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


CONCLUSIONS
Anti-MBG mAbs may be a useful tool in studies of MBG in vitro and in vivo and may offer treatment of preeclampsia.
Fedorova
Olga V
OV
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA.
Simbirtsev
Andrey S
AS
Kolodkin
Nikolai I
NI
Kotov
Alexander Y
AY
Agalakova
Natalia I
NI
Kashkin
Vladimir A
VA
Tapilskaya
Natalia I
NI
Bzhelyansky
Anton
A
Reznik
Vitaly A
VA
Frolova
Elena V
EV
Nikitina
Elena R
ER
Budny
Georgy V
GV
Longo
Dan L
DL
Lakatta
Edward G
EG
Bagrov
Alexei Y
AY
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002018:Bufanolides / Q000276:immunology*; D004077:Digoxin / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000503:physiopathology; D011247:Pregnancy / Q000502:physiology*; D011263:Pregnancy Trimester, Third; D011270:Pregnancy, Animal / Q000502:physiology*; D051381:Rats; D020303:Rats, Inbred Dahl; D012680:Sensitivity and Specificity; D017673:Sodium Chloride, Dietary; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000502:physiology
D000911:Antibodies, Monoclonal; D002018:Bufanolides; D007140:Immunoglobulin Fab Fragments; D017673:Sodium Chloride, Dietary; C050199:digoxin antibodies Fab fragments; C093896:marinobufagenin; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase