Elevated Sodium-lithium Countertransport Activity Research Articles

Primate response to angiotensin infusion and high sodium intake differ by sodium lithium countertransport phenotype

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 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 activity would be associated with the least BP sensitivity, we found that the low SLC phenotype correlated with BP sensitivity similar to the high SLC phenotype, and the normal SLC phenotype showed the least BP sensitivity to dietary sodium and ANG II.

Increased red cell sodium-lithium countertransport and lymphocyte cytosolic calcium are separate phenotypes in patients with essential hypertension.

Increased red blood cell sodium-lithium countertransport (SLC) activity and elevated intracellular calcium have been observed in hypertensive patients. The association of these ion transport abnormalities with each other and with another phenotype, insulin resistance, has been suggested. We investigated whether elevated SLC activity and increased lymphocyte cytosolic calcium (Ca(cyt)) occur in the same individuals and whether either is associated with hyperinsulinaemia. We measured SLC activity, lymphocyte Ca(cyt)and fasting insulin levels in hypertensive patients and normal subjects. Consistent with prior studies, SLC activity was significantly and positively correlated with fasting insulin levels (r = 0.45, P < 0.01). However, SLC activity and lymphocyte Ca(cyt) were significantly but inversely correlated (r = -0.42, P < 0.01) and lymphocyte Ca(cyt) was also inversely correlated with fasting insulin (r = -0.55, P < 0.001). When the study participants were instead separated into two groups based on fasting insulin levels, those above the median (15 microU/ml) had significantly higher SLC activity and significantly lower Ca(cyt). When separated by lymphocyte Ca(cyt) levels (above or below 120 nM) those patients with low lymphocyte Ca(cyt) had significantly higher SLC activity and significantly higher insulin levels. Multiple linear regression showed that fasting insulin was significantly predictive of SLC activity (P = 0.05) and Ca(cyt) (P < 0.01). Thus, elevated SLC activity and increased lymphocyte Ca(cyt) are separate and distinct ion transport phenotypes in hypertensive patients, linked through a relationship to hyperinsulinaemia that is direct with SLC activity and inverse with lymphocyte Ca(cyt).

Elevated Na+/Li+ Countertransport and Cytosolic Ca2+ Represent Separate and Distinct Phenotypes in Essential Hypertension

P124 Attempts to understand the pathogenesis of essential hypertension have focused on identifying intermediate phenotypes such as defects in cation metabolism. Elevated red blood cell sodium-lithium countertransport (SLC) activity is frequently present in hypertensive patients. Cytosolic calcium (Ca cyt ) is also elevated in blood cells from hypertensive patients. However, despite their frequent occurrence in hypertensive patients, these two markers of cation homeostasis have not been simultaneously investigated in the same individuals. We studied lymphocyte Ca cyt and red cell SLC activity in hypertensive (n = 43) and normal subjects (n = 22) to determine whether elevated SLC activity and lymphocyte Ca cyt occur in the same individuals. Red cell SLC and lymphocyte Ca cyt were significantly ( P vs. normotensives. However, SLC activity and Ca cyt were significantly but inversely correlated (r=-0.42, P cyt (84 ± 5 nM) had elevated SLC (0.41 ± 0.03 mmol/L cell x h, P cyt (188 ± 15) had lower SLC (0.32 ± 0.03 mmol/L cell x h, P P cyt was inversely correlated with fasting insulin (r=-0.55, P P vs . 0.28 ± 0.02 mmol/L cell x h) and significantly ( P =0.017) lower Ca cyt (177 ± 18 vs. 105 ± 8 nM). Thus, elevated SLC activity and elevated lymphocyte Ca cyt are separate and distinct ion transport phenotypes in hypertensive patients, but they are linked through a relationship to hyperinsulinemia that is direct with SLC and inverse with lymphocyte Ca cyt .

Elevated Na + /Li + Countertransport and Cytosolic Ca 2+ Represent Separate and Distinct Phenotypes in Essential Hypertension

P124 Attempts to understand the pathogenesis of essential hypertension have focused on identifying intermediate phenotypes such as defects in cation metabolism. Elevated red blood cell sodium-lithium countertransport (SLC) activity is frequently present in hypertensive patients. Cytosolic calcium (Ca cyt ) is also elevated in blood cells from hypertensive patients. However, despite their frequent occurrence in hypertensive patients, these two markers of cation homeostasis have not been simultaneously investigated in the same individuals. We studied lymphocyte Ca cyt and red cell SLC activity in hypertensive (n = 43) and normal subjects (n = 22) to determine whether elevated SLC activity and lymphocyte Ca cyt occur in the same individuals. Red cell SLC and lymphocyte Ca cyt were significantly ( P &lt;0.01) higher in the hypertensive patients vs. normotensives. However, SLC activity and Ca cyt were significantly but inversely correlated (r=-0.42, P &lt;0.01). Patients with low Ca cyt (84 ± 5 nM) had elevated SLC (0.41 ± 0.03 mmol/L cell x h, P&lt; 0.05) whereas those with elevated Ca cyt (188 ± 15) had lower SLC (0.32 ± 0.03 mmol/L cell x h, P&lt; 0.05). We then compared both phenotypes to a separate intermediate phenotype, fasting insulin. SLC and fasting insulin levels were significantly and positively correlated (r=0.45, P &lt;0.01), consistent with prior studies showing elevated SLC activity in the setting of hyperinsulinemia. Ca cyt was inversely correlated with fasting insulin (r=-0.55, P &lt;0.001). Individuals with insulin levels above the median (15 mU/ml) had significantly ( P &lt;0.01) higher SLC activity (0.43 ± 0.03 vs . 0.28 ± 0.02 mmol/L cell x h) and significantly ( P =0.017) lower Ca cyt (177 ± 18 vs. 105 ± 8 nM). Thus, elevated SLC activity and elevated lymphocyte Ca cyt are separate and distinct ion transport phenotypes in hypertensive patients, but they are linked through a relationship to hyperinsulinemia that is direct with SLC and inverse with lymphocyte Ca cyt .

Nisoldipine blocks the increase of intracellular free calcium-ion concentration associated with elevated sodium-lithium countertransport activity in erythrocytes in patients with NIDDM.

To understand the mechanism by which elevated sodium-lithium countertransport activity (SLC) associates with increased intracellular free calcium-ion concentration ([Ca2+]i), we investigated the relationship between SLC and the effects of the extracellular Ca2+ concentration ([Ca2+]o) and a Ca2(+)-channel blocker, nisoldipine, on [Ca2+]i in erythrocytes from 48 patients with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM). There was a significant correlation between SLC and [Ca2+]i. Nisoldipine in the incubation medium significantly decreased [Ca2+]i, and there was a significant positive correlation between SLC and the degree of [Ca2+]i decrease. When the [Ca2+]o was elevated, [Ca2+]i was significantly increased, but nisoldipine almost completely suppressed this increase of [Ca2+]i. There was a significant positive correlation between SLC and the degree of the suppression. These data suggest that elevated SLC correlates with increased [Ca2+]i, and that the increased [Ca2i]i might be due to the increased Ca2+ influx through a dihydropyridine-sensitive Ca2+ pathway.

Nisoldipine blocks the increase of intracellular free calcium‐ion concentration associated with elevated sodium–lithium countertransport activity in erythrocytes in patients with NIDDM

Nisoldipine blocks the increase of intracellular free calcium‐ion concentration associated with elevated sodium–lithium countertransport activity in erythrocytes in patients with NIDDM

Elevated sodium-lithium countertransport activity in erythrocytes is predictive of the development of microalbuminuria in IDDM.

Pathogenetic mechanisms other than the quality of metabolic control may play a role in the development of diabetic nephropathy. Some cross-sectional studies have shown that elevated erythrocyte sodium-lithium countertransport (Na+/Li+ CT) activity may be linked to incipient or overt nephropathy in insulin-dependent diabetic (IDDM) patients. The aim of the present work was to ascertain if high erythrocyte Na+/Li+ CT activity anticipates the development of microalbuminuria in IDDM patients. Evaluation of this cation transport system was carried out in 159 normotensive, normoalbuminuric IDDM patients, who were divided into two groups: those with values above (Group A) and those with values below (Group B) the median level in the overall population (300 mumol/erythrocytes x h). A total of 79 patients in Group A and 80 in Group B underwent periodic examinations over a similar time period (5.2 years, range 3.3-7.4 years and 5.4 years, range 3.4-7.5 years, respectively). Median sodium-lithium countertransport activity was stable when evaluated after 2 and 4 years of follow-up. Only seven patients were excluded from the protocol because changes in their sodium-lithium countertransport activity placed them on the other side of the median value with respect to their baseline measurement. Thus, 152 patients completed the study (76 in Group A and 76 in Group B). Of the 76 patients in Group A, 17 developed persistent microalbuminuria (22.3%). The number of patients in Group B showing persistent microalbuminuria was significantly lower (4 of 76; 5.2%; p < 0.01). The sensitivity of erythrocyte Na+/Li+ CT in predicting the development of microalbuminuria was 85% and its specificity was 55%. Seven patients of Group A and five of Group B developed arterial hypertension. Subjects in Group A had significantly higher mean HbA1c values of twice yearly measurements than those in Group B (9.6 +/- 1.7 vs 8.3 +/- 1.7%, p < 0.002, mean +/- SD) despite similar daily insulin requirements. Systolic and diastolic blood pressure levels were also evaluated every 6 months and were significantly higher in the Group A than in the Group B patients, although on average within the normal range. The odds ratio for developing persistent microalbuminuria in IDDM with elevated baseline erythrocyte Na+/Li+ CT activity after adjustment for gender and baseline albumin excretion rate, and mean 6 monthly plasma creatinine, HbA1c and systolic and diastolic blood pressure levels was 4.2 (95% confidence intervals 2.0-11.1). It was also found that the percentage of offspring having both parents with Na+/Li+ CT activity above the median value was significantly higher in Group A than in Group B (Group A vs Group B: 35 vs 19%; p < 0.01). On the contrary the percentage of offspring whose erythrocyte Na+/Li+ CT was lower in both parents was lower in Group A than in Group B: 10 vs 38%, p < 0.01). Parents of Group A offspring had arterial hypertension more frequently than those of Group B. These results indicate that erythrocyte Na+/Li+ CT activity is a useful diagnostic tool in identifying normotensive, normoalbuminuric patients who may be predisposed to develop persistent microalbuminuria. This disorder in the cation transport system is associated with poor metabolic control, higher blood pressure, and male sex; it also appears to be, at least partly, genetically transmitted.

Sodium-lithium countertransport is associated with insulin resistance and urinary albumin excretion in young African-Americans

Increased activity of the sodium transporter, sodium-lithium countertransport (SLC), is reported in hypertensive white patients with evidence of cardiac and renal injury. The purpose of this study was to determine whether increased SLC activity detects risk for nephropathy or vascular disease in nondiabetic, young adult African- Americans. We examined 85 African-Americans aged 25 to 33 years with measurement of blood pressure, an oral glucose tolerance test to measure insulin response to glucose challenge, and an insulin clamp for insulin sensitivity (M). Fasting plasma lipids were measured, and the V max and K m for Na + were assayed on red blood cells. Urinary albumin excretion (UAE) was measured on timed collections. There was a statistically significant correlation of the V max for SLC with M ( r = −0.26, P = 0.02) and with UAE ( r = 0.25, P = 0.02). The K m for Na + to activate SLC was also elevated in the subgroup of subjects with elevated V max of SLC. There was no significant correlation of SLC with blood pressure in bivariate analysis. Step-wise multiple linear regression analysis of all variables on the V max SLC demonstrated that plasma triglyceride, UAE, body mass index, systolic blood pressure, M, and fasting insulin were step-wise selected into the linear regression model (F-ratio = 3.2, df = 77, R = 0.46, P < 0.009). In this young adult African-American population, elevated SLC activity is detected in association with metabolic and lipid alterations typical of insulin resistance. Elevated SLC activity is also associated with higher rates of UAE, suggesting possible evidence of early renal injury.

Elevated Erythrocyte Sodium-lithium Countertransport Activity Correlates with Increased Intracellular Sodium and Free Calcium-ion Concentration in Type 2 Diabetes

To explore the mechanism by which elevated sodium-lithium countertransport activity (SLC) associates with both predisposition to hypertension and diabetic nephropathy, we investigated the interrelationships among SLC, intracellular sodium concentration ([Na]i), intracellular free calcium-ion concentration ([Ca2+]i), diabetic nephropathy, hypertension, family history of hypertension, and other factors in 48 patients with Type 2 diabetes and 24 healthy controls. There was a significant correlation between SLC and [Na]i (r = 0.36, p < 0.05), [Na]i and [Ca2+]i (r = 0.47, p < 0.01), SLC and [Ca2+]i (r = 0.46, p < 0.01), and between HbA1c and [Ca2+]i (r = 0.38, p < 0.01). Both [Na]i and [Ca2+]i were significantly higher in the patients with elevated SLC than in those with normal SLC (p < 0.01 and p < 0.05, respectively). In stepwise multivariate regresssion analysis, [Na]i, HbA1c, and SLC appeared as independent determinants of [Ca2+]i. These data suggest a significant correlation of elevated SLC with increased [Na]i and [Ca2+]i. This may be a possible mechanism underlying the close association of elevated SLC with both predisposition to hypertension and diabetic nephropathy.

The concomitants of elevated erythrocyte sodium - lithium countertransport activity in diabetic nephropathy: a critical assessment

Elevated erythrocyte sodium-lithium countertransport activity is an intermediate phenotype of essential hypertension among Caucasians, and may also associate with kidney disease in type 1 (insulin-dependent) diabetes mellitus. Evidence supporting the hypothesis that an inherited predisposition to essential hypertension may thus partly identify with the genetic background of susceptibility to diabetic nephropathy is, however, controversial. This review discusses the possible points of controversy, with emphasis upon the need to standardize the manifest heterogeneity in the current techniques of measurement, as well as upon the clinical concomitants and interpretation of elevated sodium-lithium countertransport activity in type 1 diabetes mellitus. Large family studies may be required in order to single out the independent contributions of genes and environment to sodium-lithium countertransport activity in type 1 diabetes mellitus. However, the original hypothesis that genes underlying elevated sodium-lithium countertransport in essential hypertension and in diabetic nephropathy may also reflect in part a predisposition to diabetic kidney disease cannot be rejected on the basis of current evidence.

Increase in Glomerular Filtration Rate in Patients with Insulin-Dependent Diabetes and Elevated Erythrocyte Sodium–Lithium Countertransport

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.

Increased sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy.

Susceptibility to diabetic nephropathy may be related to a predisposition to arterial hypertension. We have studied the activity of sodium-lithium countertransport in red cells, a marker of risk for essential hypertension, in white European adults with insulin-dependent diabetes and diabetic nephropathy, a matched group of patients with diabetes without renal disease, and nondiabetic patients with renal disease. Measures of metabolic control and concentrations of plasma free insulin and growth hormone were similar in the two diabetic groups. The degree of impairment in renal function was similar in the diabetic and nondiabetic patients with renal disease. Body-mass index and plasma potassium concentrations were similar in all three groups. Diastolic blood pressure was elevated to a similar degree in the two groups with renal disease, as compared with that in the diabetic patients without renal disease. The rates of sodium-lithium countertransport in red cells were significantly higher in the diabetic patients with renal disease (mean +/- SD, 0.55 +/- 0.19 mmol of lithium per liter of red cells per hour) than in the diabetic patients without renal disease (0.33 +/- 0.16; P less than 0.005) and in the nondiabetic patients with renal disease (0.31 +/- 0.14; P less than 0.001). Predisposition to hypertension, as indicated by elevated sodium-lithium countertransport activity in red cells, may serve as a marker for the risk of renal disease in patients with insulin-dependent diabetes.