Heart Failure Reviews

, Volume 10, Issue 1, pp 39–46 | Cite as

Effects of Aldosterone and Mineralocorticoid Receptor Blockade on Intracellular Electrolytes

  • Martin Wehling


Genomic mechanisms of mineralocorticoid action have been increasingly elucidated over the past four decades. In renal epithelia, the main effect is an increase in sodium transport through activation and de novo synthesis of epithelial sodium channels. This leads to increased concentrations of intracellular sodium activating sodium-potassium-ATPase molecules mainly at the basolateral membrane which extrude sodium back into the blood stream. In contrast, rapid steroid actions have been widely recognized only recently. The present article summarizes both traditional and rapid effects of mineralocorticoid hormones on intracellular electrolytes, e.g. free intracellular calcium in vascular smooth muscle cells as determined by fura 2 spectrofluorometry in single cultured cells from rat aorta. Latter effects are almost immediate, reach a plateau after only 3 to 5 minutes and are characterized by high specificity for mineralocorticoids versus glucocorticoids. The effect of aldosterone is blocked by neomycin and short-term treatment with phorbol esters but augmented by staurosporine, indicating an involvement of phospholipase C and protein kinase C. The Ca2+ effect appears to involve the release of intracellular Ca2+, as shown by the inhibitory effect of thapsigargin. This mechanism operates at physiological subnanomolar aldosterone concentrations and appears to result in rapid fine tuning of cardiovascular responsivity.

As a landmark feature of these rapid effects, insensitivity to classic antimineralocorticosteroids, e.g. spironolactone or canrenone has been found in the majority of observations. In an integrated view, mineralocorticoids seem to mainly effect intracellular electrolytes genomically to induce transepithelial transport, and induce nongenomically mediated alterations of cell function (e.g. vasoconstriction) by rapid effects on intracellular electrolytes such as free intracellular calcium.

Key words

mineralocorticoids intracellular electrolytes rapid effects second messengers 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Crabbe J. Stimulation of active sodium transport by the isolated toad bladder with aldosterone in vitro. J Clin Invest 1961;40:2103–2110.PubMedGoogle Scholar
  2. 2.
    Edelman IS, Bogoroch R, Porter GA. On the mechanism of action of aldosterone on sodium transport: The role of protein synthesis. Proc Natl Acad Sci USA 1963;50:1169–1177.PubMedGoogle Scholar
  3. 3.
    Arriza LA, Weinberger C, Cerelli G, Glaser TM, Handelin BL, et al. Cloning of human mineralocorticoid receptor complementary DNA: Structural and functional kinship with the glucocorticoid receptor. Science 1987;23:268–275.Google Scholar
  4. 4.
    Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger J-D, Rossier BC. Amiloride-sensitive epithelial Na_ channel is made of three homologous subunits. Nature 1994;367:463–467.PubMedGoogle Scholar
  5. 5.
    Canessa CM, Horisberger J-D Schild L, Rossier BC. Expression cloning of the epithelial sodium channel. Kidney Int 1995;48:950–955.PubMedGoogle Scholar
  6. 6.
    Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JR, Ulick S, Milora RV, Findling JW, Canessa CM, Rossier BC, Lifton RP. Liddle’s syndrome: Heritable human hypertension caused by mutations in the alpha-subunit of the epithelial sodium channel. Cell 1994;79:407–414.PubMedGoogle Scholar
  7. 7.
    Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel J. A chimaeric 11-beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992;355:262–265.PubMedGoogle Scholar
  8. 8.
    Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC. Human hypertension caused by mutations in the kidney isozyme of 11-beta-hydroxysteroid dehydrogenase. Nat Genet 1995;10:394–399.PubMedGoogle Scholar
  9. 9.
    Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FTF, Sigler PB, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 2000;289:119–123.PubMedGoogle Scholar
  10. 10.
    Wehling M. Specific, nongenomic actions of steroid hormones. Annu Rev Physiol 1997;59:365–393.PubMedGoogle Scholar
  11. 11.
    Verrey F. Early aldosterone action: Toward filling the gap between transcription and transport. Am J Physiol (Renal Physiol) 1999;277:F319–F327.Google Scholar
  12. 12.
    Pearce D. SGK1 Regulation of Epithelial Sodium Transport. Cell Physiol Biochem 2003;13:013–020.Google Scholar
  13. 13.
    Chen S-Y, Bhargava A, Mastroberardino L, Meijer OC, Wang J, Buse P, Firestone GL, Verrey F, Pearce D. Epithelial sodium channel regulated by aldosterone-induced protein SGK. Proc Natl Acad Sci USA 1999;96:2514–2519.PubMedGoogle Scholar
  14. 14.
    Debonneville C, Flores SY, Kamynina E, Plant PJ, Tauxe C, Thomas MA, Munster C, Chraibi A, Pratt JH, Horisberger JD, Pearce D, Loffing J, Staub O. Phosphorylation of Nedd4–2 by SGK1 regulates epithelial Na(+) channel cell surface expression. Embo J 2001;20:7052–7059.PubMedGoogle Scholar
  15. 15.
    Pa′cha J, Frindt G, Antonian L, Silver RB, Palmer LG. Regulation of Na channels of the rat cortical collecting tubule by aldosterone. J Gen Physiol 1993;102:25–42.PubMedGoogle Scholar
  16. 16.
    Asher C, Wald H, Rossier BC, Garty H. Aldosterone-induced increase in the abundance of Na-channel subunits. Am J Physiol Cell Physiol 1996;271:C605–C611.Google Scholar
  17. 17.
    Stokes JB, Sigmund RD. Regulation of rENaC mRNA by dietary NaCl and steroids: Organ, tissue, and steroid heterogeneity. Am J Physiol Cell Physiol 1998;274:C1699–C1707.Google Scholar
  18. 18.
    Vander AJ, Malvin RL, Wilde WS, Lapides J, Sullivan LP, McMurray VM. Effects of adrenalectomy and aldosterone on proximal and distal tubular sodium reabsorption. Proc Soc Exp Biol Med 1958;99:323–325.PubMedGoogle Scholar
  19. 19.
    Arriza LA, Weinberger C, Cerelli G, Glaser TM, Handelin BL, et al. Cloning of human mineralocorticoid receptor complementary DNA: Structural and functional kinship with the glucocorticoid receptor. Science 1987;23:268–275.Google Scholar
  20. 20.
    Edelman IS, Fimognari GM. Modes of hormone action: On the biochemical mechanism of action of aldosterone. Recent Prog Hormone Res 1968;24:1–44.Google Scholar
  21. 21.
    Funder JW. Mineralocorticoids, glucocorticoids, receptors and response elements. Science 1993;259:1132–1136.PubMedGoogle Scholar
  22. 22.
    Myers JH, Bohr D. Mechanisms responsible for the pressure elevation in sodium dependent mineralocorticoid hypertension. In: Mantero F, Biglieri EG, Edwards CRW, eds., Endocrinology of Hypertension, New York: Raven, 1985:131–148.Google Scholar
  23. 23.
    Rossier BC, Palmer LG. Mechanisms of aldosteroneaction on sodium and potassium transport. In: Seldin DW, Giebisch G, eds., The Kidney: Physiology and Pathophysiology, 2nd ed. New York: Raven Press, 1992;1373–1409.Google Scholar
  24. 24.
    Verrey F. Transcriptional control of sodium transport in tight epithelia by adrenal steroids. J Membr Biol 1995;144:93–110.PubMedGoogle Scholar
  25. 25.
    Lombes M, Kenouch S, Souque A, Farman N, Rafestin-Oblin ME. The mineralocorticoid receptor discriminates aldosterone from glucocorticoids independently of the 11 beta-hydroxysteroid dehydrogenase. Endocrinology 1994:135, 834–840.PubMedGoogle Scholar
  26. 26.
    Garty H, Palmer LG. Epithelial sodium channels: Function, structure, and regulation. Physiol Rev 1997;77:359–396.PubMedGoogle Scholar
  27. 27.
    Kemendy AE, Kleyman TR, Eaton DC. Aldosterone alters the open probability of amiloride-blockable sodium channels in A6 epithelia. Am J Physiol 1992;263:C825– C837.PubMedGoogle Scholar
  28. 28.
    El Mernissi G, Doucet A. Short-term effect of aldosterone on renal sodium transport and tubular Na-K-ATPase in the rat. Pflügers Arch 1983;339:139–146.Google Scholar
  29. 29.
    Verrey F, Beron J, Spindler B. Corticosteroid regulation of renal Na,K-ATPase. Miner Electrolyte Metab 1996;22:279–292.PubMedGoogle Scholar
  30. 30.
    Wehling M, Armanini D, Strasser T, Weber PC. Effect of aldosterone on the sodium and potassium concentrations in human mononuclear leukocytes. Am J Physiol 1987;252:E505–E508.PubMedGoogle Scholar
  31. 31.
    Wehling M, Käsmayr J, Theisen K. Aldosterone influences free intracellular calcium in human mononuclear leukocytes in vitro. Cell Calcium 1990;11:565–571.PubMedGoogle Scholar
  32. 32.
    Wehling M, Kuhls S, Armanini D. Volume regulation of human lymphocytes by aldosterone in isotonic medium. Am J Physiol 1989;257:E170–E174.PubMedGoogle Scholar
  33. 33.
    Wehling M, Käsmayr J, Theisen K. Rapid effects of mineralocorticoids on sodium-proton exchanger: Genomic or nongenomic pathway? Am J Physiol 1991;260:E719–E726.PubMedGoogle Scholar
  34. 34.
    Christ M, Eisen C, Aktas J, Theisen K, Wehling M. The inositol-1,4,5-trisphosphate system is involved in rapid effects of aldosterone in human mononuclear leukocytes. J Clin Endocrinol Metab 1993;77:1452–1457.PubMedGoogle Scholar
  35. 35.
    Christ M, Douwes K, Eisen C, Bechtner G, Theisen K, Wehling M. Rapid effects of aldosterone on sodium transport in vascular smooth muscle cells. Hypertension 1995;25:117–123.PubMedGoogle Scholar
  36. 36.
    Oberleithner H, Weigt M, Westphale HJ, Wang W. Aldosterone activates Na+/H+ exchange and raises cytoplasmic pH in target cells of the amphibian kidney. Proc Natl Acad Sci USA 1987;84:1464–1468.PubMedGoogle Scholar
  37. 37.
    Wehling M, Eisen C, Aktas J, Christ M, Theisen K. Photoaffinity labeling of plasma membrane receptors for aldosterone from human mononuclear leukocytes. Biochem Biophys Res Commun 1992;189:1424–1428.PubMedGoogle Scholar
  38. 38.
    Wehling M, Christ M, Theisen K. Membrane receptors for aldosterone: A novel pathway for mineralocorticoid action. Am J Physiol 1992;263:E974–E979.PubMedGoogle Scholar
  39. 39.
    Lösel RM, Falkenstein E, Feuring M, Schultz A, Tillmann HC, Rossol-Haseroth K, Wehling M. Nongenomic Steroid Action: Controversies, Questions, and Answers. Physiol Rev 2003;83:965–1016.PubMedGoogle Scholar
  40. 40.
    Zhu Y, Rice CD, Pang Y, Pace M, Thomas P. Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci USA 2003;100:2231–2236.PubMedGoogle Scholar
  41. 41.
    Spach C, Streeten DH. Retardation of sodium exchange in dog erythrocytes by physiological concentrations of aldosterone, in vitro. J Clin Invest 1964;43:217–227.Google Scholar
  42. 42.
    Moura AM, Worcel M. Direct action of aldosterone on transmembrane NaC efflux from arterial smooth muscle. Hypertension 1984;6:425–430.PubMedGoogle Scholar
  43. 43.
    Petzel D, Ganz MB, Nestler EJ, Lewis JJ, Goldenring J, et al. Correlates of aldosterone-induced increases in Ca2C I and Isc suggest that Ca2C i is the second messenger for stimulation of apical membrane conductance. J Clin Invest 1992;89:150–156.PubMedGoogle Scholar
  44. 44.
    Menachery A, Braley LM, Kifor I, Gleason R,Williams GH. Dissociation in plasma renin and adrenal ANG II and aldosterone responses to sodium restriction in rats. Am J Physiol 1991;261:E487–E449.PubMedGoogle Scholar
  45. 45.
    Al-Dujaili EAS, Edwards CRW. The development and application of direct radioimmunoassay for plasma aldosterone using 131I-labelled ligandcomparison of three methods. J Clin Endocrinol Metab 1978; 46:105–113.PubMedGoogle Scholar
  46. 46.
    Alzamora R, Michea L, Marusic ET. Role of 11beta-hydroxysteroid dehydrogenase in non-genomic aldosterone effects in human arteries. Hypertension 2000;35,1099–1104.PubMedGoogle Scholar
  47. 47.
    Wehling M, Neylon CB, Fullerton M, Bobik A, Funder JW. Nongenomic effects of aldosterone on intracellular calcium in vascular smooth muscle cells. Circ Res 1995;76:973– 979.PubMedGoogle Scholar
  48. 48.
    Wehling M, Ulsenheimer A, Schneider M, Neylon C, Christ M. Rapid effects of aldosterone on free intracellular calcium in vascular smooth muscle and endothelial cells: Subcellular localization of calcium release by single cell imaging. Biochem Biophys Res Commun 1994;204:475– 481.PubMedGoogle Scholar
  49. 49.
    Christ M, Eisen C, Meyer C, Theisen K, Wehling M. Immediate effects of aldosterone on diacylglycerol production and protein kinaseCtranslocation in vascular smooth muscle cells. Biochem Biophys Res Commun 1995;213:123–129.PubMedGoogle Scholar
  50. 50.
    Thornton SN, Nicolaidis S. Long-term mineralocorticoid-induced changes in rat neuron properties plus interaction of aldosterone and ANG II. Am J Physiol 1994;266:R564–R571.PubMedGoogle Scholar
  51. 51.
    Ebata S, Muto S, Okada K, Nemoto J, Amemiya M, Saito T, Asano Y. Aldosterone activates Na1/H1 exchange in vascular smooth muscle cells by nongenomic and genomic mechanisms. Kidney Int 1999;56:1400–1412.PubMedGoogle Scholar
  52. 52.
    Gekle M, Silbernagl S, Oberleithner H. The mineralocorticoid aldosterone activates a proton conductance in cultured kidney cells. Am J Physiol 1997;273:C1673–C1678.PubMedGoogle Scholar
  53. 53.
    Sato A, Liu JP, Funder JW. Aldosterone rapidly represses protein kinase C activity in neonatal rat cardiomyocytes in vitro. Endocrinology 1997;138:3410–3416.PubMedGoogle Scholar
  54. 54.
    Doolan CM, Harvey BJ. Modulation of cytosolic protein kinase C and calcium ion activity by steroid hormones in rat distal colon. J Biol Chem 1996;271:8763–8767.PubMedGoogle Scholar
  55. 55.
    Benitah JP, Vassort G. Aldosterone upregulates Ca(21) current in adult rat cardiomyocytes. Circ Res 1999;85:1139–1145.PubMedGoogle Scholar
  56. 56.
    Pietras RJ, Szego CM. Endometrial cell calcium and oestrogen action. Nature (Lond) 1975; 253:357–359.Google Scholar
  57. 57.
    Pietras RJ, Szego CM. Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells. Nature (Lond) 1977;265:69–72.Google Scholar
  58. 58.
    Pietras RJ, Szego CM. Cell membrane estrogen receptors on the surface. Nat Med 5:1330.Google Scholar
  59. 59.
  60. 60.
    Nordeen SK, Moyer ML, Bona BJ. The coupling of multiple signal transduction pathways with steroid response mechanisms. Endocrinology 1994;134:1723–1732.PubMedGoogle Scholar
  61. 61.
    Lim-Tio SS, Keightley M-C, Fuller PJ. Determinants of specificity of transactivation by the mineralocorticoid or glucocorticoid receptor. Endocrinology 1997;138: 2537–2543.PubMedGoogle Scholar
  62. 62.
    Haseroth K, Gerdes D, Berger S, Feuring M, Gunther A, Herbst C, Christ M, Wehling M. Rapid nongenomic effects of aldosterone in mineralocorticoidreceptor-knockout mice. Biochem Biophys Res Commun 1999;266:257–261.PubMedGoogle Scholar
  63. 63.
    Rossol-Haseroth K, Zhou Q, Braun S, Boldyreff B, Falkenstein E, Wehling M. Mineralocorticoid receptor antagonists do not block rapid ERK activation by aldosterone. Biochem Biophys Res Commun 2004;318:281–288.PubMedGoogle Scholar
  64. 64.
    Mihailidou AS, Mardini M, Funder JW. Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon protein kinase C. Endocrinology 2004;145:773–780.PubMedGoogle Scholar
  65. 65.
    Uhrenholt TR, Schjerning J, Hansen PB, Norregaard R, Jensen BL, Sorensen GL, Skott O. Rapid inhibition of vasoconstriction in renal afferent arterioles by aldosterone. Circ Res 2003;93:1258–1266.PubMedGoogle Scholar
  66. 66.
    Moellic C, Ouvrard-Pascaud A, Capurro C, Cluzeaud F, Fay M, Jaisser F, Farman N, Blot-Chabaud M. Early Nongenomic Events in Aldosterone Action in Renal Collecting Duct Cells: PKC Activation, Mineralocorticoid Receptor Phosphorylation, and Cross-Talk with the Genomic Response. J Am Soc Nephrol 2004;15:1145–1160.PubMedGoogle Scholar
  67. 67.
    Lösel R, Schultz A, Boldyreff B, Wehling M, Rapid effects of aldosterone on vascular cells: Clinical implications. In: Norman AW, Wehling M, Baldi E, Forti G, es., Special issue: Proceedings of the Third International Meeting on Rapid Responses to Steroid Hormones. Steroids 2004;69;575– 578.Google Scholar
  68. 68.
    Schmidt B.MW, Georgens AC, Martin N, Tillmann HC, Feuring M, Christ M, Wehling M. Interaction of rapid nongenomic cardiovascular aldosterone effects with the adrenergic system. J Clin Endocrinol Metab 2001;86,761–767.PubMedGoogle Scholar
  69. 69.
    Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 1996;98:1063–1068.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Institute of Clinical Pharmacology, Faculty for Clinical Medicine at MannheimUniversity of HeidelbergMölndalSweden
  2. 2.Institute of Clinical Pharmacology, Faculty of Clinical Medicine MannheimUniversity of HeidelbergMannheimGermany

Personalised recommendations