Involvement of the Bufodienolides in Disorders of Inflammation, Body Volume, Tissue Injury, and Ischemia

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Jules B Puschett


The bufodienolides are a group of circulating steroid hormones which, along with the cardenolides, compose the compounds referred to as the “cardiotonic steroids” or “cardiac glycosides.” The most extensively studied of the bufodienolides is marinobufogenin (MBG).  Recent evidence indicates that at least some of the effects of MBG are mediated by alterations in the MAPK signaling cascade. Previous investigations have largely been directed towards the involvement of the bufodienolides in changes in body volume and hypertension, including volume expansion-mediated essential hypertension, as well as the pregnancy-specific hypertensive disorder, preeclampsia. However, it is now clear that MBG and its antagonist, resibufogenin (RBG), are implicated in disorders characterized by the generation and maintenance of inflammation. Therefore, evidence has been presented in this review which implicates MBG in traumatic brain injury and the acute respiratory distress syndrome.  Furthermore, not only does RBG prevent preeclampsia in a rat model of the disturbance, but it is also effective in ameliorating the abnormalities in traumatic brain injury. Efforts are currently underway to determine if, as is the case in the latter two disorders, it is also effective in modifying the course of the disease in the acute respiratory distress syndrome.  Thus, the investigative future seems bright with regard to the potential activity of these and other bufodienolides in medicine.

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PUSCHETT, Jules B. Involvement of the Bufodienolides in Disorders of Inflammation, Body Volume, Tissue Injury, and Ischemia. Medical Research Archives, [S.l.], n. 3, june 2015. ISSN 2375-1924. Available at: <>. Date accessed: 03 oct. 2022.
Bufodienolides, preeclampsia, traumatic brain injury, acute respiratory distress syndrome
Review Articles


1. Agunanne E, Horvat D, Harrison R, et al. Marinobufagenin levels in preeclamptic patients: a preliminary report. Am J Perinatol 2011;28:509-514.
2. Agunanne E, Horvat D, Uddin MN, Puschett JB. The treatment of preeclampsia in a rat model employing Digibind®. Am J Perinatology 2010;27:299-305.
3. Agunanne EE, Uddin MN, Horvat D, Puschett JB. Contribution of angiogenic factors in a rat model of pre-eclampsia. Am J Nephrol 2010;32:332-339.
4. Arent AM, de Souza LF, Walz R, Dafre AL. Perspectives on molecular biomarkers of oxidative stress and antioxidant strategies in traumatic brain injury. Biomed Res Int Volume 2014, Article ID 723060, 18 pages.
5. Averina IV, Tapilskaya NI, Reznik VA, et al. Endogenous Na/K-ATPase inhibitors in patients with preeclampsia. Cell Mol Biol 2006;52:19-23.
6. Bagrov AY, Fedorova OV, Dmitrieva RI, et al. Plasma marinobufagenin-like and ouabain-like immunoreactivity during saline volume expansion in anesthetized dogs. Cardiovasc Res 1996;31:296-305.
7. Chesley LC, Valenti C, Rein H. Excretion of sodium loads by non-pregnant and pregnant normal, hypertensive and preeclamptic women. Metabolism 1958;VII:575-588.
8. Chesley LC. Sodium retention and pre-eclampsia. Am J Obstet Gynecol 1966;1:127-132.
9. Chesley LC. The renal excretion of sodium in women with preeclampsia. Am J Obstet Gynecol 1966;1:317-323.
10. Dmitrieva RI, Bagrov AY, Lalli E, et al. Mammalian bufadienolide is synthesized from cholesterol in the adrenal cortex by a pathway that is independent of cholesterol side-chain cleavage. Hypertension 2000;36:442-448.
11. Fargo BI, Morin KI, Patel B, et al. Marinobufagenin identifies patients with acute respiratory distress syndrome. Presented to the annual meeting of the Southern Society for Clinical Investigation, New Orleans, LA, February 20-22, 2014. J Invest Med 2014;62:544-545.
12. Fedorova OV, Lakatta EG, Bagrov AY. Endogenous Na, K pump ligands are differentially regulated during acute NaCl loading of DAHL rats. Circulation 2000;102:3009-3014.
13. Fedorova OV, Simbirtsev AS, Kolodkin NI, 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;26:2414-2425.
14. Fedorova OV, Talan MI, Agalakova NI, et al. Endogenous ligand of alpha 1 sodium pump, marinobufagenin, is a novel mediator of sodium chloride-dependent hypertension. Circulation 2002;105:122-1127.
15. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 2013;368:795-805.
16. Ferguson ND, Fan E, Camporota L, et al. The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med 2012;38:1773-1582.
17. Fukui S, Signoretti S, Dunbar JG, Marmarou A. The effect of cyclosporin A on brain edema formation following experimental cortical contusion. Acta Neurochir Suppl 2003;86:301-303.
18. Gonick HC, Ding Y, Vaziri ND, et al. Simultaneous measurement of marinobufagenin, ouabain, and hypertension-associated protein in various disease states. Clin Exp Hypertens 1998;20:617-627.
19. Harmon KG, Drezner JA, Gammons M, et al. American Medical Society for Sports Medicine position statement: concussion in sport. Br J Sports Med 2013;47:15-26.
20. Hasan KM, Moeller FG, Narayana PA. DTI-based segmentation and quantification of human brain lateral ventricular CSF volumetry and mean diffusivity: validation, age, gender effects and biophysical implications. Magn Reson Imaging 2014;32:405-412.
21. Hasan KM, Wilde EA, Miller ER, et al. Serial atlas-based DTI study of uncomplicated mild traumatic brain injury in adults. J Neurotrauma 2014;31:466-475.
22. Hilton PJ, White RW, Lord GA, et al. An inhibitor of the sodium pump obtained from human placenta. Lancet 1996;348:303-305.
23. Horvat D, Severson J, Uddin MN, et al. Resibufogenin prevents the manifestations of preeclampsia in an animal model of the syndrome. Hypertens Pregnancy 2010;29:1-9.
24. Ing N, Berghman L, Abi-Ghanem D, et al. Marinobufagenin regulates permeability and gene expression of brain endothelial cells. Am J Physiol Regul Integr Comp Physiol 2014;306:R918-R924.
25. Jablonski KL, Fedorova OV, Racine ML, et al. Dietary sodium restriction and association with urinary marinobufagenin, blood pressure, and aortic stenosis. Clin J Am Soc Nephrol 2013;8:1952-1959.
26. Kale RA, Gupta RK, Saraswat VA, et al. Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy. Hepatology 2006;43:698-706.
27. LaMarca HL, Morris CA, Pettit GR, et al. Marinobufagenin impairs first trimester cytotrophoblast differentiation. Placenta 2006;27:984-988.
28. Lesko MM, O'Brien SJ, Childs C, et al. Comparison of several prognostic tools in traumatic brain injury including S100B. Brain Inj 2014;28:987-994.
29. Li S, Eim C, Kirch U, et al. Bovine adrenals and hypothalamus are a major source of proscillaridin A- and ouabain-immunoreactivities. Life Sci 1998;62:1023-1033.
30. Logan BW, Goldman S, Zola M, Mackey A. Concussive brain injury in the military: September 2001 to the present. Behav Sci Law 2013;31:803-813.
31. Lopatin DA, Ailamazian EK, Dmitrieva RI, et al. Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia. J Hypertens 1999;17:1179-1187.
32. Maitra S, Bhattacharjee S, Khana P, et al. High-frequency ventilation does not provide mortality benefit in comparison with conventional lung-protective ventilation in acute respiratory distress syndrome: a meta-analysis of the randomized controlled trials. 2014 May 14. [Epub ahead of print]. PMID:24830508.
33. Malhotra A, Drazen JM. High-frequency oscillatory ventilation on shaky ground. N Engl J Med 2013;368: 863-865.
34. Manunta P, Ferrandi M. Different effects of marinobufagenin and endogenous ouabain. J Hypertens 2004;22:257-259.
35. McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: the 4th international conference on concussion in sport held in Zurich, November 2012. Br J Sports Med 2013;47:250-258.
36. Mitchell BM, Cook LG, Danchuk S, Puschett JB. Uncoupled endothelial nitric oxide synthase and oxidative stress in a rat model of pregnancy-induced hypertension. Am J Hypertens 2007;20:1297-1304.
37. Morrison AC, Srinivas SK, Elovitz MA, Puschett JB. Genetic Variation in solute carrier genes is associated with preeclampsia. Am J Obstet Gynecol 2010;203:491.
N Engl J Med 2013;368:806-813.
38. Ortiz-Diaz E, Festic E, Gajic O, Levitt JE. Emerging pharmacological therapies for prevention and early treatment of acute lung injury. Semin Respir Crit Care Med 2013;34:448-458.
39. Pridjian G, Puschett JB. Preeclampsia, Part I: Clinical and pathophysiological considerations. Obstet Gynecol Surv 2002;57:598-618.
40. Pridjian G, Puschett JB. Preeclampsia, Part II: Experimental and genetic considerations. Obstet Gynecol Surv 2002;57:619-640.
41. Puschett JB, Agunanne E, Uddin MN. Marinobufagenin, resibufogenin, and preeclampsia. Biochim Biophys Acta 2010;1802:1246-1253.
42. Puschett JB. Marinobufagenin predicts and resibufogenin prevents preeclampsia: a review of the evidence. Am J Perinatol 2012;29:777-785.
43. Puschett JB. The role of excessive volume expansion in the pathogenesis of preeclampsia. Medical Hypotheses 2006;67:1125-1132.
44. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. J Am Med Assoc 2012;307:2526-2533.
45. Schoner W, Scheiner-Bobis G. Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth. Am J Physiol Cell Physiol 2007;293:C509-536.
46. Schoner W, Scheiner-Bobis G. Endogenous cardiac glycosides: hormones using the sodium pump as signal transducer. Semin Nephrol 2005;24:343-351.
47. Shapiro L, Foresti M, Arisi G, et al. Marinobufagenin diagnoses and resibufogenin ameliorates traumatic brain injury. Presented to the annual meeting of the American Society for Clinical Pharmacology and Therapeutics, Dallas, TX, March 2-5, 2011. ASCPT Annual Meeting Program Booklet, p.78.
48. Singh R, Meier TB, Kuplicki R, et al. Relationship of collegiate football experience and concussion with hippocampal volume and cognitive outcomes. J Am Med Assoc 2014;311:1883-1888.
49. Steyerberg EW, Mushkudiani N, Perel P, et al. Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med 2008;5:e165.
50. Stocchetti N, Pagan F, Calappi E, et al. Inaccurate early assessment of neurological severity in head injury. J Neurotrauma 2004;21:1131-1140.
51. Strathmann FG, Schulte S, Goerl K, Petron DJ. Blood-based biomarkers for traumatic brain injury: evaluation of research approaches, available methods and potential utility from the clinician and clinical laboratory perspectives. Clin Biochem 2014;47:876-888.
52. Tian J, Haller S, Periyasamy S, et al. Renal ischemia regulates marinobufagenin release in humans. Hypertension 2010;56:914-919.
53. Uddin MN, Agunanne EE, Horvat D, Puschett JB. Resibufogenin administration prevents oxidative stress in a rat model of human preeclampsia. Hypertens Pregnancy 2012;31:70-78.
54. Uddin MN, Horvat D, Childs EW, Puschett JB. Marinobufagenin causes endothelial cell monolayer hyperpermeability by altering apoptic signaling. Am J Physiol Regul Integr Comp Physiol 2009;296:R1726-R1734.
55. Uddin MN, Horvat D, Glaser SS, et al. Marinobufagenin inhibits proliferation and migration of cytotrophoblast and CHO cells. Placenta 2008;29:266-273.
56. Uddin MN, McLean LB, Hunter FA, et al. Vascular leak in a rat model of preeclampsia. Am J Nephrol 2009;30:26-33.
57. Vu H, Ianosi-Irimie M, Danchuk S, et al. Resibufogenin corrects hypertension in a rat model of human preeclampsia. Exp Biol Med 2006;231:215-220.
58. Vu HV, Ianosi-Irimie MR, Pridjian CA, et al. Involvement of marinobufagenin in a rat model of human preeclampsia. Am J Nephrol 2005;25:520-528.
59. West TA, Marion DW. Current recommendations for the diagnosis and treatment of concussion in sport: a comparison of three new guidelines. J Neurotrauma 2014;31:159-168.
60. Wright DA, Lord GA, White RW, et al. Evidence for a circulating bufodienolide in a volume-expanded patient. Lancet 1997;350:409.
61. Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory distress syndrome.