Calcium-inhibitable calcium entry and blood pressure

Although at extremes of cytosolic and extracellular calcium levels, calcium ‘gates’ its own channel activity and exerts a ‘membrane stabilizing’ effect, it remains unknown whether these mechanisms operate at physiologic calcium levels, and/or are clinically relevant in regulating blood pressure. Therefore, we measured BP, PTH, renin, and intracellular and extracellular ion levels in 15 fasted essential hypertensive subjects before, and 60 and 120 minutes during a 2 hr. i.v. CaCl2 (10 mg/kg in 1 L 0.9% NaCl) infusion, utilizing ◊F-, 31P-, and 39K-NMR spectroscopy, ion-selective Ca- and K-specific electrodes, and standard RAI techniques. Serum ionized Ca (Ca-io, 1.12 ± 0.02 to 1.25 ± 0.02 mM, sig = 0.05) and K (3.6 ± 0.07 to 3.8 ± 0.07 mEq/l, sig = 0.05) rose within the normal range. Cytosolic free Ca (Cai) also rose (24 ± 3.5 to 41.7 ± 3.8 nM, sig = 0.05) while intracellular free K (Ki, 138 ± 1 to 132 ± 3 mEq/l, sig = 0.05) and free Mg (194 ± 12 to 179 ± 9 μM, sig = 0.05) fell. PTH (38.2 ± 7.6 to 8.2 ± 2.2 pg/ml, sig = 0.05) and plasma renin activity values (0.32 ± 0.01 to 0.23 ± 0.07, sig = 0.05) also fell. ΔCai was inversely related to basal Ca-io (r = −0.465, p = 0.034) and Cai levels (r = −0.404, p = 0.024)-i.e., the higher the basal Ca-io and Cai levels, the less Ca got into the cells. In turn, calcium-induced ΔSBP was also inversely related to basal Cai (r = −0.570, p < 0.01) and ΔCai (r = −0.554, p < 0.01) levels, respectively. We conclude that within the physiological range, i) the uptake of calcium from the extracellular space is negatively regulated by basal Ca-io and Cai levels, a phenomenon we term calcium-inhibitable calcium entry (CICE), and ii) that this phenomenon at least in part determines the contribution of calcium to blood pressure.