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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.

To the Editor: The report by Worley et al. (August 12 issue)1describing increased sodium–lithium countertransport in the erythrocytes of pregnant women parallels a recent study of ours. We studied three groups of women in the third trimester of pregnancy and six weeks after delivery: 18 women with pre-eclampsia, 14 women with essential hypertension, and women with uncomplicated pregnancies who were matched for gestation and parity with the women in the other two groups. We measured three aspects of erythrocyte cation transport: the ability of erythrocyte membranes to bind [3H]digoxin specifically (as a measure of the numbers of. © 1982, Massachusetts Medical Society. All rights reserved.

The aim of our study was to investigate the role of dyslipidemia on red blood cell sodium-lithium countertransport activity in healthy and hypertensive individuals. A total of 128 Caucasian individuals, aged 20 to 60 years old, were divided into 4 groups: dyslipidemic/ hypertensive, dyslipidemic/normotensive, normolipidemic/hypertensive, and normolipidemic/ normotensive (controls). Sodiumlithium countertransport activity was determined based on the Canessa et al method. Sodium-lithium countertransport activity was significantly higher in all patient groups compared with controls ( P < .001) and similar in the 3 patient groups. Sodium-lithium countertransport activity was significantly and positively associated with triglyceride levels ( P < .001), body mass index ( P < .001), total cholesterol levels ( P = .001), and systolic ( P = .001) and diastolic blood pressure ( P = .001). In multivariate regression analysis, triglycerides made the largest contribution to sodiumlithium countertransport variation among the variables tested ( R 2 = 0.273). Our results suggest that dyslipidemia affects sodium-lithium countertransport activity independently of essential hypertension and even to a greater extent than hypertension.

The association of RBC sodium-lithium countertransport (V max ) with left ventricular mass in African American women

115 children at the age of 15—18 years were examined for the purpose of determined the degree of in fl uense of the friquent respiratory desease on the level of the activity of the sodium-lithium countertransport (SLC) end lipid spectrum. Among them 67 children had the friquent relapses of the acute respiratory desease — the 1-st group, 48 — were sick rarely — the 2-d group. Also some indices of the lipidic exchange were analyzed. During the statistical processing the method of the qartile analysis was used. It was established that according to the average the more, high velocityof the (SLC) is peculiar to the children which are in poor health. The maximum importances of all the examined indices, except of the cholesterol and the malonic dialdehyde, happened to the second quartile of the fi rst group; whereas in the second group of the second qartile the more high were the levels of the cholesterol of the lipoproteins of the low and the lowest thickness. On the basis of the preceding we can suppose that the children have the velocity of the SLC which us in the limits of 166-217 mkmol/L/RBC/h. i.e. The children of the second qartile have a greater risk of the development of dislidemios.

1. We undertook a temporal study of external sodium-stimulated lithium efflux (sodium—lithium countertransport) in erythrocytes and blood pressure by measuring these two parameters in three phases of the menstrual cycle (menstrual, midcycle and luteal phases) in 22 healthy, non-medicated females with regular menstrual cycles. Plasma oestradiol and progesterone levels were also determined. 2. Sodium—lithium countertransport activity (activity in 140 mmol/1 external NaCl) in the midcycle phase (0.176 ± 0.017 mmol h−1 l−1 of cells) was lower than in the menstrual (0.192 ± 0.016 mmol h−1 l−1 of cells, P < 0.030) and luteal (0.203 ± 0.018 mmol h−1 l−1 of cells, P < 0.030) phases. The Vmax of the transporter changed similarly but the Km was unaltered. 3. The plasma oestradiol level was 628.9 ± 39.1 pmol/1 in the midcycle phase, higher than in the menstrual (232 ± 18.5 pmol/1, P < 0.001) and luteal (372.5 ± 28.1 pmol/1, P < 0.001) phases. The progesterone level was 28.6 ± 2.1 nmol/1 in the luteal phase, and values were lower in the menstrual (2.5 ± 0.3 nmol/1, P < 0.001) and midcycle (2.8 ± 0.4 nmol/1, P < 0.001) phases. 4. There was no correlation between plasma oestradiol and sodium—lithium countertransport activity or Vmax during the menstrual cycle, but plasma progesterone was positively correlated with sodium—lithium countertransport activity (r = 0.478, P < 0.025, n = 22) and Vmax (r = 0.551, P < 0.045, n = 14) in the luteal phase. 5. Systolic blood pressure did not change significantly during the menstrual cycle. However, the diastolic pressure showed variation similar to that in sodium—lithium countertransport activity/Vmax, its midcycle value of 66.6 ± 1.4 mmHg being lower than that in the luteal (71.6 ± 1.3 mmHg, P < 0.025) and menstrual (70.6 ± 1.4 mmHg, P < 0.025) phases. 6. We conclude that sodium—lithium countertransport activity exhibits catamenial variation. Therefore we suggest, given this observation, that blood sampling for the assessment of the state of activity of the transport system be standardized in relation to a phase of the menstrual cycle in future studies involving females.

OBJECTIVE It has proved difficult to separate the role of the diabetic state as distinct from its complications in causing the elevation in erythrocyte sodium-lithium (Na-Li) countertransport activity that has been observed in diabetes. The present study sought to isolate the impact of diabetes on the countertransporter by studying groups of non-nephropathic identical-twin pairs both discordant and concordant for diabetes. RESEARCH DESIGN AND METHODS We studied erythrocyte Na-Li countertransport activity in 49 identical-twin pairs who were discordant for IDDM and 26 identical twin pairs who were concordant for IDDM. Similar numbers of healthy control subjects, matched with the nondiabetic twins from the discordant pairs in respect to sex, BMI, and age were also studied. RESULTS The clinical and laboratory characteristics of both sets of twins were very similar to those of the control subjects with the exception that whole-blood glucose and glycated hemoglobin concentrations were higher in diabetic twins, whether from discordant or concordant pairs (P < 0.001), and that systolic blood pressure (P < 0.05) and serum HDL cholesterol (P < 0.05) were higher in the discordant diabetic twins than in their nondiabetic co-twins. Median (95% CI) Na-Li countertransport activities (in millimoles of lithium released from 1 liter of erythrocytes per hour) in the nondiabetic discordant twin [0.237 (0.192–0.284)], the diabetic discordant twin [0.284 (0.254–0.326)], and the concordant twin [0.262 (0.207–0.358)] groups were similar to each other and higher than in the control subjects [0.172 (0.138–0.203)]. Countertransport activities in the discordant diabetic twins correlated significantly with their nondiabetic co-twins (r = 0.34; P = 0.015; n = 49), as did those between the concordant diabetic twin pairs (r = 0.68; P < 0.005; n = 26); activity levels were not related to either disease duration or blood glucose control. CONCLUSIONS An elevation in Na-Li countertransport activity has been noted in non-nephropathic normotensive twin pairs both discordant and concordant for IDDM. The potential genetic contribution to the altered behavior of the countertransporter was similar in both types of twins studied, and individual Na-Li countertransport activities were not significantly related to either duration of diabetes or metabolic control.

Objective: Erythrocyte sodium-lithium countertransport (SLC) is elevated in patients with essential hypertension, those with a family history of hypertension, and in normotensive first-degree relatives of hypertensives. Studies on pregnant women have failed to show any difference between normotensive subjects and those with established pregnancy-induced hypertension (PIH). We therefore studied erythrocyte SLC in second and third trimester primigravid women before the onset of clinical signs of PIH to evaluate the predictive value of this test.Method: All the subjects were Chinese primigravid women. Subjects were excluded if they had a family history of hypertension or if there was any hypertensive disease. Erythrocyte SLC was determined from the difference in efflux of lithium from lithium-loaded cells into sodium-containing and sodium-free media.Results: There were no significant differences in the SLC values between subjects who subsequently developed PIH and those who remained normotensive. In both gro...

We have studied the relationship between sodium-lithium countertransport, determined in childhood, and family history of hypertension. Countertransport was measured in healthy children and those with secondary hypertension. There was no significant difference in countertransport between these two groups. In the normal children (n = 52, median age 6.8 years), there was a positive relationship between body mass index and countertransport (rs = 0.34, p < 0.02). A positive relationship between family history of hypertension using a ranked scoring system, and countertransport, not related to age, body mass or blood pressure (n = 34, rs = 0.63, p < 0.001) was also found. There was no significant relationship between intracellular sodium concentration and countertransport. These data confirm that countertransport in normal children is related to body mass index and indicate that a genetic predisposition to primary hypertension marked by sodium-lithium countertransport is identifiable in childhood.

Inheritance is a major determinant of increased sodium-lithium countertransport (SLC) activity in hypertension. However, hyperlipidaemia can also cause increased SLC activity in some individuals and it is difficult to distinguish this effect from the effect of hypertension. Erythrocyte SLC activity and its kinetic determinants sodium affinity (km) and maximum velocity (Vmax) were measured in 25 hyperlipidaemic patients and 15 normal controls (NC). Increased SLC activity (0.31 +/- SEM 0.03 mmol Li/(h x 1 cells) vs. NC 0.20 +/- 0.01, P < 0.01) in the hyperlipidaemic patients was associated with increased Vmax (0.59 +/- 0.07 vs. NC 0.41 +/- 0.03, P < 0.01) but normal km (median 120 range [40-324] mmol l-1 vs. 140 [108-260]. Lipid-lowering therapy resulted in decreased SLC activity secondary to a fall in Vmax. Km remained constant despite the changes in lipids and Vmax. The mechanism of increased SLC activity in hyperlipidaemia is different from that in essential hypertension where increased sodium affinity is found. Measurement of the kinetic characteristics of SLC may discriminate between the independent influences of hypertension and hyperlipidaemia on the sodium-lithium countertransporter.

1. We evaluated the inheritance of erythrocyte Na+/Li+ countertransport activity in IgA nephropathy by assessing this parameter in 19 patients with biopsy-proven IgA nephropathy and in their 53 relatives (32 parents and 21 siblings). The possible use of erythrocyte Na+/Li+ countertransport activity as a marker of poor prognosis was also evaluated. 2. A significant correlation was found between ‘familial’ and proband Na+/Li+ countertransport activity, but not between that of spouses. 3. Mean blood pressure, although within the normal range, and Na+/Li+ countertransport activity were significantly higher in patients with proteinuria than in those without proteinuria. 4. Parents of proteinuric patients had a higher Na+/Li+ countertransport activity than parents of non-proteinuric patients. 5. In IgA nephropathy the inheritance of erythrocyte Na+/Li+ countertransport activity was preserved. Therefore genetic factors could play a role in the non-immunological progression of IgA nephropathy.

Rates of sodium (Na+)-stimulated lithium (Li+) efflux (Na(+)-Li+ countertransport) and ouabain-sensitive Na+ efflux (Na+ pump) were determined in erythrocytes of Chinese normotensive and hypertensive subjects. Near-maximal rate of Na(+)-Li+ countertransport was found to be significantly higher in hypertensive than normotensive subjects. No significant difference was observed for the rate of Na+ pump between them. A second series of study involved normotensive subjects without and with hypertensive parent(s) (group A and B, respectively) and hypertensive subjects (group C). We found that the rate of Na(+)-Li+ countertransport in group A was significantly lower than that of group B and C, while no difference existed between group B and C. No significant difference was observed for the rate of Na+ pump among the three groups. Our results suggested that Na(+)-Li+ countertransport activity could be a genetic marker for essential hypertension in Chinese, similar to that as proposed in Caucasians.

The objectives of the present study were to determine whether increased sodium-lithium countertransport is associated with essential hypertension in the general Caucasian population and to determine whether this association is independent of the effects of gender, age, body size, and plasma lipids. We studied 543 men and 589 women from the population of Rochester, Minnesota. Mean sodium-lithium countertransport was higher in hypertensive than in normotensive subjects in men (370 +/- 147 [mean +/- SD] versus 315 +/- 110 mumol/l red blood cells [RBC]/hr, p less than 0.001) and in women (339 +/- 114 versus 269 +/- 92 mumol/l RBC/hr, p less than 0.001). Interindividual differences in plasma triglycerides, body mass index (wt/[ht]2), and plasma total cholesterol explained 13.0% of sodium-lithium countertransport variation in men (p less than 0.001) and 20.2% in women (p less than 0.001). Age did not predict additional sodium-lithium countertransport variation in either gender. Slopes of the regressions of sodium-lithium countertransport on plasma triglycerides, body mass index, and plasma total cholesterol did not differ between diagnostic groups in men (p = 0.31) or in women (p = 0.29). After adjustment to remove sodium-lithium countertransport variation attributable to these covariates, mean sodium-lithium countertransport remained significantly higher in hypertensive than in normotensive subjects in men (354 +/- 139 versus 319 +/- 104 mumol/l RBC/hr, p less than 0.01) and in women (311 +/- 103 versus 278 +/- 83 mumol/l RBC/hr, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium lithium countertransport may be a genetic marker for arterial hypertension and for the risk of diabetic nephropathy in type 1 diabetic patients. Since various factors seem to influence the transport velocity including serum lipid alterations, erythrocytes of seven patients with severe hyperlipoproteinaemia who were chronically and intermittently treated with LDL apheresis were examined before and immediately after therapy. The LDL apheresis reduced sodium lithium countertransport significantly (0.383 vs 0.269, P less than 0.02). Therefore, we conclude that serum lipid composition must be considered when interpreting sodium lithium countertransport velocity.

Erythrocyte sodium-lithium countertransport (SLC) was measured in 17 patients with either combined hyperlipidaemia or hypercholesterolaemia before and after lipid lowering therapy. Before treatment SLC related to the serum triglyceride level and was increased in combined hyperlipidaemia. After treatment the SLC had returned to normal and the change in SLC was related to the change in serum triglyceride levels. Raised SLC is associated with essential hypertension but is not related to blood pressure. Therefore, the association of raised SLC with hyperlipidaemia and essential hypertension appears to have different underlying mechanisms.

Diabetic patients who develop proteinuria show a marked increase in cardiovascular morbidity and mortality. The precise pathogenesis of human diabetic kidney disease and the factors responsible for the susceptibility to it remain, in part, obscure. However, there is now evidence that renal disease clusters in families and that genetic factors may be of central importance in determining susceptibility. Predisposition to arterial hypertension has been suggested as playing a contributory role in the development of kidney disease. Hypertrophic processes may be implicated in the susceptibility to arterial wall damage and glomerular injury in diabetes. Interestingly, fibroblasts of patients with diabetic nephropathy show a higher Na+/H+ antiport activity and a greater 3H-thymidine incorporation into DNA than fibroblasts of diabetic patients without nephropathy. The first clinical signs of renal involvement are the appearance of microalbuminuria and a small elevation in arterial pressure. Mesangial expansion accompanies these changes. Microalbuminuria is associated with abnormalities of lipoprotein profiles and higher Na+/Li+ countertransport rates. The environmental changes brought about by diabetes could lead in susceptible individuals to increased systemic and intraglomerular pressures on the one hand and to mesangial expansion on the other. These two processes would cause proteinuria and glomerulosclerosis. Lipid abnormalities may further aggravate the renal histological damage and, in combination with hypertension, contribute to the accelerated atherosclerosis typical of patients with diabetic kidney disease. A vicious circle would thus be triggered, involving reduction in renal function, further hypertension, proteinuria, glomerular obsolence and hyperlipidaemia, and eventually end-stage renal failure or premature cardiovascular death.

Increased sodium-lithium countertransport in erythrocytes is found in patients with insulin-dependent diabetes mellitus (IDDM) and nephropathy. To determine whether such an increase precedes the onset of nephropathy and, if so, whether it is associated with changes in renal function, we measured erythrocyte sodium-lithium countertransport in 52 patients with IDDM but not nephropathy or hypertension and in 32 control subjects. Seventeen of the 52 patients with IDDM (33 percent) had sodium-lithium countertransport activity that exceeded the maximal activity in the control subjects (0.39 mmol of lithium per hour per liter of cells). Eighteen of the 52 patients with IDDM were studied in more detail. The 7 patients with raised sodium-lithium countertransport values had glomerular filtration rates (median, 159 ml per minute per 1.73 m2 of body-surface area; range, 134 to 197) that were significantly higher (P less than 0.01) than those in the remaining 11 patients with IDDM and normal sodium-lithium countertransport (median, 126 ml per minute per 1.73 m2; range, 110 to 176) or in the 10 control subjects (median, 128 ml per minute per 1.73 m2; range, 93 to 151). In the seven patients with elevated sodium-lithium countertransport, the filtration fraction (median, 0.27; range, 0.22 to 0.37) was also greater (P less than 0.01) than that in control subjects (median, 0.22; range, 0.18 to 0.28). There were no differences in renal function between the patients with IDDM and normal sodium-lithium countertransport and the control subjects. We conclude that sodium-lithium countertransport is increased in patients with IDDM before the onset of nephropathy and is associated with hyperfiltration. Thus, elevated sodium-lithium countertransport activity may be an early marker of diabetic nephropathy.

Erythrocyte sodium-lithium countertransport was measured in normolipidaemic and hyperlipidaemic hypertensive patients, hyperlipidaemic normotensive patients and normal controls. Hypertension and hyperlipidaemia were each independently associated with raised sodium-lithium countertransport (by analysis of variance, P less than 0.01 and P less than 0.01). The effects were additive so that hyperlipidaemia could not explain raised sodium-lithium countertransport in hypertension. In hyperlipidaemic hypertensive patients, levels of plasma cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol were increased, and high-density lipoprotein (HDL) cholesterol was reduced. Of these patients, 73.3% had a known family history of hypertension. Their normotensive first degree relatives were studied, and 48% of these also had raised sodium-lithium countertransport and abnormal plasma lipids (raised cholesterol, triglycerides and LDL cholesterol, and reduced HDL cholesterol). Relatives with normal sodium-lithium countertransport had normal lipids. Therefore, raised sodium-lithium countertransport was associated with the inheritance of both hypertension and hyperlipidaemia, and this could explain why raised sodium-lithium countertransport has been associated with a family history of both hypertension and associated cardiovascular disease.

Introduction: Erythrocyte sodium–lithium countertransporter (SLC) has traditionally been characterised as the sodium-stimulated lithium efflux from lithium-loaded erythrocytes. Concurrent activity of the sodium–potassium cotransporter (NKCC) can be expected to lead to imprecise estimates of the activity of the SLC. In the present study, we have characterised this methodological problem and have shown that it can be corrected with the inclusion of bumetanide in the physiological salt solution. Methods: Lithium efflux was studied in lithium-loaded erythrocytes from 35 healthy, normotensive subjects. Erythrocytes were divided into two identical samples (A and B) and lithium efflux characteristics in both samples studied simultaneously by incubating aliquots from each in 10 media of differing external sodium concentrations. Efflux media employed for A and B were the same except for 0.02 mM bumetanide in the media used in B. Results: Increased external sodium was associated with increasing lithium efflux both in the absence and presence of bumetanide; efflux rates were consistently lower in media containing bumetanide (P

1. Erythrocytic sodium-lithium (Na-Li) countertransport (CT) was measured in normotensive Maori and non-Maori by in vitro and in vivo methods to determine its relationship to erythrocytic hypernatraemia previously identified in Maori. 2. In vivo and in vitro CT rates were correlated within race and were similar between races. Countertransport rate was correlated with erythrocytic sodium concentration only in Maori. 3. The findings suggest the possibility of a genetically determined alteration in CT stoichiometry in Maori.

We studied erythrocyte sodium-lithium countertransport in 33 patients with Type 1 (insulin-dependent) diabetes mellitus with diabetic nephropathy, 18 patients with Type 1 diabetes without diabetic nephropathy and in 42 non-diabetic patients with various other renal diseases. No significant differences were found in sodium-lithium countertransport between these three groups (median (range) 322 (162-676) vs 321 (189-627) vs 300 (142-655) mumol.l cells-1.h-1). We conclude, that sodium-lithium countertransport cannot be used as a marker for diabetic nephropathy.

Abstract —An elevated red blood cell (RBC) sodium-lithium countertransport (Na-Li CT) is associated with high blood pressure (BP) in cross-sectional investigations; however, its value as a predictor of future hypertension, and thus of cardiovascular risk, has not been defined. The present study evaluated the association between Na-Li CT and risk of future hypertension in a sample of 106 untreated normotensive middle-aged men participating in the Olivetti Prospective Heart Study in southern Italy. BP, anthropometric and metabolic variables, and RBC Na-Li CT were measured at baseline in 1987 and at a follow-up visit in 1994 through 1995. Na-Li CT was stable over time ( r =0.85) and was significantly associated to systolic BP in both visits. Of the 106 initially normotensive participants, 14 were found to be hypertensive at the 8-year follow-up examination. Eleven of these 14 hypertensives were in the highest tertile of systolic BP at baseline, and 9 of 11 also had an elevated baseline Na-Li CT. In multiple logistic regression analysis, baseline BP, Na-Li CT, and age were all significant predictors of the risk of future hypertension. Individuals with baseline systolic BP in the highest tertile had a 60% risk of developing hypertension if their Na-Li CT was also high, whereas their risk was only 5% if Na-Li CT was in the two lowest tertiles ( P =0.003). RBC Na-Li CT was a valuable predictor of subsequent hypertension in middle-aged men with a high-normal BP level for their age.

Current opinions on the relationships between erythrocyte sodium-lithium countertransport kinetics and primary hypertension, hyperlipidaemia and diabetic nephropathy are reviewed. Problems associated with the assay are analysed. Some possible mechanisms that could modify the kinetics of ion exchange are examined. The question of what catalyses sodium-lithium countertransport is discussed, but not answered. Some models are put forward showing how a study of sodium-lithium countertransport kinetics could further our understanding of important disease processes.

An elevated red blood cell Na/Li countertransport (Na/Li CT) is often associated with high blood pressure and metabolic abnormalities. Recent studies suggested that a reduction in serum TG levels is associated with a decrease in Na/Li CT activity. However, it is still unclear if this phenomenon could be originated from systemic metabolic alterations or from modifications of the membrane dynamic properties. Aim of the present study was to investigate whether dietary or pharmacological TG lowering therapy might have a different effect on Na/Li CT activity and related metabolic parameters. Twenty normotensive hyper-TG patients were recruited from the Lipid outpatient Clinic: they had a baseline Na/Li CT activity significantly higher compared with age- and BMI-matched normolipidemic controls (386+/-33 vs 274+/-39 umol/l RBC/h, p

Background Interest originally arose in ouabain-insensit-ive lithium transport across erythrocyte membranes when it was found that lithium could substitue for sodium, either undergoing 1 :1 lithium exchange or 1 :1 sodium-lithium countertransport in a manner that follows Michaelis-Menten kinetics. Elevation of the sodium-lithium countertransport activity in hypertension was first noted in 1980 and found to be a genetically linked phenomenon. This observation has since been confirmed on several occasions and associations with other dieases such as diabetes have been noted. Nevertheless, many unanswered questions remain about the clinical significance of disturbed sodium-lithium countertransport and its pathological basis. Methods Traditional methods for characterizing the sodium-lithium countertransporter have depended on determining differences between lithium fluxes into sodium-rich and sodium-free media. There have been inherent problems in deciding on suitable sodium substitutes. Of the available alternatives, choline has emerged as having advantages over magnesium. Reports in the literature have often failed to take into account varied assay conditions, making comparisons of data from different laboratories difficult A further complexity has been the realization that sodium-lithium countertransport activity incorporates two key elements in the form of V max and k m . Kinetic studies have shown independent variation in these two parameters with various disease states. Results Much of the published work to date has continued to rely on measurement of countertransport activity, with magnesium acting as the predominant sodium-substitute. This has occurred despite the undoubted benefits obtained from kinetic analysis. Where kinetics of the sodium-lithium countertransporter have been determined, there have emerged clear associations between V max and environmental influences such as plasma lipids with elevated values in dyslipidaemic states including diabetes. The affinity constant k m , is more clearly under genetic control and has independent associations with vascular disease. Conclusion Study of the erythrocyte sodium-lithium countertransporter has revealed interesting relationships between altered behaviour of the transporter and specific disease states. Although still somewhat of an enigma, this transporter is emerging as an important membrane constituent whose further study may help us to understand the molecular mechanisms leading to vascular disease.

The aim of this study was to assess the relationship between markers of tubular function, markers of glycaemic control and erythrocyte sodium-lithium countertransport activity (SLC) in 40 normotensive, normoalbuminuric insulin-dependent diabetic (IDDM) subjects and 11 normal control subjects. Nine IDDM subjects had SLC0.40 mmol lithium h-1 litre RBC-1. Glomerular filtration rate (GFR) and the excretion rate of retinol-binding protein (RBP), N-acetyl-beta-D-glucosaminidase (beta-NAG) and glucose were significantly higher in IDDM subjects compared to control subjects (Mann-Whitney test, p = 0.02,0.001,0.001 and0.001, respectively), whilst the two groups had similar SLC and TmPO4 levels. There was no significant relationship between SLC and the other variables in IDDM subjects, even when comparing IDDM subjects with normal and high SLC. beta-NAG excretion rate was correlated to urinary glucose (rs 0.47, p = 0.001) and, weakly, to the other markers of glycaemic control (fasting blood glucose rs = 0.31, p = 0.03, fructosamine rs 0.28, p = 0.04, HbA1 rs 0.27, p = 0.04). RBP excretion rate was correlated to the excretion rate of beta-NAG (rs 0.38; p = 0.007) and albumin (rs 0.45; p = 0.002); the excretion rates of beta-NAG and albumin were significantly associated (rs 0.37, p = 0.009). Diabetes duration did not correlate to any of the aforementioned variables. In this study, beta-NAG and RBP overnight excretion rates were higher in normoalbuminuric IDDM subjects compared to control subjects but no relationship was present between SLC and tubular function in IDDM patients without complications. Excretion rates of different proteins appear to be interrelated and, in IDDM, beta-NAG excretion is associated with glycaemic control.

Hypertension is associated with some abnormalities in cell membrane structure, including an impaired distribution of cholesterol into the monolayers of erythrocyte membrane. Transbilayer movement of membrane cholesterol modulates the formation of these structural cholesterol domains. We tested whether the rate of cholesterol movement may influence on the erythrocyte Na+-Li+ countertransport, that is a marker of human essential hypertension. In single regression analysis, the half-time for the decrease in specific radioactivity of cholestenone (inverse of membrane cholesterol transbilayer movement) was negatively related to the erythrocyte cation flux mediated by Na+-Li+ countertransport (r = -0.8983, P, Supported by a grant (AL1950073) from Comision Interministerial de Ciencia y Tecnologia (CICYT), and the Andalusian Heart Service.

Sodium-lithium countertransport (SLC) activity at a standard physiological sodium concentration is raised in uncomplicated IDDM, for which the kinetic mechanism is a raised maximum velocity (Vmax). Diabetic patients with nephropathy do not have raised values for Vmax but a low Michaelis constant (km). Transporter activity could be influenced by its membrane lipid environment. This was assessed in 21 control subjects, 32 uncomplicated diabetic patients, 17 patients with diabetic nephropathy and 11 patients with nondiabetic nephropathy by measuring the fluorescence anisotropy of DPH and TMA-DPH to assess different membrane regions. Standard SLC was higher in all the patient groups compared to the control subjects: 0.307±0.020 mmol Li/h x 1 cells in uncomplicated IDDM; 0.300±0.032 in diabetic nephropathy patients and 0.276±0.019 in non-diabetic nephropathy patients vs 0.216±0.011 mmol Li/h x 1 cells in control subjects (p

The objective of the present study was to determine whether information about a biometrically inferred single gene with large effects on erythrocyte sodium-lithium countertransport is useful in predicting the probability of having hypertension. We used multivariate logistic regression to model the relationship between the probability of having hypertension and predictor traits in a sample of 382 unrelated adult women and 347 unrelated adult men from Rochester, Minn. First, we identified a set of demographic, biochemical, and physiological predictors. Second, we analyzed whether the relationship between the probability of having hypertension and the identified predictor traits was heterogeneous between the biometrically inferred single locus genotypes with large effects on sodium-lithium countertransport level. Third, if there was no heterogeneity, we assessed whether sodium-lithium countertransport genotypes made an additional contribution to predicting the probability of having hypertension after other predictors were considered. In women, the predictors of the probability of having hypertension were age, plasma apolipoprotein CIII, body mass index, and an interaction term involving age and body mass index. The relationship between the probability of having hypertension and the identified predictors was not heterogeneous between sodium-lithium countertransport genotypes, and genotype did not contribute to the prediction of the probability of having hypertension after the identified predictors were considered. In men, predictors of the probability of having hypertension were age, plasma levels of high-density lipoprotein cholesterol, apolipoproteins AI and CII, sodium-lithium countertransport level, and sodium-lithium countertransport genotype. The relationship between the probability of having hypertension and sodium-lithium countertransport level and age were heterogeneous between biometrically inferred sodium-lithium countertransport genotypes.(ABSTRACT TRUNCATED AT 250 WORDS)

In this paper we report some results of our studies on patients with immunoglobulin (Ig)A nephropathy regarding (1) the familiar aggregation of erythrocyte sodium-lithium (Na,Li) countertransport; (2) the association of Na,Li countertransport with the presence of arterial hypertension and lipid abnormalities; (3) the correlation between Na,Li countertransport activity and renal functional reserve; and (4) the preliminary results of a longitudinal study. In 13 families of patients with IgA nephropathy, selected because both parents were available, we found a significant correlation between midparent and offspring Na,Li countertransport activity (Spearman's rank correlation = 0.65; P = 0.023), but no husband-wife relationship. In 49 patients, the activity of Na,Li countertransport was significantly higher in erythrocytes from 20 hypertensive patients than from either 29 normotensive patients or from 36 healthy age- and sex-matched normal subjects. Hyperlipidemic patients had an erythrocyte Na,Li countertransport activity significantly higher than normolipidemic patients and controls. In 17 patients a significant inverse correlation was found between the peak variation of creatinine clearance over baseline value after an oral protein load and the erythrocyte Na,Li countertransport activity (Spearman r = 0.54; P = 0.03). In a longitudinal study of 36 patients followed from 12 to 36 months, those showing a progression toward renal failure had an erythrocyte Na,Li countertransport activity higher than median value. The results of our studies show that in patients with IgA nephropathy a high erythrocyte Na,Li countertransport rate, genetically determined, is associated with the presence of arterial hypertension and lipid abnormalities, and perhaps with a less favorable disease outcome.

The objectives of the present study were to determine whether sodium-lithium countertransport contributes to predicting the probability of having hypertension and to determine whether it does so after other predictor traits have been considered. We used logistic regression to model the relation between sodium-lithium countertransport and the probability of having hypertension, estimated by the prevalence of hypertension among 172 men and 252 women, aged 47-89 years, from the Caucasian population of Rochester, Minn. When sodium-lithium countertransport was the only predictor trait considered, it made a statistically significant contribution to prediction both in men (model chi(2)1df = 20.50, p < 0.001) and in women (model chi(2)1df = 16.69, p < 0.001). For each standard deviation increase in sodium-lithium counter-transport, the expected odds of having hypertension increased 2.25 times in men (95% confidence interval [CI], 1.44-3.51) and 1.77 times in women (95% CI, 1.32-2.37). When sodium-lithium countertransport was not considered, the other traits identified as predictors were age, body mass index, and plasma apolipoprotein CII and CII squared; plasma apolipoprotein AI was an additional predictor in women but not in men. When sodium-lithium countertransport was added to models that included the other predictors, it improved prediction both in men (increase in model chi(2)1df = 12.29, p < 0.001) and in women (increase in model chi(2)1df = 4.86, p < 0.027). Based on these complete models, when the other predictors remained at their mean values, each standard deviation increase in sodium-lithium countertransport increased the expected odds of having hypertension 2.06 times in men (95% CI, 1.31-3.22) and 1.48 times in women (95% CI, 1.04-2.21). These results establish that sodium-lithium countertransport provides information that is helpful in predicting the probability of having hypertension and is not reflected in other identified predictor traits.

A total of 390 people undergoing routine examinations at the Portes Center, a screening center in Chicago, and at the Northwestern Memorial Hospital employee health service, underwent an in-depth battery of tests designed to explore the relationships of both intracellular erythrocyte sodium and sodium-lithium countertransport with age, race, gender, body mass index, pattern of alcohol intake, exogenous hormone use and the presence of hypertension. Erythrocyte sodium was significantly higher in blacks than in whites and in men than in women aged 20-39 years. Relationships of erythrocyte sodium with race and gender, as well as inverse associations with alcohol intake in men, and positive associations with age and the presence of hypertension in women were significant on multivariate analysis after control for other variables. Sodium-lithium countertransport was significantly higher in whites than in blacks and in men than in women aged 20-59 years. Associations of sodium-lithium countertransport with race and gender as well as positive associations of sodium-lithium countertransport with body mass index in men and women were significant on multivariate analysis after control for other variables. Age-related gender differences in both sodium-lithium countertransport and erythrocyte sodium, as well as the association of erythrocyte sodium with the presence of hypertension in women but not in men, suggest a hormonal interaction with sodium transport in the development of hypertension.

P-179 Key Words: Blood Pressure, Na-Li Countertransport, Children ;;2>POSTERS: Antihypertensive Drugs

To determine whether there are familial and genetic aspects of sodium-lithium countertransport activity in red cells in diabetic nephropathy.Case-control study.Teaching hospital diabetic clinic.40 Patients with insulin dependent diabetes, both of whose parents were alive: 20 with persistent proteinuria and 20 with normal albumin excretion matched for age, duration of diabetes, and body mass index. All 80 parents.Sodium-lithium countertransport activity in red cells and arterial blood pressure.Sodium-lithium countertransport activity in red cells was higher in the patients with proteinuria than in the patients with normoalbuminuria (mean (95% confidence interval) 0.47 (0.39 to 0.54) v 0.33 (0.28 to 0.38) mmol/l red cells/h respectively, p = 0.0036; mean difference 0.14 (0.04 to 0.22)). The mean countertransport activity for the two parents of each patient was calculated, and from this the mean value for each group of parents was calculated; the value was higher in the parents of the patients with proteinuria than in the parents of the patients with normoalbuminuria (0.40 (0.32 to 0.48) v 0.30 (0.26 to 0.33) mmol/l red cells/h respectively, p = 0.016; 0.10 (0.02 to 0.19)). Twenty-eight of the parents of the patients with proteinuria compared with 12 of the parents of the patients with normoalbuminuria had a countertransport activity that was above the median value in all 80 parents (p less than 0.001). Mean arterial blood pressure in the parents of the patients with proteinuria was related to that of their offspring (r = 0.46; p less than 0.01). There was a positive correlation between the sodium-lithium countertransport activity in red cells in the parents and their offspring when all parents and patients were considered (r = 0.37; p less than 0.001).Increased sodium-lithium countertransport activity in red cells in the parents of diabetic patients with nephropathy provides further evidence that familial, and possibly genetic, factors related to a predisposition to arterial hypertension have a role in the susceptibility of diabetic renal disease.