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Altered Ionic Effects of Insulin in Hypertension: Role of Basal Ion Levels in Determining Cellular Responsiveness

Cardiovascular Center, Cornell University Medical Center (M.B., L.M.R.), New York, New York 10021; the Division of Endocrinology/Hypertension, Wayne State University Medical Center (M.B., O.B., M.B., L.M.R.), Detroit, Michigan 48201; and the Department of Physiology, Albert Einstein College of Medicine (R.K.G), Bronx, New York 10463

Address all correspondence and requests for reprints to: L. M. Resnick, M.D., Division of Endocrinology and Hypertension, Wayne State University Medical Center, University Health Center-4H, 4201 St. Antoine, Detroit, Michigan 48201.

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 µmol/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 µmol/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.

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