Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension

Olga V. Fedorova, Andrey S. Simbirtsev, Nikolai I. Kolodkin, Alexander Y. Kotov, Natalia I. Agalakova, Vladimir A. Kashkin, Natalia I. Tapilskaya, Anton Bzhelyansky, Vitaly A. Reznik, Elena V. Frolova, Elena R. Nikitina, Georgy V. Budny, Dan L. Longo, Edward G. Lakatta, Alexei Y. Bagrov

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Levels of marinobufagenin (MBG), an endogenous bufadienolide Na/K-ATPase (NKA) inhibitor, increase in preeclampsia and in NaCl-sensitive hypertension. METHODS: We tested a 3E9 monoclonal anti-MBG antibody (mAb) for the ability to lower blood pressure (BP) in NaCl-sensitive hypertension and to reverse the preeclampsia-induced inhibition of erythrocyte NKA. Measurements of MBG were performed via immunoassay based on 4G4 anti-MBG mAb. RESULTS: In hypertensive Dahl-S rats, intraperitoneal administration of 50 μg/kg 3E9 mAb lowered BP by 32 mmHg and activated the Na/K-pump in the thoracic aorta by 51%. NaCl supplementation of pregnant rats (n = 16) produced a 37 mmHg increase in BP, a 3.5-fold rise in MBG excretion, and a 25% inhibition of the Na/K-pump in the thoracic aorta, compared with pregnant rats on a normal NaCl intake. In eight pregnant hypertensive rats, 3E9 mAb reduced the BP (21 mmHg) and restored the vascular Na/K-pump. In 14 patients with preeclampsia (mean BP, 126 ± 3 mmHg; 26.9 ± 1.4 years; gestational age, 37 ± 0.8 weeks), plasma MBG was increased three-fold and erythrocyte NKA was inhibited compared with that of 12 normotensive pregnant women (mean BP, 71 ± 3 mmHg) (1.5 ± 0.1 vs. 3.1 ± 0.2 μmol Pi/ml/h, respectively; P < 0.01). Ex-vivo 3E9 mAb restored NKA activity in erythrocytes from patients with preeclampsia. As compared with 3E9 mAb, Digibind, an affinity-purified antidigoxin antibody, was less active with respect to lowering BP in both hypertensive models and to restoration of NKA from erythrocytes from patients with preeclampsia. CONCLUSION: Anti-MBG mAbs may be a useful tool in studies of MBG in vitro and in vivo and may offer treatment of preeclampsia.

Original languageEnglish (US)
Pages (from-to)2414-2425
Number of pages12
JournalJournal of hypertension
Volume26
Issue number12
DOIs
StatePublished - Dec 2008
Externally publishedYes

Keywords

  • Marinobufagenin
  • Monoclonal antibody
  • Na/K-ATPase
  • Preeclampsia
  • Salt-sensitive hypertension

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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