Ions and Fluid Dynamics in Hypertension

  • Avram Z. TraumEmail author
Reference work entry


Ion transport is known to be involved in the genesis of hypertension and is utilized therapeutically. However, the mechanisms behind sodium flux that may lead to hypertension are not well understood. Target proteins of diuretic agents, monogenic forms of hypertension, and genetic disorders of renal salt wasting have all provided insight into these pathways. In this chapter, we review some of these channels and their relevance to human hypertension. We explore the role of the cytoskeletal protein adducin in the regulation of sodium transport. We examine the function of the osmotically inactive sodium compartment and its regulation, and hormonal alterations affecting this compartment in salt-sensitive hypertension.


Sodium channel Salt sensitive Adducin Ouabain Rostafuroxin Osmotically active sodium 


  1. Akita S, Sacks FM, Svetkey LP, Conlin PR, Kimura G (2003) Effects of the dietary approaches to stop hypertension (DASH) diet on the pressure-natriuresis relationship. Hypertension 42:8–13CrossRefGoogle Scholar
  2. ALLHAT Investigators (2000) Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group Jama 283:1967–1975Google Scholar
  3. ALLHAT Investigators (2003) Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension 42:239–246CrossRefGoogle Scholar
  4. Baker EH, Dong YB, Sagnella GA, Rothwell M, Onipinla AK, Markandu ND, Cappuccio FP, Cook DG, Persu A, Corvol P, Jeunemaitre X, Carter ND, Macgregor GA (1998) Association of hypertension with T594M mutation in beta subunit of epithelial sodium channels in black people resident in London. Lancet 351:1388–1392CrossRefGoogle Scholar
  5. Bianchi G, Tripodi G, Casari G, Salardi S, Barber BR, Garcia R, Leoni P, Torielli L, Cusi D, Ferrandi M et al (1994) Two point mutations within the adducin genes are involved in blood pressure variation. Proc Natl Acad Sci USA 91:3999–4003CrossRefGoogle Scholar
  6. Blaustein MP (1993) Physiological effects of endogenous ouabain: control of intracellular Ca2+ stores and cell responsiveness. Am J Physiol 264:C1367–C1387CrossRefGoogle Scholar
  7. Blaustein MP, Zhang J, Chen L, Song H, Raina H, Kinsey SP, Izuka M, Iwamoto T, Kotlikoff MI, Lingrel JB, Philipson KD, Wier WG, Hamlyn JM (2009) The pump, the exchanger, and endogenous ouabain: signaling mechanisms that link salt retention to hypertension. Hypertension 53:291–298CrossRefGoogle Scholar
  8. Block GA, Rosenbaum DP, Leonsson-Zachrisson M, Stefansson BV, Ryden-Bergsten T, Greasley PJ, Johansson SA, Knutsson M, Carlsson BC (2016) Effect of tenapanor on interdialytic weight gain in patients on hemodialysis. Clin J Am Soc Nephrol 11:1597–1605CrossRefGoogle Scholar
  9. Cacciafesta M, Ferri C, Carlomagno A, De Angelis C, Scuteri A, Guidoni L, Luciani AM, Rosi A, Viti V, Santucci A et al (1994) Erythrocyte Na-K-Cl cotransport activity in low renin essential hypertensive patients. A 23Na nuclear magnetic resonance study. Am J Hypertens 7:151–158CrossRefGoogle Scholar
  10. Canessa M, Morgan K, Goldszer R, Moore TJ, Spalvins A (1991) Kinetic abnormalities of the red blood cell sodium-proton exchange in hypertensive patients. Hypertension 17:340–348CrossRefGoogle Scholar
  11. Cao C, Payne K, Lee-Kwon W, Zhang Z, Lim SW, Hamlyn J, Blaustein MP, Kwon HM, Pallone TL (2009) Chronic ouabain treatment induces vasa recta endothelial dysfunction in the rat. Am J Physiol Renal Physiol 296:F98–F106CrossRefGoogle Scholar
  12. Capasso G, Rizzo M, Garavaglia ML, Trepiccione F, Zacchia M, Mugione A, Ferrari P, Paulmichl M, Lang F, Loffing J, Carrel M, Damiano S, Wagner CA, Bianchi G, Meyer G (2008) Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension. Am J Physiol Renal Physiol 295:F556–F567CrossRefGoogle Scholar
  13. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ (2003) The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. Jama 289:2560–2572CrossRefGoogle Scholar
  14.[NCT01847092] (2013) A study in CKD patients with type 2 diabetes mellitus and albuminuria [Online]
  15. Cui Y, Su YR, Rutkowski M, Reif M, Menon AG, Pun RY (1997) Loss of protein kinase C inhibition in the beta-T594M variant of the amiloride-sensitive Na+ channel. Proc Natl Acad Sci USA 94:9962–9966CrossRefGoogle Scholar
  16. Cusi D, Fossali E, Piazza A, Tripodi G, Barlassina C, Pozzoli E, Vezzoli G, Stella P, Soldati L, Bianchi G (1991) Heritability estimate of erythrocyte Na-K-Cl cotransport in normotensive and hypertensive families. Am J Hypertens 4:725–734CrossRefGoogle Scholar
  17. Cusi D, Niutta E, Barlassina C, Bollini P, Cesana B, Stella P, Robba C, Merati G, Bianchi G (1993) Erythrocyte Na+,K+,Cl− cotransport and kidney function in essential hypertension. J Hypertens 11:805–813CrossRefGoogle Scholar
  18. Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M, Glorioso N, Lanzani C, Manunta P, Righetti M, Rivera R, Stella P, Troffa C, Zagato L, Bianchi G (1997) Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet 349:1353–1357CrossRefGoogle Scholar
  19. Diez J, Alonso A, Garciandia A, Lopez R, Gomez-Alamillo C, Arrazola A, Fortuno A (1995) Association of increased erythrocyte Na+/H+ exchanger with renal Na+ retention in patients with essential hypertension. Am J Hypertens 8:124–132CrossRefGoogle Scholar
  20. Dudley CR, Taylor DJ, Ng LL, Kemp GJ, Ratcliffe PJ, Radda GK, Ledingham JG (1990) Evidence for abnormal Na+/H+ antiport activity detected by phosphorus nuclear magnetic resonance spectroscopy in exercising skeletal muscle of patients with essential hypertension. Clin Sci (Lond) 79:491–497CrossRefGoogle Scholar
  21. Eckel RH, Jakicic JM, Ard JD, De Jesus JM, Houston Miller N, Hubbard VS, Lee IM, Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM, Smith SC Jr, Svetkey LP, Wadden TA, Yanovski SZ, Kendall KA, Morgan LC, Trisolini MG, Velasco G, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, Demets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF, American College of Cardiology/American Heart Association Task Force on Practice Guidelines (2014) 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129:S76–S99CrossRefGoogle Scholar
  22. Efendiev R, Krmar RT, Ogimoto G, Zwiller J, Tripodi G, Katz AI, Bianchi G, Pedemonte CH, Bertorello AM (2004) Hypertension-linked mutation in the adducin alpha-subunit leads to higher AP2-mu2 phosphorylation and impaired Na+,K+-ATPase trafficking in response to GPCR signals and intracellular sodium. Circ Res 95:1100–1108CrossRefGoogle Scholar
  23. Fava C, Montagnana M, Rosberg L, Burri P, Almgren P, Jonsson A, Wanby P, Lippi G, Minuz P, Hulthen LU, Aurell M, Melander O (2008) Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure. Hum Mol Genet 17:413–418CrossRefGoogle Scholar
  24. Ferrandi M, Minotti E, Salardi S, Florio M, Bianchi G, Ferrari P (1992) Ouabainlike factor in Milan hypertensive rats. Am J Physiol 263:F739–F748PubMedGoogle Scholar
  25. Ferrari P, Ferrandi M, Tripodi G, Torielli L, Padoani G, Minotti E, Melloni P, Bianchi G (1999) PST 2238: A new antihypertensive compound that modulates Na,K-ATPase in genetic hypertension. J Pharmacol Exp Ther 288:1074–1083PubMedGoogle Scholar
  26. Ferrari P, Ferrandi M, Valentini G, Bianchi G (2006) Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+-K+- ATPase alterations in ouabain and adducin-dependent hypertension. Am J Physiol Regul Integr Comp Physiol 290:R529–R535CrossRefGoogle Scholar
  27. Fortuno A, Tisaire J, Lopez R, Bueno J, Diez J (1997) Angiotensin converting enzyme inhibition corrects Na+/H+ exchanger overactivity in essential hypertension. Am J Hypertens 10:84–93CrossRefGoogle Scholar
  28. Haas M, Askari A, Xie Z (2000) Involvement of Src and epidermal growth factor receptor in the signal-transducing function of Na+/K+-ATPase. J Biol Chem 275:27832–27837PubMedGoogle Scholar
  29. Hamlyn JM, Hamilton BP, Manunta P (1996) Endogenous ouabain, sodium balance and blood pressure: a review and a hypothesis. J Hypertens 14:151–167CrossRefGoogle Scholar
  30. Haupert GT Jr (1988) Circulating inhibitors of sodium transport at the prehypertensive stage of essential hypertension. J Cardiovasc Pharmacol 12(Suppl 3):S70–S76CrossRefGoogle Scholar
  31. Hayashi M, Yoshida T, Monkawa T, Yamaji Y, Sato S, Saruta T (1997) Na+/H+-exchanger 3 activity and its gene in the spontaneously hypertensive rat kidney. J Hypertens 15:43–48PubMedGoogle Scholar
  32. Hollier JM, Martin DF, Bell DM, Li JL, Chirachanchai MG, Menon DV, Leonard D, Wu X, Cooper RS, Mckenzie C, Victor RG, Auchus RJ (2006) Epithelial sodium channel allele T594M is not associated with blood pressure or blood pressure response to amiloride. Hypertension 47:428–433CrossRefGoogle Scholar
  33. Husted RF, Takahashi T, Stokes JB (1996) IMCD cells cultured from Dahl S rats absorb more Na+ than Dahl R rats. Am J Physiol 271:F1029–F1036PubMedGoogle Scholar
  34. Husted RF, Takahashi T, Stokes JB (1997) The basis of higher Na+ transport by inner medullary collecting duct cells from Dahl salt-sensitive rats: implicating the apical membrane Na+ channel. J Membr Biol 156:9–18CrossRefGoogle Scholar
  35. Ji W, Foo JN, O’Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP (2008) Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40:592–599CrossRefGoogle Scholar
  36. Kamitani A, Wong ZY, Fraser R, Davies DL, Connor JM, Foy CJ, Watt GC, Harrap SB (1998) Human alpha-adducin gene, blood pressure, and sodium metabolism. Hypertension 32:138–143CrossRefGoogle Scholar
  37. Kato N, Sugiyama T, Nabika T, Morita H, Kurihara H, Yazaki Y, Yamori Y (1998) Lack of association between the alpha-adducin locus and essential hypertension in the Japanese population. Hypertension 31:730–733CrossRefGoogle Scholar
  38. Kelly MP, Quinn PA, Davies JE, Ng LL (1997) Activity and expression of Na(+)-H+ exchanger isoforms 1 and 3 in kidney proximal tubules of hypertensive rats. Circ Res 80:853–860CrossRefGoogle Scholar
  39. Kobayashi K, Monkawa T, Hayashi M, Saruta T (2004) Expression of the Na+/H+ exchanger regulatory protein family in genetically hypertensive rats. J Hypertens 22:1723–1730CrossRefGoogle Scholar
  40. Kopp C, Linz P, Dahlmann A, Hammon M, Jantsch J, Muller DN, Schmieder RE, Cavallaro A, Eckardt KU, Uder M, Luft FC, Titze J (2013) 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. Hypertension 61:635–640CrossRefGoogle Scholar
  41. Lankhorst S, Severs D, Marko L, Rakova N, Titze J, Muller DN, Danser AH, Van Den Meiracker AH (2015) 6b.05: salt-sensitivity of angiogenesis inhibition-induced blood pressure (Bp) rise: role of interstitial sodium accumulation? J Hypertens 33((Suppl 1)):e77CrossRefGoogle Scholar
  42. Lanzani C, Citterio L, Glorioso N, Manunta P, Tripodi G, Salvi E, Carpini SD, Ferrandi M, Messaggio E, Staessen JA, Cusi D, Macciardi F, Argiolas G, Valentini G, Ferrari P, Bianchi G (2010) Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 2: clinical studies. Sci Transl Med 2:59ra87CrossRefGoogle Scholar
  43. Li YY (2012) Alpha-Adducin Gly460Trp gene mutation and essential hypertension in a Chinese population: a meta-analysis including 10,960 subjects. PLoS One 7:e30214CrossRefGoogle Scholar
  44. Liu J, Tian J, Haas M, Shapiro JI, Askari A, Xie Z (2000) Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. J Biol Chem 275:27838–27844PubMedGoogle Scholar
  45. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Muller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, Van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J (2009) Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med 15:545–552CrossRefGoogle Scholar
  46. Melzi ML, Bertorello A, Fukuda Y, Muldin I, Sereni F, Aperia A (1989) Na,K-ATPase activity in renal tubule cells from Milan hypertensive rats. Am J Hypertens 2:563–566CrossRefGoogle Scholar
  47. Murrell JR, Randall JD, Rosoff J, Zhao JL, Jensen RV, Gullans SR, Haupert GT Jr (2005) Endogenous ouabain: upregulation of steroidogenic genes in hypertensive hypothalamus but not adrenal. Circulation 112:1301–1308CrossRefGoogle Scholar
  48. NHBPEP Working Group on High Blood Pressure in Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114:555–576CrossRefGoogle Scholar
  49. Obarzanek E, Proschan MA, Vollmer WM, Moore TJ, Sacks FM, Appel LJ, Svetkey LP, Most-Windhauser MM, Cutler JA (2003) Individual blood pressure responses to changes in salt intake: results from the DASH-Sodium trial. Hypertension 42:459–467CrossRefGoogle Scholar
  50. Orlov SN, Adragna NC, Adarichev VA, Hamet P (1999) Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension. Am J Physiol 276:C511–C536CrossRefGoogle Scholar
  51. Parenti P, Villa M, Hanozet GM, Ferrandi M, Ferrari P (1991) Increased Na pump activity in the kidney cortex of the Milan hypertensive rat strain. FEBS Lett 290:200–204CrossRefGoogle Scholar
  52. Persu A, Barbry P, Bassilana F, Houot AM, Mengual R, Lazdunski M, Corvol P, Jeunemaitre X (1998) Genetic analysis of the beta subunit of the epithelial Na+ channel in essential hypertension. Hypertension 32:129–137CrossRefGoogle Scholar
  53. Pritchard TJ, Parvatiyar M, Bullard DP, Lynch RM, Lorenz JN, Paul RJ (2007) Transgenic mice expressing Na+-K+-ATPase in smooth muscle decreases blood pressure. Am J Physiol Heart Circ Physiol 293:H1172–H1182CrossRefGoogle Scholar
  54. Righetti M, Cusi D, Stella P, Rivera R, Bernardi L, Del Vecchio L, Bianchi G (1995) Na+,K+,Cl- cotransport is a marker of distal tubular function in essential hypertension. J Hypertens 13:1775–1778CrossRefGoogle Scholar
  55. Salvati P, Ferrario RG, Bianchi G (1990) Diuretic effect of bumetanide in isolated perfused kidneys of Milan hypertensive rats. Kidney Int 37:1084–1089CrossRefGoogle Scholar
  56. Schultheis PJ, Clarke LL, Meneton P, Miller ML, Soleimani M, Gawenis LR, Riddle TM, Duffy JJ, Doetschman T, Wang T, Giebisch G, Aronson PS, Lorenz JN, Shull GE (1998) Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nat Genet 19:282–285CrossRefGoogle Scholar
  57. Simon DB, Karet FE, Hamdan JM, Dipietro A, Sanjad SA, Lifton RP (1996) Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 13:183–188CrossRefGoogle Scholar
  58. Slagman MC, Kwakernaak AJ, Yazdani S, Laverman GD, Van Den Born J, Titze J, Navis G (2012) Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects. Nephrol Dial Transplant 27:978–982CrossRefGoogle Scholar
  59. Song H, Lee MY, Kinsey SP, Weber DJ, Blaustein MP (2006) An N-terminal sequence targets and tethers Na+ pump alpha2 subunits to specialized plasma membrane microdomains. J Biol Chem 281:12929–12940CrossRefGoogle Scholar
  60. Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Bell N, Tabora J, Joly KM, Navre M, Jacobs JW, Charmot D (2014) Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Tran Med 6:227ra36CrossRefGoogle Scholar
  61. Staessen JA, Thijs L, Stolarz-Skrzypek K, Bacchieri A, Barton J, Espositi ED, De Leeuw PW, Dluzniewski M, Glorioso N, Januszewicz A, Manunta P, Milyagin V, Nikitin Y, Soucek M, Lanzani C, Citterio L, Timio M, Tykarski A, Ferrari P, Valentini G, Kawecka-Jaszcz K, Bianchi G (2011) Main results of the ouabain and adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin. Trials 12:13CrossRefGoogle Scholar
  62. Su YR, Rutkowski MP, Klanke CA, Wu X, Cui Y, Pun RY, Carter V, Reif M, Menon AG (1996) A novel variant of the beta-subunit of the amiloride-sensitive sodium channel in African Americans. J Am Soc Nephrol 7:2543–2549PubMedGoogle Scholar
  63. Syme PD, Aronson JK, Thompson CH, Williams EM, Green Y, Radda GK (1991) Na+/H+ and HCO3-/Cl- exchange in the control of intracellular pH in vivo in the spontaneously hypertensive rat. Clin Sci (Lond) 81:743–750CrossRefGoogle Scholar
  64. Tao QF, Hollenberg NK, Price DA, Graves SW (1997) Sodium pump isoform specificity for the digitalis-like factor isolated from human peritoneal dialysate. Hypertension 29:815–821CrossRefGoogle Scholar
  65. Titze J, Krause H, Hecht H, Dietsch P, Rittweger J, Lang R, Kirsch KA, Hilgers KF (2002) Reduced osmotically inactive Na storage capacity and hypertension in the Dahl model. Am J Physiol Renal Physiol 283:F134–F141CrossRefGoogle Scholar
  66. Titze J, Lang R, Ilies C, Schwind KH, Kirsch KA, Dietsch P, Luft FC, Hilgers KF (2003) Osmotically inactive skin Na+ storage in rats. Am J Physiol Renal Physiol 285:F1108–F1117CrossRefGoogle Scholar
  67. Titze J, Shakibaei M, Schafflhuber M, Schulze-Tanzil G, Porst M, Schwind KH, Dietsch P, Hilgers KF (2004) Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin. Am J Physiol Heart Circ Physiol 287:H203–H208CrossRefGoogle Scholar
  68. Torielli L, Tivodar S, Montella RC, Iacone R, Padoani G, Tarsini P, Russo O, Sarnataro D, Strazzullo P, Ferrari P, Bianchi G, Zurzolo C (2008) Alpha-Adducin mutations increase Na/K pump activity in renal cells by affecting constitutive endocytosis: implications for tubular Na reabsorption. Am J Physiol Renal Physiol 295:F478–F487CrossRefGoogle Scholar
  69. Tripodi G, Valtorta F, Torielli L, Chieregatti E, Salardi S, Trusolino L, Menegon A, Ferrari P, Marchisio PC, Bianchi G (1996) Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. J Clin Invest 97:2815–2822CrossRefGoogle Scholar
  70. Zhu H, Sagnella GA, Dong Y, Miller MA, Onipinla A, Markandu ND, MacGregor GA (2004) Molecular variants of the sodium/hydrogen exchanger type 3 gene and essential hypertension. J Hypertens 22:1269–1275CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of NephrologyBoston Children’s HospitalBostonUSA
  2. 2.Department of PediatricsHarvard Medical SchoolBostonUSA

Section editors and affiliations

  • Julie R. Ingelfinger
    • 1
  1. 1.Pediatric Nephrology UnitMassGeneral Hospital for Children at MGH, Harvard Medical SchoolBostonUSA

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