Sodium-Lithium Countertransport Has Low Affinity for Sodium in Hyperinsulinemic Hypertensive Subjects

Abstract

Abstract We recently reported that incubation of red blood cells with insulin markedly decreases the affinity for external Na + and increases the maximal transport rate ( V max ) of Na + -Li + countertransport. The association of hypertension with insulin resistance and its compensatory hyperinsulinemia led us to investigate the relationship between insulin levels in vivo and the Na + activation kinetics of this antiporter. We studied normotensive (n=28) and hypertensive (n=25) subjects after they had fasted overnight and determined their plasma glucose and insulin concentrations. Insulin levels were higher in the hypertensive subjects (11.7±1.5 μU/mL, mean±SEM) than in the normotensive subjects (8.2±1.2 μU/mL), but glucose levels were similar and within normal limits. Antiporter activity was measured as sodium-stimulated Li + efflux by a new procedure that uses isosmotic conditions to raise external Na + to 280 mmol/L. In normotensive subjects, V max was reached between 50 and 100 mmol/L Na + , whereas in most hypertensive subjects, Na + concentrations higher than 150 mmol/L were needed. This different kinetic behavior was because the Na + concentration for half-maximal activation ( K m ) was twofold higher in hypertensive subjects (58.9±5.3 mmol/L) than in normotensive subjects (29.8±2.6 mmol/L, P <.001). Hypertensive subjects with fasting insulin levels greater than 10 μU/mL (n=12) had a higher K m for Na + than subjects with insulin levels less than 10 μU/mL (n=13) (73.4±8.7 versus 45.6±3.9 mmol/L, respectively, P <.01) and similar V max (0.57±0.05 versus 0.41±0.05 mmol · L −1 · h −1 ). In contrast, normotensive subjects with insulin levels greater than 10 μU/mL (n=6) had V max and K m values similar to those with insulin levels less than 10 μU/mL (n=22). Simple regression analysis showed that body mass index, insulin, and blood pressure correlated with both kinetic parameters. However, stepwise multiple regression analysis showed that the main determinant of V max was blood pressure and for K m , blood pressure and insulin levels. The association of a low affinity for Na + with in vivo hyperinsulinemia and its concomitant insulin resistance observed in hypertensive subjects agrees with the in vitro effects of insulin on this antiporter.