title: Magnesium sulfate potentiates effect of DigiFab on marinobufagenin-induced Na/K-ATPase inhibition.
abstract: 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 ± 2 mm Hg), the 12 patients with PE (30 ± 1 years; gestational age = 37.9 ± 0.3 weeks; blood pressure = 159 ± 5/99 ± 3 mm 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.
authors.affiliation: Institutes of Neonatology and Heart and Vessels, Almazov Federal Heart, Blood and Endocrinology Center, St. Petersburg, Russia;
authors.forename: Irina E
authors.initials: IE
authors.lastname: Zazerskaya
authors.affiliation: Institutes of Neonatology and Heart and Vessels, Almazov Federal Heart, Blood and Endocrinology Center, St. Petersburg, Russia;
authors.forename: Valentina V
authors.initials: VV
authors.lastname: Ishkaraeva
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia;
authors.forename: Elena V
authors.initials: EV
authors.lastname: Frolova
authors.affiliation: Institutes of Neonatology and Heart and Vessels, Almazov Federal Heart, Blood and Endocrinology Center, St. Petersburg, Russia;
authors.forename: Nelly G
authors.initials: NG
authors.lastname: Solodovnikova
authors.affiliation: Institutes of Neonatology and Heart and Vessels, Almazov Federal Heart, Blood and Endocrinology Center, St. Petersburg, Russia; National Institute on Aging, National Institutes of Health, Baltimore, MD;
authors.forename: Yulia N
authors.initials: YN
authors.lastname: Grigorova
authors.affiliation: Department of Obstetrics and Gynecology, University of Tennessee, Chattanooga, Tennessee.
authors.forename: C
authors.initials: C
authors.lastname: David Adair
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, MD;
authors.forename: Olga V
authors.initials: OV
authors.lastname: Fedorova
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, MD; bagrova@mail.nih.gov.
authors.forename: Alexei Y
authors.initials: AY
authors.lastname: Bagrov
mesh_terms: D000328:Adult; D000818:Animals; D002018:Bufanolides / Q000097:blood*; D016022:Case-Control Studies; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D008278:Magnesium Sulfate / Q000627:therapeutic use*; D011225:Pre-Eclampsia / Q000097:blood / Q000188:drug therapy*; D011247:Pregnancy; D012756:Sheep; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D015149:Tocolytic Agents / Q000627:therapeutic use*
chemical_list: D002018:Bufanolides; D007140:Immunoglobulin Fab Fragments; D015149:Tocolytic Agents; C050199:digoxin antibodies Fab fragments; C093896:marinobufagenin; D008278:Magnesium Sulfate; D000254:Sodium-Potassium-Exchanging ATPase
keywords: NA/K-ATPase; blood pressure; cardiotonic steroids; digifab; digitalis-like factors; hypertension; immunotherapy; magnesium; marinobufagenin; preeclampsia.