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Selective association of endogenous ouabain with subclinical organ damage in treated hypertensive patients

Journal of Human Hypertension volume 25, pages 122–129 (2011)Cite this article

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Abstract

According to previous studies endogenous ouabain (EO) closely correlates with high blood pressure, congestive heart failure and kidney disease in humans. Our aims were to analyse associations between plasma, urinary EO level and various markers of cardiovascular damage in treated hypertensive patients. Forty-one adult patients with hypertension and/or diabetes mellitus (DM) and/or chronic kidney disease (CKD) were studied. We assessed plasma and urinary EO, pro-brain natriuretic peptide and catecholamines, profile of ambulatory blood pressure monitor and cardiovascular status by echocardiography and echo-tracking. The highest level of plasma EO (19.7±9.5 pmol l–1) was measured in hypertensive patients with DM and CKD. The nighttime mean arterial blood pressure independently correlated with the level of plasma EO (P=0.004), while independent predictor of the β-stiffness of carotid artery was the urinary EO (P=0.011). Elevated level of EO was associated with nighttime blood pressure and subclinical organ damage in treated hypertensive patients, suggesting possible role of EO in the pathogenesis of impaired diurnal blood pressure rhythm and arterial stiffness.

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References

  1. Hamlyn JM, Blaustein MP, Bova S, DuCharme DW, Harris DW, Mandel F et al. Identification and characterization of an ouabain-like compound from human plasma. Proc Natl Acad Sci USA 1991; 88: 6259–6263.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Bagrov AY, Shapiro JI . Endogenous digitalis: pathophysiologic roles and therapeutic applications. Nat Clin Pract Nephrol 2008; 4: 378–392.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Manunta P, Ferrandi M, Bianchi G, Hamlyn JH . Endogenous ouabain in cardiovascular function and disease. J Hypertens 2009; 27: 9–18.

    Article  CAS  PubMed  Google Scholar 

  4. Stella P, Manunta P, Mallamaci F, Melandri M, Spotti D, Tripepi G et al. Endogenous ouabain and cardiomyopathy in dialysis patients. J Intern Med 2008; 263: 274–280.

    Article  CAS  PubMed  Google Scholar 

  5. Bauer N, Müller-Ehmsen J, Krämer U, Hambarchian N, Zobel C, Schwinger RH et al. Ouabain-like compound changes rapidly on physical exercise in humans and dogs: effects of ß-blockade and angiotensin-converting enzyme inhibition. Hypertension 2005; 45: 1024–1028.

    Article  CAS  PubMed  Google Scholar 

  6. Balzan S, Montali U, Biver P, Ghione S . Antidigoxin antibodies neutralize the effect of newborn endogenous digitalis-like factor on erythrocyte 86Rb uptake. J Nucl Biol Med 1991; 35: 38–40.

    CAS  PubMed  Google Scholar 

  7. Bagrov AY, Shapiro JI, Fedorova OV . Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev 2009; 61: 9–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Blaustein MP, Zhang J, Chen L, Song H, Raina H, Kinsey SP et al. The pump, the exchanger, and endogenous ouabain: signaling mechanisms that link salt retention to hypertension. Hypertension 2009; 53: 291–298.

    Article  CAS  PubMed  Google Scholar 

  9. Dostanic-Larson I, Lorenz JN, Van Huysse JW, Neumann JC, Moseley AE, Lingrel JB . Physiological role of the alpha1- and alpha2-isoforms of the Na+-K+-ATPase and biological significance of their cardiac glycoside binding site. Am J Physiol Regul Integr Comp Physiol 2006; 290: R524–R528.

    Article  CAS  PubMed  Google Scholar 

  10. Huang BS, Huang X, Harmsen E, Leenen FHH . Chronic central versus peripheral ouabain, blood pressure, and sympathetic activity in rats. Hypertension 1994; 23: 1087–1090.

    Article  CAS  PubMed  Google Scholar 

  11. Skoumal R, Szokodi I, Aro J, Földes G, Göoz M, Seres L et al. Involvement of endogenous ouabain-like compound in cardiac hypertrophic process in vivo. Life Sci 2007; 80: 1303–1310.

    Article  CAS  PubMed  Google Scholar 

  12. Liu J, Tian J, Haas M, Shapiro JI, Askari A, Xie Z . Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. J Biol Chem 2000; 275: 27838–27844.

    CAS  PubMed  Google Scholar 

  13. Aydemir-Koksoy A, Abramowitz J, Allen JC . Ouabain-induced signaling and vascular smooth muscle cell proliferation. J Biol Chem 2001; 276: 46605–46611.

    Article  CAS  PubMed  Google Scholar 

  14. 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: 215–224.

    Article  CAS  PubMed  Google Scholar 

  15. Manunta P, Stella P, Rivera R, Ciurlino D, Cusi D, Ferrandi M et al. Left ventricular mass, stroke volume, and ouabain-like factor in essential hypertension. Hypertension 1999; 34: 450–456.

    Article  CAS  PubMed  Google Scholar 

  16. Balzan S, Neglia D, Ghione S, D’Urso G, Baldacchino MC, Montali U et al. Increased circulating levels of ouabain-like factor in patient with asymptomatic left ventricular dysfunction. Eur J Heart Fail 2001; 3: 165–171.

    Article  CAS  PubMed  Google Scholar 

  17. 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: 664–670.

    Article  PubMed  Google Scholar 

  18. Grossmann M, Jamieson MJ, Kirch W . Effects of digoxin and digitoxin on circadian blood pressure profile in healthy volunteers. Eur J Clin Invest 1998; 28: 701–706.

    Article  CAS  PubMed  Google Scholar 

  19. Kirch C, Grossmann M, Fischer S, Neumeister V, Kirch W . Effect of digoxin on circadian blood pressure values in patients with congestive heart failure. Eur J Clin Invest 2000; 30: 285–289.

    Article  CAS  PubMed  Google Scholar 

  20. Grossmann M . Effects of cardiac glycosides on 24-h ambulatory blood pressure in healthy volunteers and patients with heart failure. Eur J Clin Invest 2001; 31 (Suppl 2): S26–S30.

    Article  Google Scholar 

  21. Clerico A, Giampietro O, Gregori G, Del Chicca MG, Bertoli S, Miccoli R et al. Excretion of digoxin-like immunoreactivity in urine of normal subjects: Correlations with excretion of creatinine and electrolytes. Clin Chem 1988; 34: 554–556.

    CAS  PubMed  Google Scholar 

  22. Vakkuri O, Arnason SS, Joensuu P, Jalonen J, Vuolteenaho O, Leppäluoto J . Radioionated tyroly-ouabain and measurement of a circulating ouabain-like compound. Clin Chem 2001; 47: 95–101.

    CAS  PubMed  Google Scholar 

  23. Collinson PO, Barnes SC, Gaze DC, Galasko G, Lahiri A, Senior R . Analytical performance of the N terminal pro B type natriuretic peptide (NT-proBNP) assay on the Elecsys 1010 and 2010 analysers. Eur J Heart Fail 2004; 6: 365–368.

    Article  CAS  PubMed  Google Scholar 

  24. Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ et al. American Society of Echocardiography. American Society of Echocardiography recommendations for use of echocardiography in clinical trials; a report from the American Society of Echocardiography's Guidelines and Standards Committee and The Task Force on Echocardiography in Clinical Trials. J Am Soc Echocardiogr 2004; 17: 1086–1119.

    PubMed  Google Scholar 

  25. Niki K, Sugawara M, Chang D, Harada A, Okada T, Sakai R et al. A new noninvasive measurement system for wave intensity: evaluation of carotid arterial wave intensity and reproducibility. Heart Vessels 2002; 17: 12–21.

    Article  PubMed  Google Scholar 

  26. Schillaci G, Verdecchia P, Borgioni C, Ciucci A, Gattobigio R, Sacchi N et al. Predictors of diurnal blood pressure changes in 2042 subjects with essential hypertension. J Hypertens 1996; 14: 1167–1173.

    Article  CAS  PubMed  Google Scholar 

  27. Giles TD . Circadian rhythm of blood pressure and the relation to cardiovascular events. J Hypertens Suppl 2006; 24: 11–16.

    Article  Google Scholar 

  28. Tripodi G, Citterio L, Kouznetsova T, Lanzani C, Florio M, Modica R et al. Steroid biosythesis and renal excretion in human essential hypertension: association with blood pressure and endogenous ouabain. Am J Hypertens 2009; 22: 357–363.

    Article  CAS  PubMed  Google Scholar 

  29. Vakkuri O, Arnason SS, Pouta A, Vuolteenaho O, Leppäluoto J . Radioimmunoassay of plasma oaubain in healthy and pregnant individuals. J Endocrinol 2000; 165: 669–677.

    Article  CAS  PubMed  Google Scholar 

  30. Manunta P, Iacoviello M, Forleo C, Messaggio E, Hamlyn JM, Lucarelli K et al. High circulating levels of endogenous ouabain in the offspring of hypertensive and normotensive individuals. J Hypertens 2005; 23: 1677–1681.

    Article  CAS  PubMed  Google Scholar 

  31. Crabos M, Ausiello DA, Haupert Jr GT, Cantiello HF . Atrial natriuretic peptide regulates release of Na+, K+-ATPase inhibitor from rat brain. Am J Physiol 1988; 254: F912–F917.

    CAS  PubMed  Google Scholar 

  32. Salomaa V, Riley W, Kark JD, Nardo C, Folsom AR . Non-insulin-dependent diabetes mellitus and fasting glucose and insulin concentrations are associated with arterial stiffness indexes. The ARIC Study. Atherosclerosis Risk in Communities Study. Circulation 1995; 91: 1432–1443.

    Article  CAS  PubMed  Google Scholar 

  33. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM . Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999; 99: 2434–2439.

    Article  CAS  PubMed  Google Scholar 

  34. Safar ME, Levy BI, Struijker-Boudier H . Current perspectives on arterial siffness and pulse pressure in hypertension and cardiovascular disease. Circulation 2003; 107: 2864–2869.

    Article  PubMed  Google Scholar 

  35. Briones AM, Xavier FE, Arribas SM, González MC, Rossoli LV, Alonso MJ et al. Alterations in structure and mechanics of resistance arteries from ouabain-induced hypertensive rats. Am J Physiol Heart Circ Physiol 2006; 291: H193–H201.

    Article  CAS  PubMed  Google Scholar 

  36. Kawamoto R, Kohara K, Tabara Y, Miki T, Ohtsuka N, Kusunoki T et al. An association between decreased estimated glomerular filtration rate and arterial stiffness. Intern Med 2008; 47: 593–598.

    Article  PubMed  Google Scholar 

  37. Nakagawa N, Takahashi F, Chinda J, Kobayashi M, Hayashi Y, Abe M et al. A newly estimated glomerular filtration rate is independently associated with arterial stiffness in Japanase patients. Hypertens Res 2008; 31: 193–201.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. 2nd Department of Medicine and Nephrological Center, Faculty of Medicine, University of Pécs, Pécs, Hungary

    G Nagy, L Markó, J Cseh & I Wittmann

  2. Faculty of Medicine, Heart Institute, University of Pécs, Pécs, Hungary

    B Gaszner & A Cziráki

  3. Department of Laboratory Medicine, Faculty of Medicine, University of Pécs, Pécs, Hungary

    É Lányi & T Kõszegi

  4. Department of Radiology, Faculty of Medicine, University of Pécs, Pécs, Hungary

    E Fehér

  5. Department of Emergency Care, Faculty of Health Sciences, University of Pécs, Pécs, Hungary

    G Nagy & J Betlehem

  6. Faculty of Health Sciences, University of Pécs, Pécs, Hungary

    E Sulyok

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  1. G Nagy
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Correspondence to I Wittmann.

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Nagy, G., Gaszner, B., Lányi, É. et al. Selective association of endogenous ouabain with subclinical organ damage in treated hypertensive patients. J Hum Hypertens 25, 122–129 (2011). https://doi.org/10.1038/jhh.2010.24

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