Erythrocyte sodium-lithium countertransport activity in non-nephropathic diabetic twins.

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.

Muzolimine: renal site of action and interaction with probenecid in humans.

Muzolimine (60 mg, administered orally) was administered to eight healthy volunteers, under conditions of altered fluid load, to elucidate its renal site of action. The duration of action and the effect of probenecid pretreatment on muzolimine response was also investigated. Muzolimine had a rapid onset of action, with the diuresis complete within 4 hours after dosing. At peak natriuresis, under hydrated conditions, fractional excretion of free water remained unaltered (9.72% +/- 0.59% versus 9.07% +/- 0.44%; difference not significant) but was accompanied by a significant increase in the delivery of sodium out of the proximal tubule, as measured by fractional excretion of lithium (22% +/- 2% to 31% +/- 1%; p less than 0.01). The fraction of sodium reabsorbed in the distal tubule also decreased from 94% +/- 1% to 67% +/- 1% (p less than 0.001) of the delivered load. The fractional reabsorption of free water during hydropenia decreased after muzolimine (5.63% +/- 0.26% to 2.00% +/- 0.81%; p less than 0.05). Pretreatment with probenecid resulted in a prominent decrease in urinary sodium excretion (246 +/- 25 mmol/24 hr for muzolimine alone 161 +/- 24 mmol/24 hr for muzolimine and probenecid; p less than 0.01). These findings suggest that muzolimine has a major site of action in the medullary portion of the thick ascending limb of Henle with additional inhibitory activity on the proximal tubule. It is likely that the active secretion of one or more of the acidic metabolites of muzolimine, by way of the probenecid sensitive organic acid pathway, is responsible for mediating the renal actions this basic drug.

Effects of intravenous and oral propantheline and metoclopramide on ethanol absorption.

The separate effects of propantheline, atropine, and metoclopramide on ethanol absorption have been studied in man. Intravenous propantheline lowered blood ethanol levels after ingestion of a standard ethanol load. Oral propantheline, at dose levels currently recommended for therapeutic use, was without significant effect on ethanol tolerance, whereas the tolerance was reduced by oral atropine. Propantheline bromide tablets have been shown to undergo significant hydrolysis at alkaline pH in vitro. Metoclopramide, given intravenously and orally, significant elevated blood ethanol levels soon after ingestion of a standard ethanol load. It is suggested that when propantheline is selected as an anticholinergic for clinical use, there is need for greater awareness of the marked reduction in bioavailablity that results when the drug is administered at conventional therapeutic dosage by the oral as opposed to the intravenous route.

The influence of nonsteroidal anti-inflammatory drugs and probenecid on the renal response to and kinetics of piretanide in man.

The mechanism by which nonsteroidal antiinflammatory drugs interfere with the action of loop diuretics is not clear. We studied the renal response to an acute challenge of piretanide superimposed on pretreatment with either placebo, probenecid, indomethacin, or piroxicam in seven maximally hydrated subjects. No change was seen in glomerular filtration rate, as measured by creatinine clearance, throughout the experiments. When compared with responses to piretanide challenge after placebo pretreatment, probenecid reduced by 65% the peak fractional excretion of sodium (FENa), with a corresponding reduction in diuretic excretion. Pretreatment with indomethacin reduced peak FENa by 35%, but urinary delivery of piretanide was not altered. In contrast, piroxicam did not influence FENa but significantly reduced the delivery of both sodium and piretanide into urine. We conclude that the activity of nonsteroidal antiinflammatory drugs within the renal tubule varies among individual drugs and cannot be explained solely by their common mechanism of antiinflammatory action.

Renal actions of piretanide and three other "loop" diuretics.

Thirty-nine clearance studies were performed in 17 healthy subjects under conditions of maximal hydration or hydropenia to compare the effects on renal solute and water handling of three sulfamoylbenzoic acid derivatives-piretanide, bumetanide, and furosemide-and the phenoxyacetic acid diuretic ethacrynic acid. Except for furosemide, which caused a 7% fall in effective renal plasma flow (ERPF), and ethacrynic acid, which reduced both the glomerular filtration rate (16%) and ERPF (23%) during maximal hydration, changes in hemodynamics were insignificant. At peak saluresis piretanide induced a mean reduction of -18.3% +/- 4.9% in fractional free-water clearance during hydration and -73.2% +/- 5.9% in fractional free-water reabsorption during hydropenia. The other sulfamoylbenzoates lowered fractional clearance and reabsorption of free water to similar extents, implying a major site of action within the medullary portion of the ascending limb. Ethacrynic acid reduced fractional free-water clearance to a greater degree than did the sulfamoylbenzoates. The mean reduction in fractional free-water reabsorption after ethacrynic acid (71.4% +/- 8.2%) was of the same order as that caused by the sulfamoylbenzoates. Similar excretory maxima for sodium, chloride, potassium, calcium, and magnesium were achieved for all four diuretics. Except for piretanide under hydropenia, sulfamoylbenzoate action did not change urinary pH. Ethacrynic acid consistently lowered urinary pH. During hydration piretanide induced phosphaturia (35.3% +/- 8.8%) and uricosuria (40.9% +/- 9.1%). Both bumetanide and piretanide increased fractional urate clearance during hydropenia (16.7% +/- 5.6% and 34.2% +/- 10.5%). There were no changes in phosphate or urate excretion after ethacrynic acid. Our data support the view that sulfamoylbenzoate diuretics exert additional effects on proximal tubular segments that are not shared by ethacrynic acid. Renal responses to piretanide most closely resemble those to bumetanide.

Foscarnet-induced changes in plasma concentrations of total and ionized calcium and magnesium in HIV-positive patients.

The time course and magnitude of foscarnet-induced changes in plasma concentrations of total and ionized calcium and magnesium were investigated in 13 male HIV-positive patients who had no active cytomegalovirus-associated disease. The patients had a mean age of 36 years (range 25-49 years) and a mean CD4 cell count of 550 cells/mm3 (range 130-1280 cells/mm3). Peak (mean +/- SD) plasma concentrations of foscarnet (0.89+/-0.10 mmol/l) were seen at the end of the period of drug infusion (90 mg/kg of foscarnet was infused over 2 hours) and declined with a terminal half-life of 5.7+/-0.7 hours. Plasma concentrations of total calcium declined over an 8-hour period, with the lowest concentration occurring after 4 hours (baseline: 2.29+/-0.09 mmol/l; lowest: 2.18+/-0.07 mmol/l; P < 0.001). By contrast, the lowest plasma concentration of ionized calcium occurred after 2 hours (baseline: 1.25+/-0.04 mmol/l; lowest: 0.99+/-0.05 mmol/l; P < 0.001), before gradually recovering to baseline levels over the next 10 hours. The mean maximal decrease in total calcium was 0.11+/-0.06 mmol/l, compared with 0.26+/-0.04 mmol/l for ionized calcium (P < 0.001). Plasma concentrations of total magnesium declined from 0.79+/-0.06 mmol/l (baseline) to 0.74+/-0.04 mmol/l (P < 0.05) after 4 hours and remained at this level after 8 hours. However, plasma concentrations of ionized magnesium fell steeply from 0.56+/-0.03 mmol/l to 0.39+/-0.03 mmol/l at 2 hours (P < 0.001), followed by a gradual recovery over the next 10 hours. The mean maximal decrease in total magnesium was 0.05+/-0.08 mmol/l, compared with 0.18+/-0.03 mmol/l (P < 0.001) for ionized magnesium. In summary, we found that foscarnet-induced changes in the plasma concentrations of total calcium and magnesium were dissociated from the corresponding changes in ionized calcium and magnesium. The maximal decreases in the plasma concentrations of total calcium and magnesium were smaller in magnitude and occurred much later than did the changes in ionized calcium and magnesium. The relative changes in the plasma concentration of ionized magnesium were greater than those of ionized calcium, indicating that foscarnet binds preferentially to the magnesium ion.

Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is caused by mutations in the gene for the low density lipoprotein (LDL) receptor. It is generally believed that homozygous FH patients do not respond well to lipid-lowering drug therapy with inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase because they cannot respond to an increased demand for hepatic cholesterol by up-regulation of LDL-receptor activity. In this paper we show that serum cholesterol in a homozygous FH patient with a receptor-negative LDL-receptor phenotype was reduced by 30% after treatment with simvastatin alone and by a further 11% with simvastatin in combination with probucol and nicotinic acid. The patient was a true homozygote, with two identical alleles of the LDL receptor gene in which a previously undescribed point mutation in exon 11 introduces a premature termination codon at residue 540 in the protein; the mutant protein is predicted to be truncated in the domain with homology to the epidermal growth factor precursor. Cultured cells from the patient were unable to bind, internalise or degrade LDL by the receptor pathway and there was no immunodetectable LDL receptor protein in the cells. Thus the lipid lowering effect of simvastatin in this individual must involve mechanisms other than stimulation of LDL receptors.

Controversies surrounding erythrocyte sodium-lithium countertransport.

BACKGROUND: Interest originally arose in ouabain-insensitive lithium transport across erythrocyte membranes when it was found that lithium could substitute 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 diseases 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 Vmax 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 Vmax 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 effects of enalapril on blood pressure and the kidney in normotensive subjects under altered sodium balance.

Eight healthy volunteers received both oral enalapril (EN; MK-421) 20 mg and placebo (PL) under stable conditions of sodium repletion, 300 mmol sodium/day (HS) and sodium depletion, 10 mmol sodium/day (LS). During PL therapy, fivefold increases in the plasma concentrations of renin and aldosterone were observed when measurements under LS were compared with those under HS conditions. Basal blood pressure (BP) readings were consistently higher and the hypotensive response to EN greater under LS compared with HS conditions. After EN, renal plasma flow increased significantly over the first 4 h, while the glomerular filtration rate, measured both by inulin and creatinine clearances, did not change. A significant natriuretic response was observed within 2 h; further natriuresis between 6 and 12 h after EN was accompanied by increased phosphate excretion.

Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects.

Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15+/-0.24 microg/ml (100 mg) and 1.92+/-0.47 microg/ml (200 mg; p<0.001), which were achieved (Tmax) at 2.5+/-1.5 h and 3.3+/-1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-15.6 liters (100 mg) and 82.7+/-34.9 liters (200 mg) while total body clearances (Cl/F) were 10.4+/-2.1 and 10.8+/-1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.

Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in subjects with coronary artery disease.

Sodium-lithium countertransport activity, external affinity for sodium (kNa) and maximal rate of turnover (Vmax), were characterized in 21 male subjects (aged 45 to 65 years) with angiographically proven coronary artery disease; these were compared with a matched group of healthy controls. No significant differences in countertransport activity were noted between the coronary artery disease patients and the healthy controls. By contrast, the median [range] kNa in the coronary artery disease group (8.5 [2.6 to 30.5] mmol/L Na) was significantly lower than that in the controls (59.9 [5.9 to 240.5] mmol/L Na; P < .0001). This reduction was accompanied by a significantly lower mean Vmax (controls 0.403 +/- 0.187 v coronary artery disease group 0.248 +/- 0.121 mmol Li/L RBC/h; P < .01). The findings suggest that disturbed behavior of the sodium-lithium countertransporter is not confined to hypertension but may represent a broader-based membrane dysfunction associated with vascular disease.

Relation between sodium-lithium countertransport and hypertriglyceridemia in type V hyperlipidemia.

Sodium-lithium countertransport (SLC) kinetics were measured in 30 patients with type V hyperlipidemia, 30 patients with type IIB hyperlipidemia on similar treatment, and 30 age- and sex-matched healthy controls. Clinical and laboratory data including basic anthropometry and blood pressure were obtained and blood was taken for detailed lipid biochemistry, glucose, insulin, and leptin measurements. Patients with type V hyperlipidemia were normotensive but more obese than controls, had elevated triglycerides, very low-density lipoprotein, glucose, and insulin; and reduced HDL cholesterol compared with type IIb controls. The median SLC activity (0.23 v 0.21 mmol Li+/L RBC/h) and median maximal velocity (0.33 v 0.31 mmol Li+/L RBC/h) were increased, but not significantly, compared to controls. In patients with type V hyperlipidemia SLC maximal velocity correlated with log triglycerides (r2 = 0.853; P < .001) and log very low-density lipoprotein (VLDL) triglycerides (r2 = 0.947; P < .001). Sodium-lithium countertransport maximal velocity correlated weakly with the homeostasis model assessment index of insulin resistance (r2 = 0.224; P = .06). The sodium affinity of the transporter did not differ between the groups and was independent of any of clinical or biochemical parameter studied. We conclude that VLDL triglyceride is strongly correlated with SLC maximal velocity and activity in patients with type V hyperlipidemia.

Sodium-lithium countertransport activity is not affected by short-term insulin exposure in vivo or in a physiologic medium in vitro.

This study examined the acute effects of physiologic concentrations of insulin in vitro and in vivo on sodium-lithium countertransport (SLC) kinetics in nondiabetic subjects. SLC was measured at eight different external sodium concentrations including the standard 150 mmol/L, allowing calculation of both maximal velocity (Vmax) and external sodium affinity (Km). Incubation with insulin (50 mU/L) in 110 MgCl2 but not in 150 mmol/L NaCl decreased standard SLC activity. The decrease was accounted for by a reduction in Vmax, whereas Km remained constant. There was no difference in standard SLC activity, Vmax, or Km when endogenous insulin concentrations were altered either by fasting or by a carbohydrate load. Similarly, standard SLC activity, Vmax, or Km were not significantly different before or at the completion of a euglycemic hyperinsulinemic clamp. These findings provide no support for an action of physiologic concentrations of insulin either in vitro or in vivo on the kinetics of the countertransporter measured in vitro in isotonic sodium-containing media.

Kinetic behavior of the erythrocyte sodium-lithium countertransporter in nonnephropathic diabetic twins.

Elevated erythrocyte sodium-lithium countertransport activity occurs in diabetes and may be genetically mediated. The relation of this abnormality to the disease and its complications is unclear. To remove confounding genetic factors and the impact of complications, we studied sodium-lithium countertransport activity together with its kinetic components, maximal rate of turnover (Vmax) and external affinity for sodium (kNa), in identical-twin pairs discordant for insulin-dependent diabetes who were normotensive and had no evidence of nephropathy. Fifteen twin pairs were studied along with the same number of healthy control subjects matched with the twins for gender, age, and body mass index. Clinical and laboratory characteristics of the twins and controls were similar, with the exception that whole blood glucose and glycated hemoglobin concentrations were higher in diabetic twins (P < .001). Comparison of countertransport activity between nondiabetic and diabetic twin groups failed to uncover any significant differences (P = .30, Wilcoxon). Similarly, there were no differences in countertransport activity between the nondiabetic twin group and the controls (P = .38, Mann-Whitney). Furthermore, no associations were noted between residual activity values and residual data of any of the other clinical or laboratory characteristics measured. Comparison of Vmax between nondiabetic and diabetic twin groups showed a significant elevation in the diabetic twins (0.515 + 0.220 v 0.439 + 0.229 mmol Li/L RBC x h, P = .049, paired t test). By contrast, no significant differences were noted between the nondiabetic twin group and the controls (P = .15, unpaired t test). Comparison of kNa between nondiabetic and diabetic twin groups found no significant differences in kNa (P = .42, Wilcoxon). Similarly, there were no differences in kNa between nondiabetic twins and controls (P = .14, Mann-Whitney). Neither the residual data for Vmax nor kNa showed any association with the residual data of any of the other clinical or laboratory characteristics measured. When intertwin correlations were examined, all three parameters describing the behavior of the sodium-lithium countertransporter showed significant intertwin correlations (activity, r = .51, P = .04; Vmax, r = .82, P = .001; kNa, r = .76, P = .001). In conclusion, the diabetic state has a small effect on the Vmax of the sodium-lithium countertransporter. Failure to consider the complex nature of the activity measurement is likely to have been partly responsible for earlier confusion with regard to the effect of diabetes on the countertransporter, since experimental conditions varied between studies and individual kinetic components were not measured. The associations between twins in this study with respect to Vmax and kNa indicate a genetic influence on both constants of the countertransporter. Vmax appears also to be sensitive to certain as yet unidentified environmental factors.

Effect of salt balance on the renal and hemodynamic actions of benazepril in normal men.

Renal and hemodynamic effects of diet alone and of single oral doses of the nonsulphydryl angiotensin converting enzyme (ACE) inhibitor, benazepril (10 mg), were investigated in eight healthy volunteers under stable conditions of high salt intake (300 mmol NaCl/day) and low salt intake (10 mmol NaCl/day), in a double blind, placebo controlled study. There were no changes in blood pressure between the two dietary extremes either during the run-in period or once sodium balance had been achieved. Mean renal plasma flow was higher, by approximately 10% and renal vascular resistance lower by 15%, on high salt diet compared to low salt diet. Glomerular filtration rates were found to be similar irrespective of the state of salt balance. Both plasma urate concentration and plasma renin activity were significantly elevated in the low salt compared to high salt state. Benazepril caused a greater fall in blood pressure in the sodium depleted state. Significant increases in the mean renal plasma flow, in the order of 15-20%, were seen over 6 h postbenazepril when compared with placebo response, regardless of the level of salt intake. Glomerular filtration rate over the same period remained unaltered. Benazepril doubled the urinary excretion of sodium over the first 4 hours after dosing whilst on the low salt diet; the equivalent increase during salt loading was approximately 20%. These results suggest that benazepril may exert direct effects on renal tubular function additional to those achieved through ACE blockade.

Relation of sodium-lithium countertransport activity to markers of cardiovascular risk in normotensive subjects.

A study was undertaken in 298 normotensive, normolipidaemic and normoglycaemic subjects to define the range of erythrocyte sodium-lithium countertransport activity in this cohort and to determine the associations between countertransport activity and markers of vascular risk. Countertransport activity showed a positively skewed non-normal distribution with a median (95% confidence interval) of 0.197 (0.123-0.271) mmol Li/L erythrocytes per hour. Countertransport activity was elevated in women who were taking oral contraceptives (median (95% CI) mmol Li/L erythrocytes per hour, 0.270 (0.162-0.320) vs. 0.147 (0.110-0.201)). Countertransport activity was also found to be elevated in subjects who had alcohol intakes greater than the recommended weekly maximum (median (95% CI) mmol Li/L erythrocytes per hour, 0.193 (0.139-0.211) vs. 0.260 (0.148-0.317)). Positive correlations with sodium-lithium countertransport activity were noted with resting diastolic blood pressures (n = 298; P = 0.004) and maximal systolic blood pressure at peak exercise (n = 123; P = 0.003). In respect of serum biochemical variables, positive correlations were only found with triglycerides (P = 0.025) and creatinine (P = 0.005). These results support the view that elevation of erythrocyte sodium-lithium countertransport activity may reflect an alteration in the behaviour of cell membrane proteins through the influence of environmental factors associated with vascular risk.

Association of angiotensin converting enzyme DD genotype with hypertension in diabetes.

Angiotensin converting enzyme (ACE) genotypes have been associated with hypertension in the general population. However, the relation of ACE genotype to the prevalence of hypertension in diabetic populations is less clear. This study investigated ACE genotypes in 100 patients with diabetes mellitus, of whom 41 were on anti-hypertensive medication. A significant association was found between the presence of the ACE-D allele and hypertension in both the overall diabetic group (D = 0.66, P < 0.01) and in the subset of diabetics who had non-insulin-dependent diabetes (D = 0.69, P < 0.001). There was no correlation of ACE genotype with hypertension in insulin-dependent diabetes (D = 0.57).

Ethnic origin and hypertension-associated alterations in sodium-lithium countertransport kinetics.

In Caucasian subjects, elevated erythrocyte sodium-lithium countertransport (SLC) activity, displaying an increased affinity for external Na+ (decreased KNa), has a strong association with hypertension and has also been proposed as a potential marker for vascular disease. We have compared SLC activity and the kinetic components, KNa and maximal rate of turnover (Vmax), of the countertransporter in groups of Caucasian, Asian and Black hypertensive subjects matched for ethnicity, age and sex with healthy normotensive controls. SLC activity was the same in all ethnic groups irrespective of the presence of hypertension. Similarly, hypertension had no impact on Vmax values within each ethnic group (normotensive vs. hypertensives: Caucasian, 0.360 +/- 0.186 vs. 0.335 +/- 0.137; Asian, 0.324 +/- 0.078 vs. 0.273 +/- 0.105; black people, 0.192 +/- 0.123 vs. 0.178 +/- 0.082 mmol Li/l erythrocytes h). However, in black people compared with the other two ethnic groups, Vmax was lower for both controls and hypertensives (P < 0.05; ANOVA). Median KNa values in hypertensive subjects were consistently lower than their normotensive counterparts in all ethnic groups (P < 0.01; Kruskal-Wallis); Caucasians, (89.1 vs. 41.2 mmol Na; P = 0.01), Asians (121.1 vs. 33.1; P = 0.04) and black people (74.4 vs. 27.2 mmol Na; P = 0.02; Wilcoxon). The results show that Vmax is altered in black people independently of the presence of hypertension. This contrasts with KNa which, for each ethnic group studied, is reduced in the hypertensive compared with the normotensive state.

Angiotensin-converting enzyme (ACE) gene polymorphism and the erythrocyte sodium-lithium countertransporter (SLC) phenotype in hypertension.

It has been suggested that the association between altered behaviour of the erythrocyte sodium-lithium countertransporter (SLC) and hypertension could be secondary to its association with the risk of vascular disease rather than raised blood pressure (BP) per se. Homozygosity for the angiotensin-converting enzyme (ACE) deletion allele has also been linked to a more severe phenotype for cardiovascular disease. The present study investigated whether there is an association between these two indicators of vascular risk in patients with hypertension. The kinetic characteristics of the countertransporter (SLC activity, Vmax and KNa) of patients having the ID ACE-genotype (n = 16) were compared with those patients who had the DD genotype (n = 12). The median (range) SLC activity (mmol Li/l Red Blood Cells.h) in the ID (0.221 [0.061-0.422]) and DD (0.173 [0.094-0.408]) groups were similar (P = 0.28; Mann-Whitney). No significant differences in Vmax (mmol Li/l RBC.h) emerged between the two study groups (0.279 + 0.124 [ID] vs 0.244 + 0.123 [DD]; P = 0.46; unpaired Student's t-test); similarly, no differences emerged between the two groups with respect to KNa (median [range]; ID, 39.8 [12.4-84.4] vs DD, 35.9 [14.6-78.3]; P = 0.47). These data suggest that the SLC phenotype and the ACE-D allele dose are risk factors for cardiovascular disease that function independently of one another.

Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in black normotensive subjects compared with three other ethnic groups.

Sodium-lithium countertransport activity has been proposed as a marker for hypertension and is lower in black compared to Caucasian subjects both with and without vascular disease. The question arises of what is the primary kinetic locus of the altered behaviour of the countertransporter in black subjects and whether this is also seen in normotensive subjects from other non-Caucasian ethnic groups. We studied the sodium-lithium countertransporter in four ethnic groups (black [n = 45], Caucasian [n = 45], Chinese [n = 40], and South Asian [n = 39]) of age-matched normotensive males (age range 18-35 y) with no first-degree family history of hypertension or diabetes. The clinical and laboratory characteristics of the subjects were similar in all four ethnic groups. Minor differences noted were: significantly higher mean height, weight and serum creatinine concentration (P < 0.001) and significantly lower plasma triglyceride concentration (P = 0.02) in the black compared to the other study groups. Sodium-lithium countertransport activity (mmol Li/l RBC h) was significantly lower in the black subjects (0.113 [0.013-0.265]) compared with the other groups (Caucasian, 0.247 [0.037-0.614]; Chinese, 0.210 [0.100-0.707]; South Asian, 0.211 [0.037-0.617]; P < 0.001). No differences were noted between the four study groups in respect of kNa. Mean (s.d.) Vmax values (mmol Li/l RBC h) were also reduced in the black subjects (0.152 [0.088]) compared to the other ethnic groups (Caucasian, 0.376 [0.159]; Chinese, 0.364 [0.182]; South Asian, 0.329 [0.155]; P < 0.001) and there was a strong relationship between countertransport activity and Vmax (r > 0.52; P < 0.001; for each of the study groups). The differences in mean Vmax noted between the Caucasian, South Asian and Chinese subjects were not significant. These results show that, when compared with three other selected ethnic groups, black subjects demonstrate an altered behaviour with respect to Vmax of the sodium-lithium countertransporter, which occurs in the absence of demonstrable vascular pathology.