Brain Na,K-ATPase Enzymatic Activity and Cardiovascular Regulation

  • Mary-Anne H. Kent
  • JAMES W. VAN Huysse
  • Frans H. H. Leenen
Part of the Progress in Experimental Cardiology book series (PREC, volume 8)


Na,K-ATPase enzymatic activity, by maintaining intracellular cation homeostasis regulates many cellular functions. This review focuses on the role of brain Na,K-ATPase activity in cardiovascular regulation. Na,K-ATPase activity in cardiovascular/osmo-regulatory nuclei may regulate cardiovascular function by modulating neurotransmitter release and/or cell responsiveness. Inhibition of Na,K-ATPase activity in cardiovascular/osmo-regulatory nuclei increases blood pressure and causes hypertension. Inversely, an increase in Na,K-ATPase activity in nuclei involved in cardiovascular/osmo-regulation decreases blood pressure in normotensive and hypertensive rats. A decrease in brain Na, K-ATPase activity is associated with several cardiovascular diseases such as salt-sensitive hypertension, heart failure post myocardial infarction (MI) and hypertension induced by suprarenal aortic constriction (SRC). In hyper-tension induced by SRC, brain Na,K-ATPase isozyme expression and activity decrease in the early phase but increase in the established phase of the hypertension. The decrease in brain Na,K-ATPase activity in salt-sensitive hypertension appears to be mediated by a direct inhibitory action of brain ouabain-like-compounds (OLCs) and reflects mainly a decrease in OC2/GC3 isozyme activity. In rats post MI, brain OLCs decrease both (Xi and a2/OC3 Na,K-ATPase isozyme activity by direct and indirect mechanisms that may not involve a change in expres-sion. Brain OLCs may indirectly modulate Na,K-ATPase activity by increasing the release of neurotransmitters such as NE and ACh that regulate Na,K-ATPase activity. The neurotransmitters involved in mediating the changes in Na,K-ATPase activity in rats post MI or in hypertension are not yet known. However, these studies suggest that brain a2/OC3 as well as C*! Na,K-ATPase isozymes may play a role in the central control of the circulation.

Key words

Na K-ATPase enzymatic activity αsubunit isoform expression Cardiovascular regulation Endogenous ouabain-like-compounds 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Blanco G, Mercer R. 1998. Isozymes of the Na,K-ATPase: Heterogeneity in structure, diversity in function. Am J Physiol 275:F633–F650.PubMedGoogle Scholar
  2. 2.
    Mobasheri A, Avila J, Cozar-Castellano I, Brownleader MD, Trevan M, Lamb JF, Martin-Vasallo P. 2000. Na+,K+-ATPase Isozyme diversity; Comparative biochemistry and physiological implications of novel functional interactions. Biosci Rep 20:51–91.PubMedCrossRefGoogle Scholar
  3. 3.
    McGrail KM, Phillips JM, Sweadner KJ. 1991. Immunofluorescent localization of the three Na,K- ATPase isozymes in the rat central nervous system: Both neurons and glia can express more than one Na,K-ATPase. The J Neurosci 11:381–391.Google Scholar
  4. 4.
    Brines ML, Gulanski BI, Gilmore-Herbert M, Greene AL, Benz Jr EJ, Robbins RJ. 1991. Cytoar-chitectural relationships between [3H]ouabain binding and mRNA for isoforms of the sodium pump catalytic subunit in rat brain. Mol Brain Res 10:139–150.PubMedCrossRefGoogle Scholar
  5. 5.
    Brines ML, Robbins RJ. 1993. Cell-type specific expression of the Na+,K+-ATPase catalytic subunits in cultured neurons and glia: evidence for polarized distribution in neurons. Brain Res 631:1–11.PubMedCrossRefGoogle Scholar
  6. 6.
    Peng L, Martin-Vasallo P, Sweadner KJ. 1997. Isoform of the Na,K-ATPase a and (3 subunits in the rat cerebellum and in granule cell cultures. The I Neurosci 17:3488–3502.Google Scholar
  7. 7.
    Dobretsov M, Hastings SL, Stimers HR. 1999. Non-uniform expression of a subunit of the Na+/K+ pump in rat dorsal root ganglia neurons. Brain Res 821:212–217.PubMedCrossRefGoogle Scholar
  8. 8.
    Blaustein MP. 1993. Physiological effects of endogenous ouabain: control of intracellular Ca+ stores and cell responsiveness. Am J Physiol 264:C1367–C1387.PubMedGoogle Scholar
  9. 9.
    Hajek I, Subbarao KVS, Hertz L. 1996. Acute and chronic effects of potassium and noradrenaline on Na+,K+-ATPase activity in cultured mouse neurons and astrocytes. Neurochem Int 28:335–342.PubMedCrossRefGoogle Scholar
  10. 10.
    Katz AM. 1985. Effects of digitalis on cell biochemistry: Sodium pump inhibition. J Am Coll Cardiol 5:16A–21A.PubMedCrossRefGoogle Scholar
  11. 11.
    Sweadner KJ. 1989. Isozyme of the Na,K-ATPase. Biochim Biophys Acta 988:185–220.PubMedCrossRefGoogle Scholar
  12. 12.
    Therien AG, Nestor NB, Ball WJ, Blostein R. 1996. Tissue-specific vs isoform specific differences in cation activation kinetics of the Na,K-ATPase. J Biol Chem 271:7104–7112.PubMedCrossRefGoogle Scholar
  13. 13.
    Ewart HS, Klip A. 1995. Hormonal regulation of the Na,K-ATPase: mechanisms underlying rapid and sustained changes in pump activity. Am J Physiol 269:C295–C311.PubMedGoogle Scholar
  14. 14.
    Huang BS, Harmsen E, Yu H, Leenen FHH. 1992. Brain ouabain-like activity and the sympatho-excitatory and pressor effects on central sodium in rats. Circ Res 71:1059–1066.PubMedCrossRefGoogle Scholar
  15. 15.
    Jones DL, Lo S. 1990. Ouabain injected into the hypothalamus elicits pressor responses in anaes-thetized rats. A mapping study. Pharmac Biochem Behav 36:979–983.CrossRefGoogle Scholar
  16. 16.
    Budzikowski AS, Leenen FHH. 1997. Brain ouabain in the median preoptic nucleus mediates salt-sensitive hypertension in spontaneously hypertensive rats. Hypertension 29:599–605.PubMedCrossRefGoogle Scholar
  17. 17.
    Teruya H, Yamazato M, Muratani H, Sakima A, Takishita S, Terano Y, Fukiyama K. 1997. Role of ouabain-like-compound in the rostral ventral medulla in rats. J Clin Invest 99:2791–2798.PubMedCrossRefGoogle Scholar
  18. 18.
    Huang BS, Huang X, Harmsen E, Leenen FHH. 1994. Chronic central versus peripheral ouabain, blood pressure and sympathetic nerve activity in rats. Hypertension 23:1087–1090.PubMedCrossRefGoogle Scholar
  19. 19.
    Kent MA, Van Hyusse JW, Leenen FHH. 2002. The effects of ouabain and endogenous ouabain like compounds on Na,K-ATPase activity and expression. The FASEB J 16:A465.Google Scholar
  20. 20.
    Meyer EM, Cooper JR. 1981. Correlation between Na,K-ATPase activity and acetylcholine release in rat cortical synaptosomes. J Neurochem 36:467–475.PubMedCrossRefGoogle Scholar
  21. 21.
    Vizi ES. 1978. Na,K-activated adenosinetriphosphatase as a trigger in neurotransmitter release. Neurosci 3:367–384.CrossRefGoogle Scholar
  22. 22.
    Vizi ES, Oberfrank F. 1992. Na+/K+-ATPase, its endogenous ligands and neurotransmitter release. Neurochem Int 20:11–17.PubMedCrossRefGoogle Scholar
  23. 23.
    Torok TL. 1989. Neurochemical transmission and the sodium pump. Progress Neurobiol 32:11–76.CrossRefGoogle Scholar
  24. 24.
    Santos MS, Goncalves PP, Carvalho AP. 1991. Release of y-[3H]aminobutyric acid from synapto-somes: effect of external cations and ouabain. Brain Res 547:135–141.PubMedCrossRefGoogle Scholar
  25. 25.
    Blasi JMV, Cena V, Gonzalez-Garcia C, Marsal J, Solsona C. 1988. Ouabain induces acetylcholine release from pure cholinergic synaptosomes independently of extracellular calcium concentrations. Neurochem Res 13:1035–1041.PubMedCrossRefGoogle Scholar
  26. 26.
    Sweadner KJ. 1985. Ouabain-evoked norepinephrine release from intact rat sympathetic neurons: evidence for carrier mediated release. J Neurosci 5:2397–2406.PubMedGoogle Scholar
  27. 27.
    Schoffelmeer ANM, Mulder AH. 1983. [3H]Noradrenaline release from brain slices induced by an increase in intracellular sodium concentration: role of intracellular calcium stores. J Neurochem 40:615–621.PubMedCrossRefGoogle Scholar
  28. 28.
    Satoh E, Nakazato Y. 1989. [3H]Acetylcholine release and the change in cytosolic free calcium level induced by high K+ and ouabain in rat synaptosomes. Neurosci Lett 107:284–288.PubMedCrossRefGoogle Scholar
  29. 29.
    Vyas S, Marchbanks RM. 1981. The effect of ouabain on the release of [14C]acetylcholine and other substances from synaptosomes. J Neurochem 37:1467–1474.PubMedCrossRefGoogle Scholar
  30. 30.
    Juhaszova M, Blaustein MP. 1997. Na+ pump low and high ouabain affinity a subunit isoforms are differently distributed in cells. Prot Natl Acad Sci USA 94:1800–1805.CrossRefGoogle Scholar
  31. 31.
    Arnon A, Hamlyn JM, Blaustein MP. 2000. Ouabain augments Ca2+ transients in arterial smooth muscle without raising cytosolic Na+. Am J Physiol 279:H679–H691.Google Scholar
  32. 32.
    Phillis JW 1992. Na+/K+-ATPase as an effector of synaptic transmission. Neurochem Int 20:19–22.PubMedCrossRefGoogle Scholar
  33. 33.
    Matsuba T, Murata Y, Kawamura N, Hayashi M, Tamada K, Takuma K, Maeda S, Baba A. 1993. Selec-tive induction of (Xi isoform of (Na+ + K+)-ATPase by insulin/insulin-like growth factor-1 in cul-tured rat astrocytes. Arch Biochem Biophys 307:175–182.CrossRefGoogle Scholar
  34. 34.
    Brodsky JL. 1990. Insulin activation of brain Na+,K+-ATPase is mediated by OC2 isoform of the enzyme. Am J Physiol 258:C812–C817.PubMedGoogle Scholar
  35. 35.
    Shah Jui, Jandhyala S. 1991. Role of the Na +,K+ -ATPase in the centrally mediated hypotensive effects of potassium in anaesthetized rats. J Hypertension 9:167–170.CrossRefGoogle Scholar
  36. 36.
    Shah J, Jandhyala B. 1993. Physiological significance of the Na+/K+-ATPase activity in the central nervous system and endogenous sodium-pump inhibitors in the neural regulation of arterial blood pressure. J Cardiovasc Pharm 22(Supp 2):S13–S15.CrossRefGoogle Scholar
  37. 37.
    Nishimura M, Takahashi H, Matsusawa M, Ikegaki I, Nakanishi T, Yoshimura M. 1991. The effects of insulin-like materials in the brain on central cardiovascular regulation: with special reference to the central effects of sodium chloride. T Hypertension 9:509–517.CrossRefGoogle Scholar
  38. 38.
    Shah J, Jandhyala BS. 1995. Age-dependent alterations in Na+,K+-ATPase in the central nervous system of spontaneously hypertensive rats: Relationship to the development of high blood pressure. Clin Exper Hypertension 17:751–767.CrossRefGoogle Scholar
  39. 39.
    Baski DG, Davidson DA, Corp ES, Lewellen T, Graham M. 1986. An inexpensive microcomputer digital imaging system for densitometry; quantitative autoradiography of insulin receptors with I125 and LKB Ultrofilm. T Neurosci Methods 16:119–129.CrossRefGoogle Scholar
  40. 40.
    Abdelrahman AM, Harmsen E, Leenen FHH. 1992. Dietary sodium and Na,K-ATPase activity in Dahl salt-sensitive versus salt-resistant rats. J Hypertens 13:517–522.CrossRefGoogle Scholar
  41. 41.
    Ou C, Harmsen E, Leenen FHH. 1993. Effects of high sodium on Na7K+-ATPase activity in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR).The FASEB J 7:A547Google Scholar
  42. 42.
    Chow MK, Shao Q, Ren B, Leenen FHH, Van Huysse JW. 2002. Changes in brain Na,K-ATPase isoform expression and enzymatic activity after aortic constriction. Brain Res 944:124–134.PubMedCrossRefGoogle Scholar
  43. 43.
    Chen CC, Lin-Shiau SY. 1986. Decreased Na+-K+-ATPase activity and [3H]ouabain binding sites in various tissues of spontaneously hypertensive rats. Eu J Pharmacol 122:311–319.CrossRefGoogle Scholar
  44. 44.
    Leenen FHH, Harmsen E, Yu H, Ou C. 1993. Effects of dietary sodium on central and peripheral ouabain-like activity in the spontaneously hypertensive rats. Am J Physiol 264:H2051–H2055.PubMedGoogle Scholar
  45. 45.
    Leenen FHH, Harmsen E, Yu H. 1994. Dietary sodium and central vs peripheral ouabain-like activ-ity in Dahl salt-sensitive vs salt-resistant rats. Am J Physiol 267:H1916–H1920.PubMedGoogle Scholar
  46. 46.
    Balzan, S, Montali U, Biver P, Ghione S. 1991. Digoxin-binding antibodies reverse the effect of endogenous digitalis-like compounds on Na,K-ATPase in erythrocytes. J Hypertension 9:S304–S305.Google Scholar
  47. 47.
    Huang BS, Leenen FHH. 1994. Brain “ouabain” mediates the sympathoexcitatory and hypertensive effects of high sodium intake in Dahl salt-sensitive rats. Circ Res 74:586–595.PubMedCrossRefGoogle Scholar
  48. 48.
    Huang BS, Leenen FHH. 1996. Blockade of brain “ouabain” prevents sympathoexcitatory and pressor responses to high sodium in SHR.Am J Physiol 271(40):H103–H108.PubMedGoogle Scholar
  49. 49.
    Sahin-Erdemli I, Medford RM, Songu-Mize E. 1995. Regulation of Na+,K+ -ATPase α subunit isoforms in rat tissues during hypertension. Eu J Pharmacol 292:163–171.Google Scholar
  50. 50.
    Grillo C, Coirini H, McEwen BS, De Nicola AF 1989. Changes of salt intake and of (Na+K)-ATPase activity in brain after high dose treatment with deoxycorticosterone. Brain Res 499:225–233.PubMedCrossRefGoogle Scholar
  51. 51.
    Leenen FHH, Huang BS, Yu H, Yuan B. 1995. Brain ouabain mediates sympathetic hyperactivity in congestive heart failure. Cir Res 77:993–1000.CrossRefGoogle Scholar
  52. 52.
    Leenen FHH, Yuan B, Huang BS. 1999. Brain ouabain or angiotensin II contribute to cardiac dysfunction after myocardial infarction. Am J Physiol 277:H1786–H1792.PubMedGoogle Scholar
  53. 53.
    Swann AC. 1983. Stimulation of brain Na+,K+-ATPase by norepinephrine in vivo: prevention by receptor antagonists and enhancement by repeated stimulation. Brain Res 260:338–341.PubMedCrossRefGoogle Scholar
  54. 54.
    Swann AC, Steketee JD. 1989. Subacute noradrenergic agonist infusions in vivo increase Na+,K+- ATPase and ouabain binding in rat cerebral cortex. J Neurochem 52:1598–1604.PubMedCrossRefGoogle Scholar
  55. 55.
    Viola MS, Antonelli MC, Enero MA, Rodriguez de Lores Arnaiz G. 1997. Desipramine modulates 3H-ouabain binding in rat hypothalamus. J Neurosci Res 47:77–89.Google Scholar
  56. 56.
    Viola MS, Bojorge G, Rodriguez de Lores Arnaiz G, Enero MA. 1989. Stimulation of Na+,K+ -ATPase activity in certain membranes of the rat central nervous system by acute administration of desipramine (DMI). Cell Mol NeuroBiol 9:263–271.PubMedGoogle Scholar
  57. 57.
    Stojanonic T, Djuricic BM, Mursulja BB. 1980. The effect of physostigmine on (Na++K+)-ATPase activity in different rat brain regions. Experientia 36:1348–1350.CrossRefGoogle Scholar
  58. 58.
    Therien AG, Blostein R. 2000. Mechanisms of sodium pump regulation. Am J Physiol 279.-C541–C566.Google Scholar
  59. 59.
    Swann AC, Steketee J. 1989. Forskolin infusions in vivo increase ouabain binding in brain. Brain Res 476:351–355.PubMedCrossRefGoogle Scholar
  60. 60.
    Daly JW, Pagett W, Crevelin CR, Cantacuzene D, Kirk KL. 1981. Cyclic AMP-generating systems: regional differences in activation by adrenergic receptors in rat brain. J Neurosci 1(1):49–59.Google Scholar
  61. 61.
    Dubocovich ML. 1984. Presynaptic alpha-adrenoreceptors in the central nervous system. Ann NY Acad Sci 430:7–35.PubMedCrossRefGoogle Scholar
  62. 62.
    Langer SZ. 1981. Presynaptic regulation of the release of catecholamines. Pharmacol Rev 32:337–362.Google Scholar
  63. 63.
    L’Heureux R, Dennis T, Curet O, Scatton B. 1986. Measurement of endogenous noradrenaline release in the rat cerebral cortex in vivo by transcortical dialysis: Effects of drugs affecting noradrenergic transmission. J Neurochem 46:1794–1801.PubMedCrossRefGoogle Scholar
  64. 64.
    Taube HD, Starke K, Borowski E. 1977. Presynaptic receptor systems on the noradrenergic neurons in rat brain. Naunyn-Schmiedebergs Arch Pharmacol 299:123–141.PubMedCrossRefGoogle Scholar
  65. 65.
    Van der Zee EA, Strosberg AD, Bohus B, Luiten PG. 1993. Colocalization of muscarinic acetyl-choline receptors and protein kinase C gamma in rat parietal cortex. Brain Res Mol Brain Res 18:152–162.PubMedGoogle Scholar
  66. 66.
    Nishi A, Fisone G, Snyder GL, Dulubova SI, Aperia A, Nairn AC, Greengard P. 1999. Regulation of Na,K-ATPase isoforms in rat neostriatum by dopamine and protein kinase C. J Neurochem 73:1492–1501.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Mary-Anne H. Kent
  • JAMES W. VAN Huysse
    • 1
  • Frans H. H. Leenen
    • 2
  1. 1.Hypertension UnitHypertension Unit, University of Ottawa Heart InstituteOttawaCanada
  2. 2.Hypertension UnitHypertension Unit, University of Ottawa Heart InstituteOttawaCanada

Personalised recommendations