Intracellular ionic consequences of dietary salt loading in essential hypertension. Relation to blood pressure and effects of calcium channel blockade.

Abstract

To study the ionic basis of salt sensitivity in hypertension, Tl_-, 31p-, and 'Na-nuclear magnetic resonance techniques were used to measure cytosolic free calcium (Ca1), pH (pH,), free magnesium (Mg1), and sodium (Na4) in erythrocytes of essential hypertensive subjects (n = 19). Individuals were studied for 2 mo each on low-(UNaV < 50 meq/d) and high-(UNaV > 200 meq/d) salt diets, with the concomitant administration of nifedipine (10 mg t i.d.) or placebo tablets for 1 mo of each diet. Salt loading elevated Ca1 and Na1 while suppressing Mg, and pH,; these changes occurred predominantly in salt-sensitive subjects (n = 9). Nifedipine blunted the pressor response to salt loading > 50% (A diastolic BP [high-low salt vs placebo] = 5±2 vs 14±2 mmHg, P < 0.05) and reversed salt-induced ionic changes, lowering Cal and elevating Mg& and pHi. Regardless of the definition of salt sensitivity, continuous relationships were observed between the pressure response to salt loading, the levels of Ca1 (r = 0.726, P < 0.001), Nai (r = 0.747, P < 0.001), and pH1 (r = -0.754, P < 0.001), and the salt-induced change in Mg& (r = -0.757, P < 0.001). Altogether, these results emphasize the reciprocal and coordinate nature of intracellular ionic changes in response to dietary salt loading and calcium channel blockade in essential hypertension. They suggest that salt sensitivity is mediated by cellular calcium accumulation from the extracellular space, in association with magnesium depletion and acidification. Lastly, interpretation of intracellular ion measurements in the future will require concurrent assessment of dietary salt intake. (J. Clin. Invest. 1994. 94:1269-1276

Abnormal platelet Ca2+handling accompanied by increased cytosolic free Mg2+in essential hypertension

“…Our basal [Ca 2ϩ ] i level probably reflects improved methods with minimal activation of platelets and correction for dye leakage from platelets. Recent data from careful investigations of methods have shown basal [Ca 2ϩ ] i in human platelets as low as the level determined in our study (6,11,17,27).…”

“…Resnick et al (26,27) previously described a decrease in intraerythrocyte concentration of free Mg 2ϩ in essential hypertension based on studies employing nuclear magnetic resonance spectroscopy. Results contrary to ours may be due to differences in the cells used for [Mg 2ϩ ] i measurement.…”

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

“…However, in a previous report we showed that lymphocyte Na + -H + exchange is elevated in hypertensive patients 12 and a number of previous studies have confirmed elevated Ca cyt in red cells from hypertensive patients. 9,26 It is not clear what mechanism(s) mediate the in vitro phenomenon of elevated red cell SLC activity or increased Ca cyt in hypertensive patients. However, elevated SLC activity is not only present in patients with essential hypertension but also in patients with diabetic nephropathy and is a predictor of progression to microalbuminuria in nondiabetics.…”

“…6 However, SLC activity may be affected by other intracellular processes such as protein kinase C (PKC) 7 and cell calcium. 8 In this regard, increased cell calcium is present in red blood cells, platelets and lymphocytes from hypertensive patients [9][10][11][12] and has a multimodal distribution in hypertensives. 12 Cell calcium may also be modulated by insulin 13 and increased intracellular calcium has been associated with insulin resistance.…”

Catecholamine-induced vasoconstriction is sensitive to carbonic anhydrase I activation

“…Furthermore, nifedipine consistently elevated intracellular pH values (23). An enhanced activity of the H + -Na + antiporter (as a major mechanism of cell defense against cellular acidification) has been reported in lymphocytes (24) as well as in the renal brush border membrane of spontaneously hypertensive rats (25) and in hypertensive rats (26).…”