ influx: the magnitude of these effects was dependent onthe intracellular Na+. The reduction in the net Na+ gain as [Na+]i increased was unaffected by depletion of cellular ATP to values below 10 mumol/1 cells, and this effect was independent of the depletion method used
THE administration of lithium salts is often used in the treatment of affective psychoses1. Mendels et al.2-4 and others5 have measured the concentrations of lithium in blood plasma and red cells of patients and normal individuals receiving such salts. They have argued that the lithium concentrations in red cells can be correlated with the clinical status of these people4 and, therefore, can possibly be related to the pathogenesis of the mental disorders. They found that the concentration of lithium in red cell water is about one-third of that in the blood plasma during chronic administration of LiCl (ref. 4). This fact is surprising since it would suggest that Li+ is actively transported by the red cell membrane. The steady-state value of the ratio of internal to external concentration for a monovalent cation which is not actively transported should be about 1.2 (ref. 6). Previous observations in red cells7 and squid axons8 suggested that Li+ is not transported by the Na-K pump. Furthermore, the net efflux of Li+ into Li+-free medium was unaffected by the presence of ouabain4. The experiments described here were designed to clarify the mechanisms of this seemingly ouabain-insensitive `active' transport of lithium ions in human red cells.
An easy and reliable (spectro-)photometric procedure is described for the determination of hemoglobin as hemiglobincyanide. The time needed for a determination has been shortened from 20 to 4 min by shifting the ph of the diluent from 8.6 to 7.2. This has been accomplished by substituting (140 mg/l) KH2PO4 for the NaHCO3 in the diluent conventionally used in the HiCN method. Turbidity through precipitation of plasma proteins is prevented by the addition of a small amount of a detergent (Sterox SE) which also promotes rapid lysis of the red cells.