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

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 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
• Journal: Journal of hypertension (J Hypertens) Vol. 26 Issue 12 Pg. 2414-25 (Dec 2008) ISSN: 0263-6352 [Print] England
• PMID: 19008721 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Bufanolides
• Immunoglobulin Fab Fragments
• Sodium Chloride, Dietary
• digoxin antibodies Fab fragments
• marinobufagenin
• Digoxin
• Sodium-Potassium-Exchanging ATPase

Topics

• 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)