Eleven normotensive pregnant subjects (29+/-1 years;gestational age, 39+/-2 weeks;blood pressure 114+/-2 / 74+/-2 mmHg) had plasma levels of marinobufagenin increased three-fold (1.38 +/-0.40 vs. 0.38 +/- 0.10 nmol/L;P<0.01) and lower activity of Na/K-ATPase in erythrocytes (1.16 +/- 0.11 vs. 2.80 +/- 0.20 micromol Pi/ml/hr;P<0.01) vs. 12 patients with PE (30 +/- 1 years;gestational age, 37.9 +/- 0.3 weeks;blood pressure 159 +/- 5 / 100 +/- 3 mmHg). Ex vivo, DigiFab (1 microgramm/mL) restored erythrocyte Na/K-ATPase activity (1.72 +/- 0.13 micromol Pi/ml/hr;P<0.01) and 3 mmol magnesium sulfate potentiated the effect of DigiFab (2.30 +/- 0.20 micromol Pi/ml/hr;P<0.01). The main observation of this study is that MgSO4 potentiates the effect of DigiFab with respect to reversal of preeclampsia-induced inhibition of Na/K-ATPase by an endogenous MBG. In preeclampsia, elevated plasma levels of MBG exhibit pro-hypertensive effect via inhibition of vascular Na/K-ATPase. Erythrocyte Na/K-ATPase is sensitive to endogenous CTS, and changes in its activity could serve as a marker characterizing the magnitude of CTS-dependent effects. Accordingly, in the present study heightened levels of MBG in patients with preeclampsia were associated with substantial inhibition of erythrocyte Na/K-ATPase, while ex vivo incubation of blood from preeclamptic patients in the presence of the CTS-neutralizing antibody, DigiFab, restored Na/K-ATPase activity. In the present study DigiFab ex vivo restored Na/K-ATPase activity, and an increase in levels of Mg2+ ions in incubation medium potentiated the effect of DigiFab. Accordingly, in vitro, MBG potently inhibited Na/K-ATPase in erythrocytes from control subjects and Mg2+ desensitized Na/K-ATPase to MBG. These findings agree with previous clinical data demonstrating that MgSO4 is capable of offsetting the deleterious cardiac effects of digitalis overdose, and that Mg2+ ions are capable of changing Na/K-ATPase conformation. Our present observations suggest that MgSO4 is capable of increasing the efficacy of DigiFab-mediated immunoneutralization of MBG-induced Na/K-ATPase inhibition in pathological states in which levels of CTS are elevated.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000869-06
Application #
8736639
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$445,413
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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Ishkaraeva-Yakovleva, Valentina V; Fedorova, Olga V; Solodovnikova, Nelly G et al. (2012) DigiFab interacts with endogenous cardiotonic steroids and reverses preeclampsia-induced Na/K-ATPase inhibition. Reprod Sci 19:1260-7
Haller, Steven T; Kennedy, David J; Shidyak, Amjad et al. (2012) Monoclonal antibody against marinobufagenin reverses cardiac fibrosis in rats with chronic renal failure. Am J Hypertens 25:690-6
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