The Na+K+-ATPase Inhibitor Marinobufagenin and Early Cardiovascular Risk in Humans: a Review of Recent Evidence

  • Michél Strauss
  • Wayne Smith
  • Olga V. Fedorova
  • Aletta E. SchutteEmail author
Secondary Hypertension: Nervous System Mechanisms (Michael Wyss, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Secondary Hypertension: Nervous System Mechanisms


Purpose of Review

This review synthesizes recent findings in humans pertaining to the relationships between marinobufagenin (MBG), a steroidal Na+/K+-ATPase inhibitor and salt-sensitivity biomarker, and early cardiovascular risk markers.

Recent Findings

Twenty-four-hour urinary MBG strongly associates with habitual salt intake in young healthy adults (aged 20–30 years). Furthermore, in young healthy adults free of detected cardiovascular disease, MBG associates with increased large artery stiffness and left ventricular mass independent of blood pressure. These findings in human studies corroborate mechanistic data from rat studies whereby stimulation of MBG by a high salt intake or MBG infusion increased vascular fibrosis and cardiac hypertrophy.


Twenty-four-hour urinary MBG may be a potential biomarker of early cardiovascular risk. Adverse associations between MBG—which increases with salt consumption—and early cardiovascular risk markers support the global efforts to reduce population-wide salt intake in an effort to prevent and control the burden of non-communicable diseases.


Early cardiovascular risk Humans Marinobufagenin Women Salt-sensitivity 



The sources of funding of this research are the South African Medical Research Council (SAMRC), the South African Research Chairs Initiative (SARChI) of the Department of Science and Technology, and National Research Foundation (NRF) of South Africa (UID 86895 and 111862). This research was supported in part by the Intramural research Program of the NIH, National Institute on Aging, Baltimore, Maryland, USA.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Ethical Considerations

This manuscript does not contain patient data.


Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors, and therefore, the NRF does not accept any liability in regard.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    He FJ, MacGregor GA. Role of salt intake in prevention of cardiovascular disease: controversies and challenges. Nat Rev Cardiol. 2018;15:371–7. Scholar
  2. 2.
    Powles J, Fahimi S, Micha R, Khatibzadeh S, Shi P, Ezzati M, et al. Global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide. BMJ Open. 2013;3:e003733. Scholar
  3. 3.
    World Health Organization. Guideline: sodium intake for adults and children. Geneva: World Health Organization; 2012.Google Scholar
  4. 4.
    Mozaffarian D, Fahimi S, Singh GM, Micha R, Khatibzadeh S, Engell RE, et al. Global sodium consumption and death from cardiovascular causes. N Engl J Med. 2014;371:624–34. Scholar
  5. 5.
    Gakidou E, Afshin A, Abajobir AA, Abate KH, Abbafati C, Abbas KM, et al. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1345–422. Scholar
  6. 6.
    World Health Organization. Global action plan for the prevention and control of NCDs 2013–2020. Geneva: World Health Organization; 2013.Google Scholar
  7. 7.
    United Nations General Assembly Resolution 66/2. Political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases, A/RES/66/2. New York: United Nations. 19 September 2011. Available from
  8. 8.
    United Nations General Assembly Resolution 73/2. Political declaration of the third high-level meeting of the General Assembly on the prevention and control of non-communicable diseases, a/res/73/2. 10 October 2018. Available from
  9. 9.
    Resolve to Save Lives Initiative. Sodium reduction [press release]. Available from: Accessed 28 Dec 2018.
  10. 10.
    •• Strauss M, Smith W, Wei W, Bagrov AY, Fedorova OV, Schutte AE. Large artery stiffness is associated with marinobufagenin in young adults: the African-PREDICT study. J Hypertens. 2018;36:2333–9. This study indicates a blood pressure independent relationship between MBG and arterial stiffness in young healthy adults. Results from this study support findings from animal studies demonstrating increased vascular fibrosis, and concurrently arterial stiffness, in response to increased MBG.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lichtstein D, Gati I, Babila T, Haver E, Katz U. Effect of salt acclimation on digitalis-like compounds in the toad. BBA. 1991;1073:65–8.PubMedGoogle Scholar
  12. 12.
    Flier J, Edwards MW, Daly JW, Myers CW. Widespread occurrence in frogs and toads of skin compounds interacting with the ouabain site of Na+, K+-ATPase. Science. 1980;208:503–5.CrossRefGoogle Scholar
  13. 13.
    Bagrov AY, Roukoyatkina NI, Fedorova OV, Pinaev AG, Ukhanova MV. Digitalis-like and vasoconstrictor effects of endogenous digoxin-like factor(s) from the venom of Bufo marinus toad. Eur J Pharmacol. 1993;234:165–72.CrossRefGoogle Scholar
  14. 14.
    Bagrov AY, Dmitrieva RI, Fedorova OV, Kazakov GP, Roukoyatkina NI, Shpen VM. Endogenous marinobufagenin-like immunoreactive substance. A possible endogenous Na, K-ATPase inhibitor with vasoconstrictor activity. Am J Hypertens. 1996;9:982–90. Scholar
  15. 15.
    Bagrov AY, Fedorova OV, Dmitrieva RI, Howald WN, Hunter AP, Kuznetsova EA, et al. Characterization of a urinary bufodienolide Na+,K+-ATPase inhibitor in patients after acute myocardial infarction. Hypertension. 1998;31:1097–103. Scholar
  16. 16.
    Bagrov AY, Fedorova OV. Effects of two putative endogenous digitalis-like factors, marinobufagenin and ouabain, on the Na+,K+-pump in human mesenteric arteries. J Hypertens. 1998;16:1953–8.CrossRefGoogle Scholar
  17. 17.
    Fedorova OV, Doris PA, Bagrov AY. Endogenous marinobufagenin-like factor in acute plasma volume expansion. Clin Exp Hypertens. 1998;20:581–91.CrossRefGoogle Scholar
  18. 18.
    • Fedorova OV, Zernetkina VI, Shilova VY, Grigorova YN, Juhasz O, Wei W, et al. Synthesis of an endogenous steroidal Na pump inhibitor marinobufagenin, implicated in human cardiovascular diseases, is initiated by CYP27A1 via bile acid pathway. Circ Cardiovasc Genet. 2015;8:736–45. This study demonstrates the biosynthesis of mammalian MBG.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Fedorova OV, Agalakova NI, Talan MI, Lakatta EG, Bagrov AY. Brain ouabain stimulates peripheral marinobufagenin via angiotensin II signalling in NaCl-loaded Dahl-S rats. J Hypertens. 2005;23:1515–23.CrossRefGoogle Scholar
  20. 20.
    • Fedorova OV, Lakatta EG, Bagrov AY, Melander O. Plasma level of the endogenous sodium pump ligand marinobufagenin is related to the salt-sensitivity in men. J Hypertens. 2015;33:534–41. This study is one of 4 studies investigating the relationship between MBG and blood pressure in adults with no kidney or heart disease.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    • Anderson DE, Fedorova OV, Morrell CH, Longo DL, Kashkin VA, Metzler JD, et al. Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives. Am J Physiol Regul Integr Comp Physiol. 2008;294:R1248–54. This is the first human study investigating the relationship between MBG and blood pressure.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    •• Strauss M, Smith W, Kruger R, Wei W, Fedorova OV, Schutte AE. Marinobufagenin and left ventricular mass in young adults: The African-PREDICT study. Eur J Prev Cardiol. 2018;25:1587-95. This cross-sectional study for the first time indicates that excessive levels of MBG is associated with increased left ventricular mass, independent of blood pressure, in young healthy adults.CrossRefGoogle Scholar
  23. 23.
    •• Strauss M, Smith W, Wei W, Fedorova OV, Schutte AE. Marinobufagenin is related to elevated central and 24-h systolic blood pressures in young black women: the African-PREDICT Study. Hypertens Res. 2018;41:183–92. This is the first study to investigate the relationship between MBG and SBP in a young healthy biethnic cohort - including young black and white, men and women.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    • Kennedy DJ, Shrestha K, Sheehey B, Li XS, Guggilam A, Wu Y, et al. Elevated plasma marinobufagenin, an endogenous cardiotonic steroid, is associated with right ventricular dysfunction and nitrative stress in heart failure. Circ Heart Fail. 2015;8:1068–76. This study demonstrates the effect of increased MBG on the cardiac structure of rats, that supported the need to investigate the relationship between MBG and cardiac structure in humans with excessively high levels of salt intake and 24h MBG excretion.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Fedorova OV, Lakatta EG, Bagrov AY. Endogenous Na,K pump ligands are differentially regulated during acute NaCl loading of dahl rats. Circulation. 2000;102:3009–14. Scholar
  26. 26.
    • Fedorova OV, Talan MI, Agalakova NI, Lakatta EG, Bagrov AY. Endogenous ligand of alpha(1) sodium pump, marinobufagenin, is a novel mediator of sodium chloride--dependent hypertension. Circulation. 2002;105:1122–7. Here Fedorova et al. describe that sustained high levels of MBG may promote a vasoconstrictive response, thereby increasing blood pressure, due to the blunted natriuretic functionality of MBG.CrossRefPubMedGoogle Scholar
  27. 27.
    Fedorova OV, Talan MI, Agalakova NI, Droy-Lefaix M-T, Lakatta EG, Bagrov AY. Myocardial PKC β2 and the sensitivity of Na/K-ATPase to marinobufagenin are reduced by cicletanine in Dahl hypertension. Hypertension. 2003;41:505–11. Scholar
  28. 28.
    • Jablonski KL, Fedorova OV, Racine ML, Geolfos CJ, Gates PE, Chonchol M, et al. Dietary sodium restriction and association with urinary marinobufagenin, blood pressure, and aortic stiffness. Clin J Am Soc Nephrol. 2013;8:1952–9. This is the first human study demonstrating a relationship between increased salt intake, MBG and arterial stiffness.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    •• Strauss M, Smith W, Wei W, Fedorova OV, Schutte AE. Autonomic activity and its relationship with the endogenous cardiotonic steroid marinobufagenin: the African-PREDICT study. Nutr Neurosci. 2019;7:1–11. This observational study is the first study in a human cohort demonstrating associations of salt intake, autonomic activity and aldosterone with MBG. This study supports the proposed angiotensinergic-sympatho-excitatory pathway implicated in MBG sythesis and secretion.CrossRefGoogle Scholar
  30. 30.
    • Bagrov AY, Shapiro JI, Fedorova OV. Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev. 2009;61:9–38. This useful review thoroughly describes the pathways whereby MBG may effect the cardiovasculature.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Adrogué HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med. 2007;356:1966–78.CrossRefGoogle Scholar
  32. 32.
    Grigorova Y, Wei W, Petrashevskaya N, Zernetkina V, Juhasz O, Fenner R, et al. Dietary sodium restriction reduces arterial stiffness, vascular TGF-β-dependent fibrosis and marinobufagenin in young normotensive rats. Int J Mol Sci. 2018;19:3168. Scholar
  33. 33.
    Fedorova OV, Emelianov IV, Bagrov KA, Grigorova YN, Wei W, Juhasz O, et al. Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists. J Hypertens. 2015;33:1602–10. Scholar
  34. 34.
    Elkareh J, Kennedy DJ, Yashaswi B, Vetteth S, Shidyak A, Kim EG, et al. Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy. Hypertension. 2007;49:215–24. Scholar
  35. 35.
    Elkareh J, Periyasamy SM, Shidyak A, Vetteth S, Schroeder J, Raju V, et al. Marinobufagenin induces increases in procollagen expression in a process involving protein kinase C and Fli-1: implications for uremic cardiomyopathy. Am J Physiol Renal Physiol. 2009;296:F1219–26. Scholar
  36. 36.
    • Fedorova OV, Kolodkin NI, Agalakova NI, Lakatta EG, Bagrov AY. Marinobufagenin, an endogenous α-1 sodium pump ligand, in hypertensive Dahl salt-sensitive rats. Hypertension. 2001;37:462–6. This study firstly investigated the role of MBG in Dahl salt-sensitive hypertension.CrossRefPubMedGoogle Scholar
  37. 37.
    Uddin MN, Horvat D, Childs EW, Puschett JB. Marinobufagenin causes endothelial cell monolayer hyperpermeability by altering apoptotic signaling. Am J Physiol-Regul Integ Comp Physiol. 2009;296:R1726–R34. Scholar
  38. 38.
    Fedorova OV, Shilova V, Zernetkina V, Zhang Y, Lehrmann E, Becker KG, et al. A monoclonal antibody to an endogenous Na/K-ATPase ligand, marinobufagenin, reverses expression of pro-fibrotic genes and reduces cardiovascular fibrosis in aged rats. Artery Res. 2013;7:169. Scholar
  39. 39.
    Fedorova LV, Raju V, El-Okdi N, Shidyak A, Kennedy DJ, Vetteth S, et al. The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition. Am J Physiol Renal Physiol. 2009;296:F922–F34. Scholar
  40. 40.
    • Kennedy DJ, Vetteth S, Periyasamy SM, Kanj M, Fedorova L, Khouri S, et al. Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy. Hypertension. 2006;47:488–95. This study demonstrates the effect of increased MBG on the cardiac structure of rats, that supported the need to investigate the relationship between MBG and cardiac structure in humans with excessively high levels of salt intake and 24h MBG excretion.CrossRefPubMedGoogle Scholar
  41. 41.
    Tomaschitz A, Piecha G, Ritz E, Meinitzer A, Haas J, Pieske B, et al. Marinobufagenin in essential hypertension and primary aldosteronism: a cardiotonic steroid with clinical and diagnostic implications. Clin Exp Hypertens. 2015;37:108–15. Scholar
  42. 42.
    • Tian J, Haller S, Periyasamy S, Brewster P, Zhang H, Adlakha S, et al. Renal ischemia regulates marinobufagenin release in humans. Hypertension. 2010;56:914–9. This study indicates elevated levels of MBG in patients with renal artery stenosis.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    • Kolmakova EV, Haller ST, Kennedy DJ, Isachkina AN, Budny GV, Frolova EV, et al. Endogenous cardiotonic steroids in chronic renal failure. Nephrol Dial Transplant. 2011;26:2912–9. This study indicates elevated levels of MBG in patients with chronic kidney disease.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    • Piecha G, Kujawa-Szewieczek A, Kuczera P, Skiba K, Sikora-Grabka E, Wiecek A. Plasma marinobufagenin immunoreactivity in patients with chronic kidney disease: a case control study. Am J Physiol Renal Physiol. 2018;315:F637–F43. This study indicates elevated levels of MBG in patients with chronic kidney disease.CrossRefPubMedGoogle Scholar
  45. 45.
    Elijovich F, Weinberger MH, Anderson CA, Appel LJ, Bursztyn M, Cook NR, et al. Salt sensitivity of blood pressure: a scientific statement from the American Heart Association. Hypertension. 2016;68:e7–e46. Scholar
  46. 46.
    Fedorova OV, Simbirtsev AS, Kolodkin NI, Kotov AY, Agalakova NI, Kashkin VA, et al. Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension. J Hypertens. 2008;26:2414–25. Scholar
  47. 47.
    • Schutte AE, Gona PN, Delles C, Uys AS, Burger A, Mels CM, et al. The African prospective study on the early detection and identification of cardiovascular disease and hypertension (African-PREDICT): design, recruitment and initial examination. Eur J Prev Cardiol. 2019;6:2047487318822354. The African-PREDICT study is a unique longitudinal study tracking the early development of hypertension in black and white men and women from South-Africa. Follow up data from this study will provide valuable prognostic information on the role of MBG in the development and progression of cardiovascular disease.CrossRefGoogle Scholar
  48. 48.
    Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: A systematic review and meta-analysis. J Am Coll Cardiol. 2010;55:1318–27. Scholar
  49. 49.
    • Koivistoinen T, Lyytikäinen L-P, Aatola H, Luukkaala T, Juonala M, Viikari J, et al. Pulse wave velocity predicts the progression of blood pressure and development of hypertension in young adults novelty and significance. Hypertension. 2018;71:451–6. This study highlights the predictive value of arterial stiffness for the development of hypertension, supporting the significance of a relationship observed between MBG and arterial stiffness at an early age.CrossRefPubMedGoogle Scholar
  50. 50.
    Willum-Hansen T, Staessen JA, Torp-Pedersen C, Rasmussen S, Thijs L, Ibsen H, et al. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation. 2006;113:664–70. Scholar
  51. 51.
    Wang KL, Cheng HM, Sung SH, Chuang SY, Li CH, Spurgeon HA, et al. Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities: a community-based study. Hypertension. 2010;55:799–805. Scholar
  52. 52.
    Najjar SS, Scuteri A, Shetty V, Wright JG, Muller DC, Fleg JL, et al. Pulse wave velocity is an independent predictor of the longitudinal increase in systolic blood pressure and of incident hypertension in the Baltimore Longitudinal Study of Aging. J Am Coll Cardiol. 2008;51:1377–83. Scholar
  53. 53.
    Mitchell GF, Hwang S-J, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and cardiovascular events. Circulation. 2010;121:505–11. Scholar
  54. 54.
    Todd AS, Macginley RJ, Schollum JB, Johnson RJ, Williams SM, Sutherland WH, et al. Dietary salt loading impairs arterial vascular reactivity. Am J Clin Nutr. 2010;91:557–64. Scholar
  55. 55.
    He FJ, Marciniak M, Visagie E, Markandu ND, Anand V, Dalton RN, et al. Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and asian mild hypertensives. Hypertension. 2009;54:482–8. Scholar
  56. 56.
    • Strauss M, Smith W, Kruger R, van der Westhuizen B, Schutte AE. Large artery stiffness is associated with salt intake in young healthy black but not white adults: the African-PREDICT study. Eur J Nutr. 2018;57:2649–56. This study cross-sectional study demonstrates the relationship between salt intake and arterial stiffness in young adults who consume large amounts of salt.CrossRefPubMedGoogle Scholar
  57. 57.
    Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30:445–8. Scholar
  58. 58.
    Mitchell GF. Arterial stiffness and hypertension: chicken or egg? Hypertension. 2014;64:210–4. Scholar
  59. 59.
    Nichols WW. Clinical measurement of arterial stiffness obtained from noninvasive pressure waveforms. Am J Hypertens. 2005;18(S1):3S–10S. Scholar
  60. 60.
    Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322:1561–6. Scholar
  61. 61.
    Rodriguez CJ, Bibbins-Domingo K, Jin Z, Daviglus ML, Goff DC Jr, Jacobs DR Jr. Association of sodium and potassium intake with left ventricular mass: coronary artery risk development in young adults. Hypertension. 2011;58:410–6. Scholar
  62. 62.
    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J - Cardiovasc Imag. 2015;16:233–71. Scholar
  63. 63.
    Bochud M, Staessen JA, Maillard M, Mazeko MJ, Kuznetsova T, Woodiwiss A, et al. Ethnic differences in proximal and distal tubular sodium reabsorption are heritable in black and white populations. J Hypertens. 2009;27:606–12. Scholar
  64. 64.
    Falkner B, Kushner H. Effect of chronic sodium loading on cardiovascular response in young blacks and whites. Hypertension. 1990;15:36–43.CrossRefGoogle Scholar
  65. 65.
    Palacios C, Wigertz K, Martin BR, Jackman L, Pratt JH, Peacock M, et al. Sodium retention in black and white female adolescents in response to salt intake. J Clin Endocrinol Metab. 2004;89:1858–63. Scholar
  66. 66.
    Anderson DE, Scuteri A, Agalakova N, Parsons DJ, Bagrov AY. Racial differences in resting end-tidal CO2 and circulating sodium pump inhibitor. Am J Hypertens. 2001;14:761–7.CrossRefGoogle Scholar
  67. 67.
    Reimann M, Hamer M, Schlaich M, Malan NT, Rudiger H, Ziemssen T, et al. Autonomic responses to stress in Black versus Caucasian Africans: the SABPA study. Psychophysiology. 2012;49:454–61. Scholar
  68. 68.
    Abate NI, Mansour YH, Tuncel M, Arbique D, Chavoshan B, Kizilbash A, et al. Overweight and sympathetic overactivity in black Americans. Hypertension. 2001;38:379–83.CrossRefGoogle Scholar
  69. 69.
    Calhoun DA, Mutinga ML, Collins AS, Wyss JM, Oparil S. Normotensive blacks have heightened sympathetic response to cold pressor test. Hypertension. 1993;22:801–5.CrossRefGoogle Scholar
  70. 70.
    Vranish JR, Holwerda SW, Young BE, Credeur DP, Patik JC, Barbosa TC, et al. Exaggerated vasoconstriction to spontaneous bursts of muscle sympathetic nerve activity in healthy young black men. Hypertension. 2018;71:192–8. Scholar
  71. 71.
    He J, Gu D, Chen J, Jaquish CE, Rao DC, Hixson JE, et al. Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt Study. J Hypertens. 2009;27:48–54. This study indicates increased salt-sensitivity in women, that may be important considering the sex specific relationships observed between MBG and markers of early cardiovascular risk.. CrossRefGoogle Scholar
  72. 72.
    • Murao S, Takata Y, Yasuda M, Osawa H, Kohi F. The influence of sodium and potassium intake and insulin resistance on blood pressure in normotensive individuals is more evident in women. Am J Hypertens. 2018;31:876–85. This study indicates increased salt-sensitivity in women, that may be important considering the sex specific relationships observed between MBG and markers of early cardiovascular risk.CrossRefPubMedGoogle Scholar
  73. 73.
    • Shukri MZ, Tan JW, Manosroi W, Pojoga LH, Rivera A, Williams JS, et al. Biological sex modulates the adrenal and blood pressure responses to angiotensin II. Hypertension. 2018;71:1083–90. This study indicates increased salt-sensitivity in women, that may be important considering the sex specific relationships observed between MBG and markers of early cardiovascular risk.CrossRefPubMedGoogle Scholar
  74. 74.
    Fedorova O, Grigorova Y, Hagood M, Mcdevitt R, Long J, Mcpherson R, et al. Age-dependent hypertension and vascular remodeling in dahl-s rats are associated with elevated levels of marinobufagenin and cognitive decline. J Hypertens. 2018;36:e47. Scholar
  75. 75.
    Fedorova OV, Talan MI, Agalakova NI, Lakatta EG, Bagrov AY. Coordinated shifts in Na/K-ATPase isoforms and their endogenous ligands during cardiac hypertrophy and failure in NaCl-sensitive hypertension. J Hypertens. 2004;22:389–97. Scholar
  76. 76.
    Vu HV, Ianosi-Irimie MR, Pridjian CA, Whitbred JM, Durst JM, Bagrov AY, et al. Involvement of marinobufagenin in a rat model of human preeclampsia. Am J Nephrol. 2005;25:520–8. Scholar
  77. 77.
    Fedorova OV, Kolodkin NI, Agalakova NI, Namikas AR, Bzhelyansky A, St-Louis J, et al. Antibody to marinobufagenin lowers blood pressure in pregnant rats on a high NaCl intake. J Hypertens. 2005;23:835–42. Scholar
  78. 78.
    Goel A, Zhang Y, Anderson L, Rahimian R. Gender difference in rat aorta vasodilation after acute exposure to high glucose: involvement of protein kinase C β and superoxide but not of Rho Kinase. Cardiovasc Res. 2007;76:351–60. Scholar
  79. 79.
    Barron WM. Volume homeostasis during pregnancy in the rat. Am J Kidn Dis. 1987;9:296–302. Scholar
  80. 80.
    Lindheimer MD, Katz AI, Nolten WE, Oparil S, Ehrlich EN. Sodium and mineralocorticoids in normal and abnormal pregnancy. Adv Nephrol Necker Hosp. 1977;7:33–59.PubMedGoogle Scholar
  81. 81.
    Luft FC, Gallery EDM, Lindheimer MD. Chapter 15 - Normal and abnormal volume homeostasis. In: Lindheimer MD, Roberts JM, Gary Cunningham F, editors. Chesley’s hypertensive disorders in pregnancy. 3rd ed. San Diego: Academic Press; 2009. p. 269–85.CrossRefGoogle Scholar
  82. 82.
    Lopatin DA, Ailamazian EK, Dmitrieva RI, Shpen VM, Fedorova OV, Doris PA, et al. Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia. J Hypertens. 1999;17:1179–87.CrossRefGoogle Scholar
  83. 83.
    Nikitina ER, Mikhailov AV, Nikandrova ES, Frolova EV, Fadeev AV, Shman VV, et al. In preeclampsia endogenous cardiotonic steroids induce vascular fibrosis and impair relaxation of umbilical arteries. J Hypertens. 2011;29:769–76. Scholar
  84. 84.
    Fedorova OV, Tapilskaya NI, Bzhelyansky AM, Frolova EV, Nikitina ER, Reznik VA, et al. Interaction of Digibind with endogenous cardiotonic steroids from preeclamptic placentae. J Hypertens. 2010;28:361–6. Scholar
  85. 85.
    Fedorova O, Ishkaraeva V, Grigorova Y, Reznik V, Kolodkin N, Zazerskaya I, et al. Antibody to marinobufagenin reverses placenta-induced fibrosis of umbilical arteries in preeclampsia. Int J Mol Sci. 2018;19:2377. Scholar
  86. 86.
    Uddin MN, Horvat D, Glaser SS, Mitchell BM, Puschett JB. Examination of the cellular mechanisms by which marinobufagenin inhibits cytotrophoblast function. J Biol Chem. 2008;283:17946–53. Scholar
  87. 87.
    Uddin MN, Horvat D, Glaser SS, Danchuk S, Mitchell BM, Sullivan DE, et al. Marinobufagenin inhibits proliferation and migration of cytotrophoblast and CHO cells. Placenta. 2008;29:266–73. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Michél Strauss
    • 1
  • Wayne Smith
    • 1
    • 2
  • Olga V. Fedorova
    • 3
  • Aletta E. Schutte
    • 1
    • 2
    Email author
  1. 1.Hypertension in Africa Research Team (HART)North-West UniversityPotchefstroomSouth Africa
  2. 2.MRC Research Unit: Hypertension and Cardiovascular DiseaseNorth-West UniversityPotchefstroomSouth Africa
  3. 3.Laboratory of Cardiovascular ScienceNational Institute on Aging, NIHBaltimoreUSA

Personalised recommendations