Magnesium Sulfate Potentiates Effect of Digifab on Marinobufagenin-Induced Na/K-ATPase Inhibition

• Published in: American journal of hypertension 2013-11, Vol.26 (11), p.1269-1272
• Main Authors: Zazerskaya, Irina E., Ishkaraeva, Valentina V., Frolova, Elena V., Solodovnikova, Nelly G., Grigorova, Yulia N., David Adair, C., Fedorova, Olga V., Bagrov, Alexei Y.
• Format: Article
• Language: English
• Subjects: Adult; Animals; Brief Communication; Bufanolides - blood; Case-Control Studies; Drug Evaluation, Preclinical; Drug Synergism; Erythrocytes - enzymology; Female; Humans; Immunoglobulin Fab Fragments - therapeutic use; Magnesium; Magnesium Sulfate - therapeutic use; Pre-Eclampsia - blood; Pre-Eclampsia - drug therapy; Pregnancy; Sheep; Sodium-Potassium-Exchanging ATPase - metabolism; Tocolytic Agents - therapeutic use
• ISSN: 0895-7061; 1941-7225
• DOI: 10.1093/ajh/hpt117

BACKGROUND Immunoneutralization of elevated circulating levels of endogenous digitalis-like Na/K-ATPase inhibitors (i.e. cardiotonic steroids (CTS)) represents a novel approach in the treatment of preeclampsia (PE). Recently we demonstrated that DigiFab (Fab fragments of affinity-purified ovine digoxin antibody) restores PE-induced inhibition of Na/K-ATPase in erythrocytes ex vivo. Previously magnesium ions were shown to antagonize digitalis-induced toxicity, which is mediated by Na/K-ATPase inhibition. We hypothesized that magnesium sulfate would potentiate the effect of DigiFab in the reversal of CTS-induced Na/K-ATPase inhibition. METHODS To test this hypothesis, we studied the ex vivo effect of DigiFab on Na/K-ATPase activity in erythrocytes from patients with PE in the absence and in the presence of 3 mmol/L magnesium sulfate. RESULTS Compared with 11 normotensive pregnant subjects (29±1 years; gestational age = 39.0±0.2 weeks; blood pressure = 111±2/73±2mm Hg), the 12 patients with PE (30±1 years; gestational age = 37.9±0.3 weeks; blood pressure = 159±5/99±3mm Hg) had plasma levels of marino bufagenin increased 3-fold (1.38±0.40 vs. 0.38±0.10 nmol/L; P < 0.01) and activity of Na/K-ATPase in erythrocytes was inhibited (1.16±0.11 vs. 2.80±0.20 μmol Pi/ml/h; P < 0.01). Ex vivo, DigiFab (1 µg/ml) restored erythrocyte Na/K-ATPase activity (1.72±0.13 µmol Pi/ml/h; P < 0.01), and 3 mmol magnesium sulfate potentiated the effect of DigiFab (2.30±0.20 µmol Pi/ml/h; P < 0.01). CONCLUSIONS Magnesium is capable of increasing the efficacy of immunoneutralization of marinobufagenin-induced Na/K-ATPase inhibition.