Human hypertensive placenta contains an increased amount of Na, K‐ATPase with higher affinity for cardiac glycosides

Amler, Evžen; Cester, N.; Salvolini, Eleonora; Staffolani, R.; Burkhard, Martin; Mazzanti, Laura; Romaninï, Carlo

doi:10.1006/cbir.1994.1101

Cited by 14 publications

(8 citation statements)

References 7 publications

(8 reference statements)

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“…Observations of the antihypertensive activity of Digibind in preeclampsia agree with the results of studies demonstrating that Digibind produces vasorelaxation in isolated perfused preeclamptic placentae [16]. Moreover, it has also been observed that the Na/K-ATPase from preeclamptic placentae exhibited heightened sensitivity to CTS [21]. The mechanism underlying the antihypertensive effects of Digibind is based on the cross-reactivity with endogenous CTS; this is illustrated by several observations including the restoration of erythrocyte Na/K-ATPase activity by Digibind ex vivo [13,14] and the reduction in plasma Na/K-ATPase inhibitory activity following Digibind infusion [22].…”

Section: Discussionsupporting

confidence: 80%

Interaction of Digibind with endogenous cardiotonic steroids from preeclamptic placentae

Федорова

Tapilskaya²,

Bzhelyansky

et al. 2010

Journal of Hypertension

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Background-Preeclampsia (PE) is a major cause of maternal and fetal mortality, and its pathogenesis is not fully understood. Endogenous digitalis-like cardiotonic steroids (CTS) have been implicated in the pathophysiology of PE; this is illustrated by clinical observations that Digibind, a therapeutic digoxin antibody fragment which binds CTS, lowers blood pressure and reverses Na/KATPase inhibition in patients with PE. Recently we reported that plasma levels of marinobufagenin (MBG), a bufadienolide vasoconstrictor CTS, are increased four-fold in patients with severe PE.

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Section: Discussionsupporting

confidence: 80%

Interaction of Digibind with endogenous cardiotonic steroids from preeclamptic placentae

Федорова

Tapilskaya²,

Bzhelyansky

et al. 2010

Journal of Hypertension

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“…In preeclampsia however, plasma and placental levels of CTS, and especially MBG, become substantially elevated and associate with heightened arterial pressure and inhibition of erythrocyte Na/K-ATPase (5–7,13). Moreover, in PE placental vascular bed exhibits heightened sensitivity to CTS-induced vasoconstriction (25). Recent evidence, however, indicates that the contribution of CTS to PE is not limited to only vasoconstriction.…”

Section: Discussionmentioning

confidence: 99%

DigiFab Interacts With Endogenous Cardiotonic Steroids and Reverses Preeclampsia-Induced Na/K-ATPase Inhibition

Ishkaraeva-Yakovleva¹,

Федорова

Солодовникова³

et al. 2012

Reprod. Sci.

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Elevated levels of endogenous Na/K-ATPase (NKA) inhibitors, cardiotonic steroids (CTS) including marinobufagenin (MBG), contribute to pathogenesis of preeclampsia (PE) and represent a target for immunoneutralization by Digibind (Ovine Digoxin Immune Antibody, Glaxo-Smith Kline). Because Digibind is no longer commercially available we studied whether DigiFab (BTG International Ltd, UK) can substitute Digibind for immunoneutralization of CTS in patients with PE. We compared DigiFab, Digibind and anti-MBG monoclonal antibody (mAb) with respect to their ability to interact with CTS in PE plasma and to restore NKA activity in erythrocytes from patients with PE. Using immunoassays based on DigiFab, Digibind, and anti-MBG mAb we studied the elution profile of CTS following HPLC-fractionation of PE plasma. Seven patients with mild PE (28±2 years; gestational age, 39±0.5 weeks; blood pressure 156±5/94±2 mmHg) and six normotensive pregnant subjects (28±1 years; gestational age, 39±0.4 weeks; blood pressure 111±2/73±2 mmHg) were enrolled. PE was associated with a substantial inhibition of erythrocyte NKA (1.47±0.17 vs. 2.65±0.16 μmol Pi/mL/hr in control group, P<0.001). Ex vivo, at concentration 10 μg/mL, which is consistent with the clinical dosing of Digibind administered previously in PE, DigiFab and Digibind as well as anti-MBG mAb (0.5 μg/mL) restored erythrocyte NKA activity. Following HPLC fractionation of pooled PE and control plasma, PE-associated increase in CTS material was detected by Digibind (176 vs. 75 pmoles), DigiFab (221 vs. 70 pmoles) and anti-MBG mAb (1056 vs. 421 pmoles). Therefore, because DigiFab interacts with CTS from PE plasma and reverses PE-induced NKA inhibition, it can substitute Digibind for immunoneutralization of CTS in patients with PE.

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“…However, this study remains prospective, and all the different aspects of this regulation need to be investigated in the future, including the precise regulatory mechanisms involved, as well as the time course of recorded changes during pregnancy and the effect of the endogenous analogue of ouabain. At the same time, it is noteworthy that in hypertensive pregnancies, the presence of a greater number of Na + –K + ‐ATPase molecules (Amler et al 1994 a , b ) suggests a lack of decrease in the sodium pump proteins (Graves et al 1995; Martinka et al 1996; Lopatin et al 1999; Fedorova et al 2005). In addition, Na + –K + ‐ATPase is known to be regulated by angiotensin and aldosterone, hormones that are increased in normal pregnancy, but blunted in pregnancy‐induced hypertension (Mihailidou et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Regulation of the sodium pump during cardiomyocyte adaptation to pregnancy

Elzwiei

Bassien-Capsa

St‐Louis

et al. 2012

Experimental Physiology

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New findings r What is the central question of this study?Pregnancy leads to sustained increases in cardiac output and stroke volume. The cellular mechanisms underlying the associated changes in myocardial function are poorly understood. We investigated the role of the sodium pump in the functional adaptations of cardiomyocytes to normal pregnancy. r What is the main finding and its importance?We found that in normal pregnancy the expression of the α1 Na + -K + -ATPase isoform is reduced in cardiomyocytes, and there is decreased sodium pump membrane current and elevated steady-state intracellular sodium. Our findings suggest an important role for reduced expression and activity of the myocardial membrane sodium pump in the cardiac adaptations to pregnancy.Regulation of the sodium pump during normal pregnancy and its effect on the function of cardiomyocytes is poorly understood. Our objective was to evaluate the possible implication of the Na + -K + -ATPase, the sodium pump which controls cellular ionic and metabolic homeostasis, in the adaptations of cardiomyocytes to normal pregnancy. We have used Western blots and patch-clamp measurements to identify changes in the sodium pump proteins. Confocal microscopy was applied to estimate intracellular sodium concentration. Time-resolved spectroscopy was employed to measure mitochondrial NAD(P)H fluorescence and estimate oxidative metabolic state. Optical microscopy was adopted to study the contractility responses of cardiomyocytes. Cells from non-pregnant and pregnant rats (1 day prior parturition) were studied. Our results showed lower protein expression of the α1 Na + -K + -ATPase isoform in cardiomyocytes in pregnant rats, decreased sodium pump membrane current and elevated steady-state sodium concentration. In addition, ouabain, the inhibitor of the sodium pump capable of increasing cardiomyocyte contractility in non-pregnant rats in a concentrationdependent manner, failed to affect cell contractions in pregnant rats. We also noted modified responsiveness of the mitochondrial metabolic state to ouabain in cardiac cells. The gathered data confirmed that in pregnant rats, the sodium pump protein content and transmembrane flux are decreased, while the sensitivity of cardiomyocyte contractility and the sensitivity of mitochondrial metabolic redox state to ouabain are modified, pointing to regulation of the Na + -K + -ATPase during cardiac cell adaptations to normal pregnancy.

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Human hypertensive placenta contains an increased amount of Na, K‐ATPase with higher affinity for cardiac glycosides

Cited by 14 publications

References 7 publications

Interaction of Digibind with endogenous cardiotonic steroids from preeclamptic placentae

Interaction of Digibind with endogenous cardiotonic steroids from preeclamptic placentae

DigiFab Interacts With Endogenous Cardiotonic Steroids and Reverses Preeclampsia-Induced Na/K-ATPase Inhibition

Regulation of the sodium pump during cardiomyocyte adaptation to pregnancy

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