arthyperАртериальная гипертензия"Arterial’naya Gipertenziya" ("Arterial Hypertension")1607-419X2411-8524Antihypertensive League10.18705/1607-419X-2006-12-1-37-40arthyper-1043Research ArticleОБЗОРREVIEWЭндогенный ингибитор Na/K-АТФазы, маринобуфагенин, при преэклампсииMarinobufagenin, an endogenous Na/K-ATPase inhibitor, in preeclampsiaАверинаИ. В.AverinaI. V.noemail@neicon.ruРезникВ. А.ReznikV. A.noemail@neicon.ruТапильскаяН. И.TapilskayaN. I.noemail@neicon.ruГайдуковС. Н.GaidukovS. N.noemail@neicon.ruФроловаЕ. В.FrolovaE. V.noemail@neicon.ruФедороваО. В.FedorovaO. V.noemail@neicon.ruБагровА. Я.BagrovA. Y.BagrovA@mail.nih.govСанкт-Петербургская государственная педиатрическая медицинская академия ; Институт эволюционной физиологии и биохимии им. И.M. Сеченова РАН; Национальный институт старения, Национальные институты здоровьяРоссияNational Institute on AgingRussian FederationИнститут эволюционной физиологии и биохимии им. И.М. Сеченова РАНРоссияNational Institute on AgingRussian FederationНациональный институт старения, Национальных институтов здоровьяРоссияNational Institute on AgingRussian Federation2006280220061213740Copyright © Аверина И.В., Резник В.А., Тапильская Н.И., Гайдуков С.Н., Фролова Е.В., Федорова О.В., Багров А.Я., 20062006Аверина И.В., Резник В.А., Тапильская Н.И., Гайдуков С.Н., Фролова Е.В., Федорова О.В., Багров А.Я.Averina I.V., Reznik V.A., Tapilskaya N.I., Gaidukov S.N., Frolova E.V., Fedorova O.V., Bagrov A.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://htn.almazovcentre.ru/jour/article/view/1043

Преэклампсия является основной причиной материнской смертности при беременности, однако патогенез этого заболевания изучен недостаточно. На основании антигипертензивного действия препарата DIGIBIND (аффинно-очищенных антител к дигоксину) при преэклампсии, было предположено, что эндогенные дигиталис-подобные ингибиторы Na/K-АТФазы играют роль в патогенезе преэклампсии. Мы предположили, что маринобуфагенин (МБГ), эндогенный ингибитор Na/К-АТФазы и вазоконстриктор, выбывает угнетение Na/К-АТФазы при преэклампсии. Уровень концентрации МБГ в плазме кропи у 12 больных с преэклампсией средней тяжести (28 ± 2 лет, срок беременности 37 ± 1 недель, артериальное давление 149 ± 3 / 93 ± 3 мм рт. ст.) был и 2 раза выше чем у 6 обследованных с неосложненной беременностью (1,58 ± 0,15 и 0,80 ± 0,11 нмоль/Л; Р < 0,01). Повышение содержания МБГ в плазме крови сопровождалось 50 % угнетением активности Na/K-АТФазы в эритроцитах. Инкубация эритроцитов в присутствии антител к оуабанину не вызывала статистически достоверного восстановления активности фермента, эффект DIGIBIND имел пограничную достоверность, а антитела к МБГ вызывали восстановление активности Na/K-АТФазы до уровня контрольных значений. Полученные данные свидетельствуют о том. что МБГ являетея вероятным фактором патогенеза преэклампсии и что связывание циркулирующего МБГ специфическими антителами может быть одним из подходов к лечению этого заболевания.

Although preeclampsia (PE) is a major cause of maternal and fetal mortality, its pathogenesis is not fully understood. Endogenous digitalis-like sodium pump ligands (SPLs) are believed to be involved in pathophysiology of PE, as illustrated by clinical observations that DIGIBIND, a digoxin antibody which binds SPLs. Lowers blood pressure (BP) in PE. Recently we reported that plasma levels of marinobufagenin (MBG), a vasoconstrictor SPL, are increased four-fold in patients with severe PE. In the present study, we tested whether polyclonal antibodies to MBG and ouabain, and DIGIBIND can reverse inhibition of erythrocyte Na/K-ATPase (NKN) from patients with mild PE. Development of PE was associated with two-told rise in plasma MBG levels (1.58 ± 0.15 vs. 0.80 ± 0.11 nmol/E: P < 0.01). The activity of erythrocyte NKA in 12 patients with PE (BP, 149 ± 3 / 93 ± 3 mm Hg; 28 ± 2years; gestational age, 37 ± 1 weeks) was lower, than in 6 normotensive gestational age-matched subjects (1.56 ± 0.18 vs. 3.11 ± 0.16 umol Pi/ml/hr; P < 001). In vitro treatment of erythrocytes from PE patients with anti-MBG antibody hilly restored the NKA activity (3.26 ± 0.41 umol Pi/ml/hr; P < 0.01), the effects of DIGIBIND was marginally significant (2.53 ± 0.32 pmol Pi/ml/hr), while anti-ouabain antibody was not effective (2.25 ± 0.25 umol Pi/ml/hr, P > 0.5) were less effective. Our present observations provide evidence for a role of MBG in pathogenesis of PE, and suggest that antibodies against MBG may be used to treat the syndrome.

преэклампсиявазоконстрикциямаринобуфагенинNa/K-АТФазаPreeclampsiaNa/K-ATPasevasoconstrictionmarinobufageninDIGIBINDReferencesMac Kay A.P., Berg C.J., Atrash H.K. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet. Gynecol. 2001; 97: 533-538.Mac Kay A.P., Berg C.J., Atrash H.K. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet. Gynecol. 2001; 97: 533-538.Sihai B., Dekker G., Kupfermine M. Pre-eclampsia. Lancet. 2005; 365: 785-799.Sihai B., Dekker G., Kupfermine M. Pre-eclampsia. Lancet. 2005; 365: 785-799.Graves S.W. The possible role of digitalislike factors in pregnancy-induced hypertension. Hypertension 1987; 10: 184-186.Graves S.W. The possible role of digitalislike factors in pregnancy-induced hypertension. Hypertension 1987; 10: 184-186.de Wardener H.E., Clarkson E.M. Concept of natriuretic hormone. Physiol Rev. 1985; 65: 658-759.de Wardener H.E., Clarkson E.M. Concept of natriuretic hormone. Physiol Rev. 1985; 65: 658-759.Blaustein M.P. Physiological effects of endogenous ouabain control of intracellular Ca-2+ stores and cell responsiveness. Am J Physiol 1993; 264: С. 1367-1387.Blaustein M.P. Physiological effects of endogenous ouabain control of intracellular Ca-2+ stores and cell responsiveness. Am J Physiol 1993; 264: С. 1367-1387.Bagrov A.V., Fedorova O.V., Dmitrieva R.I., Howald W.N., Hunter A.P., Kuznetsova E.A., Shpen V.M. Bufodienolide nature of endogenous inhibitor of Na/К ATPase in the urine from patients with acute myocardial infarction. Hypertension, 1998; 31: 1097 1103.Bagrov A.V., Fedorova O.V., Dmitrieva R.I., Howald W.N., Hunter A.P., Kuznetsova E.A., Shpen V.M. Bufodienolide nature of endogenous inhibitor of Na/К ATPase in the urine from patients with acute myocardial infarction. Hypertension, 1998; 31: 1097 1103.Fedorova O.V., Lakatta E.G., Bagrov A.Y. Differential effects at acute NaCl loading ov endogenous ouabain-like and marinobufagenin-like ligands of the sodium pump in Dahl hypertensive rats. Circulation. 2000; 102: 3009-3014.Fedorova O.V., Lakatta E.G., Bagrov A.Y. Differential effects at acute NaCl loading ov endogenous ouabain-like and marinobufagenin-like ligands of the sodium pump in Dahl hypertensive rats. Circulation. 2000; 102: 3009-3014.Fedorova O.V., Agalakova N.I., Talan M.I., I.akatta E.G., Bagrov A.Y. Brain ouabain stimulates peripheral marinobufagenin via angiotensin II signalling in NaCl loaded Dahl-S rats. J Hypertens 2005:23: 1515-1523.Fedorova O.V., Agalakova N.I., Talan M.I., I.akatta E.G., Bagrov A.Y. Brain ouabain stimulates peripheral marinobufagenin via angiotensin II signalling in NaCl loaded Dahl-S rats. J Hypertens 2005:23: 1515-1523.Gonick H.C., Y. Ding, Vaziri N.D., Bagrov A.Y., Fedorova O.V. Simultaneous measurement of marinobufagenin. ouabain and hypertension -associated protein various disease state. Clin Exp Hypertens 1998; 20 : 617-627.Gonick H.C., Y. Ding, Vaziri N.D., Bagrov A.Y., Fedorova O.V. Simultaneous measurement of marinobufagenin. ouabain and hypertension -associated protein various disease state. Clin Exp Hypertens 1998; 20 : 617-627.Fridman A.I., Matveev S.A., Agalakova N.I., Fedorova O.V., Lakatta E.G., Bagrov A.Y. Marinobufagenin an endogenous ligand of a I Na/К ATPase, is a marker of congest ire heart failure severity. J Hypertension. 2002; 20: 1189-1194.Fridman A.I., Matveev S.A., Agalakova N.I., Fedorova O.V., Lakatta E.G., Bagrov A.Y. Marinobufagenin an endogenous ligand of a I Na/К ATPase, is a marker of congest ire heart failure severity. J Hypertension. 2002; 20: 1189-1194.Fedorova O.V., Talan M.I., Agalakova N.I., Lakatta E.G., Bagrov A.Y. An endogenous ligand of a 1 sodium pump, marinobufagenin, is a novel mediator of sodium chloride dependent hypertension. Circulation. 2002: 105: 1122-1127.Fedorova O.V., Talan M.I., Agalakova N.I., Lakatta E.G., Bagrov A.Y. An endogenous ligand of a 1 sodium pump, marinobufagenin, is a novel mediator of sodium chloride dependent hypertension. Circulation. 2002: 105: 1122-1127.Gallery E.D.M., Hunyor S.M., Gyory A.Z. Plasma volume concentration: a significant factor in both pregnancy-associated hypertension (pre-eclampsia) and chronic hypertension in pregnancy. Q J Med 1979, 192: 593-602.Gallery E.D.M., Hunyor S.M., Gyory A.Z. Plasma volume concentration: a significant factor in both pregnancy-associated hypertension (pre-eclampsia) and chronic hypertension in pregnancy. Q J Med 1979, 192: 593-602.Fedorova O.V., Kolodkin N.I., Agalakova N.I., Namikas A.R., Bzhelyansky A. St-Louts J., Lakatta E.G., Bagrov A.Y. Antibody to marinobufagenin lowers blood pressure in pregnant rats on a ligh NaCl intake. J Hypertens 2005; 23: 835-842.Fedorova O.V., Kolodkin N.I., Agalakova N.I., Namikas A.R., Bzhelyansky A. St-Louts J., Lakatta E.G., Bagrov A.Y. Antibody to marinobufagenin lowers blood pressure in pregnant rats on a ligh NaCl intake. J Hypertens 2005; 23: 835-842.Lopatin D.A., Ailamazian F.K., Dmitrieva R.I., Slipen V.M., Fedorova O.V., Doris P.A., Bagrov A.Y. Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia. J Hypertension. 1999; 17: 1179-1187.Lopatin D.A., Ailamazian F.K., Dmitrieva R.I., Slipen V.M., Fedorova O.V., Doris P.A., Bagrov A.Y. Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia. J Hypertension. 1999; 17: 1179-1187.Vu H.V., Lanost-trume М.R., Pridjian C.A., Whitbred J.M., Durst J.M., Bagrov A.Y., Fedorova O.V., Pridjian F.G., Puschen J.B. The involvement of marinobufagenin in a rat model of human preeclampsia. Am J Nephrol 2005; 25: 520-528.Vu H.V., Lanost-trume М.R., Pridjian C.A., Whitbred J.M., Durst J.M., Bagrov A.Y., Fedorova O.V., Pridjian F.G., Puschen J.B. The involvement of marinobufagenin in a rat model of human preeclampsia. Am J Nephrol 2005; 25: 520-528.Goodlin R.C. Antidigoxin antibodies in eclampsia. New Engl J Med 1988: 318: 518-519.Goodlin R.C. Antidigoxin antibodies in eclampsia. New Engl J Med 1988: 318: 518-519.Adan C.D., Buckalew V., Taylor K., Ernest J.M., Frye A.H., Evans C., Veille J.C. Elevated endoxin-like factor complicating a multifelat second trimester pregnancy: treatment with digoxin-binding immunoglobulin. Am J Nephrol 1996; 16: 529-531.Adan C.D., Buckalew V., Taylor K., Ernest J.M., Frye A.H., Evans C., Veille J.C. Elevated endoxin-like factor complicating a multifelat second trimester pregnancy: treatment with digoxin-binding immunoglobulin. Am J Nephrol 1996; 16: 529-531.Adair D., Hinshaw A., Russell C., Rose J., Veille J., Buckalew V. Effects of Fab digoxin-specific antibodies on mean arterial picture in severe preeclampsia Am J Hypertens 1997; 10: 11A.Adair D., Hinshaw A., Russell C., Rose J., Veille J., Buckalew V. Effects of Fab digoxin-specific antibodies on mean arterial picture in severe preeclampsia Am J Hypertens 1997; 10: 11A.Bagrov A.Y., Dmitrieva R.I., Fedorova O.V., Kazakov G.P., Roukoyatkina N.I., Shpen V.M. Endogenous marinobufagenin-like immunoreactive substance. A possible endogenous Na/K-ATPase inhibitor with vasoconstriction activity. Am J Hypertens. 1990; 9; 982-990.Bagrov A.Y., Dmitrieva R.I., Fedorova O.V., Kazakov G.P., Roukoyatkina N.I., Shpen V.M. Endogenous marinobufagenin-like immunoreactive substance. A possible endogenous Na/K-ATPase inhibitor with vasoconstriction activity. Am J Hypertens. 1990; 9; 982-990.Bagrov A.Y., Fedorova O.V. Effects of two pittance endogenous digitalis-like factors, marinobufagenin and ouabain, on the Na/К pump in human mesentern arteries. J Hypertension. 1998; 16: 1953-1958.Bagrov A.Y., Fedorova O.V. Effects of two pittance endogenous digitalis-like factors, marinobufagenin and ouabain, on the Na/К pump in human mesentern arteries. J Hypertension. 1998; 16: 1953-1958.

The authors declare that there are no conflicts of interest present.