Document Detail


Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension.
MedLine Citation:
PMID:  19008721     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 microg/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 micromol 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.
Authors:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of hypertension     Volume:  26     ISSN:  0263-6352     ISO Abbreviation:  J. Hypertens.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-14     Completed Date:  2009-02-13     Revised Date:  2013-06-04    
Medline Journal Info:
Nlm Unique ID:  8306882     Medline TA:  J Hypertens     Country:  England    
Other Details:
Languages:  eng     Pagination:  2414-25     Citation Subset:  IM    
Affiliation:
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Animals
Antibodies, Monoclonal / immunology,  pharmacology,  therapeutic use*
Blood Pressure / drug effects,  physiology
Bufanolides / immunology*
Digoxin / immunology
Disease Models, Animal
Female
Humans
Hypertension / drug therapy*,  physiopathology
Immunoglobulin Fab Fragments / immunology,  pharmacology,  therapeutic use
Pre-Eclampsia / drug therapy*,  physiopathology
Pregnancy / physiology*
Pregnancy Trimester, Third
Pregnancy, Animal / physiology*
Rats
Rats, Inbred Dahl
Sensitivity and Specificity
Sodium Chloride, Dietary
Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors*,  physiology
Grant Support
ID/Acronym/Agency:
Z01 AG000609-15/AG/NIA NIH HHS; Z01 AG000869-01/AG/NIA NIH HHS; Z99 AG999999/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Bufanolides; 0/Immunoglobulin Fab Fragments; 0/Sodium Chloride, Dietary; 0/digoxin antibodies Fab fragments; 20830-75-5/Digoxin; 470-42-8/marinobufagenin; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase
Comments/Corrections

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