Red blood cell Na+/H+ exchange activity is insulin resistant in hypertensive patients

A number of ion transport defects have been described in human red blood cells (RBC) from patients with essential hypertension. Insulin resistance is also frequently present in hypertensive patients and insulin levels in vitro correlate with red blood cell Na+/H+ exchange (NHE) activity. We studied the kinetics of insulin-stimulated NHE activity in freshly isolated RBC from 14 patients with essential hypertension and 8 normotensive subjects. We measured an estimate of maximal activity (Vmax) for NHE activity as net Na+ influx driven by an outward H+ gradient in acid-loaded and Na+-depleted erythrocytes. NHE activity was significantly greater in hypertensives than in normotensives (22.0 vs 14.5 mmol/L cell x h, respectively; P<0.01). When RBC were pre-incubated with a physiologic dose of insulin (100 microU/mL), NHE activity increased significantly in both groups but the increase was greater in normotensives than in hypertensives (9.6 vs 8.5 mmol/L cell x h, respectively; P < 0.05). Phosphatidylinositol-3 kinase (PI-3 kinase) inhibitors, wortmannin and LY294,002, had no effect on basal NHE activity but similarly and significantly inhibited insulin-stimulated NHE activity in both normal and hypertensive subjects. Insulin increased the Km for extracellular Na+ in normotensive subjects but not in hypertensive patients. In addition, the dose response curve for insulin and NHE activity showed that the curve for hypertensive patients was shifted rightward in relation to the normotensive subjects. These data suggest that insulin stimulates RBC NHE activity in vitro and this activation is mediated via a pathway that includes activation of PI-3 kinase. Hypertensive patients have elevated basal NHE activity but a blunted response to insulin suggesting that RBC may be a model to study insulin resistance in essential hypertensive patients.