Elevated Na+/Li+ Countertransport and Cytosolic Ca2+ Represent Separate and Distinct Phenotypes in Essential Hypertension
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 (Cacyt) 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 Cacyt and red cell SLC activity in hypertensive (n = 43) and normal subjects (n = 22) to determine whether elevated SLC activity and lymphocyte Cacyt occur in the same individuals. Red cell SLC and lymphocyte Cacyt were significantly (P<0.01) higher in the hypertensive patients vs. normotensives. However, SLC activity and Cacyt were significantly but inversely correlated (r=-0.42, P<0.01). Patients with low Cacyt (84 ± 5 nM) had elevated SLC (0.41 ± 0.03 mmol/L cell x h, P< 0.05) whereas those with elevated Cacyt (188 ± 15) had lower SLC (0.32 ± 0.03 mmol/L cell x h, P< 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<0.01), consistent with prior studies showing elevated SLC activity in the setting of hyperinsulinemia. Cacyt was inversely correlated with fasting insulin (r=-0.55, P<0.001). Individuals with insulin levels above the median (15 mU/ml) had significantly (P<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 Cacyt(177 ± 18 vs. 105 ± 8 nM). Thus, elevated SLC activity and elevated lymphocyte Cacyt 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 Cacyt.