Alterations of cell ion content have been reported acutely after oral glucose ingestion, and chronically in subjects with hypertension and noninsulin dependent diabetes mellitus (NIDDM). We have hypothesized that these ionic abnormalities, elevated cytosolic free calcium (Cai), and suppressed intracellular pH (pHi) and free magnesium (Mgi), common to both of these syndromes, may explain their frequent clinical coincidence. To investigate the potential role of glucose in this process, we utilized 19F- and 31P-NMR spectroscopy to measure Cai, Mgi, and pHi in normal human red blood cells before and 60, 120, and 180 min after in vitro incubation with glucose (15 mmol/L) and equimolar concentrations of the glucose analogs, L-glucose, 2-deoxyglucose, and 3-O-methylglucose. At each point in time (from t = 0 to t = 60, 120, 180 min), glucose induced significant (P < .05) elevations in Cai (27.2 +/- 2.2 to 68.3 +/- 7.2, 70.7 +/- 10.5, 59.8 +/- 10.1 nmol/L), while suppressing pHi (7.28 +/- 0.02 to 7.22 +/- 0.03, 7.23 +/- 0.03, 7.22 +/- 0.03), and Mgi (206 +/- 10 to 151 +/- 7, 131 +/- 7, 143 +/- 5 mumol/L). This glucose induced ionic effect was dose dependent, significant elevations in Cai being observed at 10 and 15 mmol/L, but not at the other concentrations tested. It was also specific, no changes in Cai being observed with any of the glucose analogs tested. Thus, hyperglycemia per se elevates Cai and suppresses Mgi and pHi in normal human red cells.(ABSTRACT TRUNCATED AT 250 WORDS)