Altered ionic effects of insulin in hypertension: role of basal ion levels in determining cellular responsiveness.

Abstract

To investigate the ionic actions of insulin in hypertension, 19F- and 31P-nuclear magnetic resonance spectroscopy were used to measure cytosolic free calcium (Ca(i)) and intracellular free magnesium (Mg(i)) levels in red blood cells from normal (n = 9) and hypertensive (n = 9) subjects before and 30, 60, 120, and 180 min after in vitro incubation with insulin. In hypertensive patients, basal Ca(i) levels were significantly higher (30.0 +/- 2.2 vs. 19.8 +/- 2.5 nmol/L; P < 0.05), and basal Mg(i) levels were significantly lower (170 +/- 10.9 vs. 209 +/- 8 micromol/L; P < 0.05) than in normotensive subjects. In normal cells, insulin significantly elevated Ca(i) to 39.8 +/- 8.0, 50.1 +/- 8.2, 69.3 +/- 11.1, and 50.9 +/- 13.4 nmol/L at 30, 60, 120, and 180 min and Mg(i) to 238 +/- 10,264 +/- 14,226 +/- 11, and 216 +/- 10 micromol/L at 30, 60, 120, and 180 min. In hypertensive subjects, the insulin-dependent Ca(i) elevation was blunted, and Mg(i) accumulation was completely suppressed. Continuous relationships were observed between basal values of each ion and insulin responses; the greater the Ca(i), the less the Ca(i) rose (r = -0.574; P = 0.013), and the lower the Mg(i), the less Mg(i) rose (r = 0.524; P = 0.025). Furthermore, a blunting of Mg(i) responses to insulin could be reproduced in normal cells that were magnesium depleted by prior treatment either with A23187 in a calcium-free medium or with high glucose concentrations (15 mmol/L). Once again, insulin responsiveness followed basal Mg(i) levels (r = 0.637; P < 0.001). Together, these data demonstrate ionic aspects of insulin resistance in hypertension and suggest that Ca(i) and Mg(i) levels may regulate cellular responsiveness to insulin. This may help to explain the different vascular actions attributed to insulin in normal compared with insulin-resistant states such as hypertension.