Disregulation of Cell Calcium and Calcium-Binding Proteins in Experimental Hypertension

  • Ramachandra M. Rao
  • Eric W. Young
  • David A. McCarron
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 255)


Hypertension in experimental animal models is often associated with several distinct abnormalities in calcium metabolism from the level of the cell to the whole organism. The physiological and biochemical defects in the regulation of calcium include: low serum ionized calcium, elevated serum PTH, hypercalciuria, decreased intestinal calcium absorption, altered vitamin D metabolism, decreased calcium reabsorption, altered membrane- binding, and decreased binding to intracellular calcium-binding proteins. These derangements of systemic and intracellular calcium regulation lead to the overall calcium imbalance best reflected by reduced bone density and bone mineralization.


Experimental Hypertension Hypertensive Animal Intestinal Calcium Transport Calmodulin Level Intracellular Free Calcium Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Stern N, Lee DBN, Silis V., et al. Effects of high calcium intake on blood pressure and calcium metabolism in young SHR. Hypertension 1984;6:639–646.PubMedGoogle Scholar
  2. 2.
    McCarron D, Yung NN, Ugoretz BA, Krutzik S. Disturbances of calcium metabolism in the spontaneously hypertensive rat: attenuation of hypertension by calcium supplementation. Hypertension 1981;3(Suppl 1:1162–1167.Google Scholar
  3. 3.
    Young EW, Hsu CH, Patel S, et al. Metabolic degradation and synthesis of calcitriol in the spontaneously hypertensive rat. Am J Physiol 1987;252:E778–E782.PubMedGoogle Scholar
  4. 4.
    Merke J, Slotkowski A, Mann H, et al. Abnormal 1,25(OH)2D3 receptor status in genetically hypertensive rats. Kidney Int 1987;31:303.Google Scholar
  5. 5.
    Lau K, Chen S, Eby B. Evidence for an intestinal mechanism in hypercalciuria of the spontaneously hypertensive rat. Am J Physiol 1984;247:E625–E633.PubMedGoogle Scholar
  6. 6.
    Hsu CH, Chen PS, Smith DE, Yang CS. Pathogenesis of hypercalciuria in spontaneously hypertensive rats. Miner Electrolyte Metab 1986;12:130–141.PubMedGoogle Scholar
  7. 7.
    Lucas PA, Brown RC, Drueke T, Lacour B, Metz JA, McCarron DA. Abnormal vitamin D metabolism, intestinal calcium transport, and bone status in the spontaneously hypertensive rat compared with its genetic control. J Clin Invest 1986;78:221–227.PubMedCrossRefGoogle Scholar
  8. 8.
    Kurtz TW, Portale AA, Morris RC. Evidence for a difference in vitamin D metabolism between spontaneously hypertensive and Wistar-Kyoto rats. Hypertension 1986;8:1015–1020.PubMedGoogle Scholar
  9. 9.
    Kawashima H. Altered vitamin D metabolism in the kidney of the spontaneously hypertensive rat. Biochem J 1986;237:893–897.PubMedGoogle Scholar
  10. 10.
    Bindeis RJM, van den Brock LAM, Jongen MJM, et al. Increased plasma calcitonin levels in young spontaneously hypertensive rats: role in disturbed phosphate homeostasis. Pflugers Arch 1987;408:395–400.CrossRefGoogle Scholar
  11. 11.
    Lau K, Langman CB, Gafter U, et al. Increased calcium absorption in prehypertensive spontaneously hypertensive rats. J Clin Invest 1986;78:1083–1090.PubMedCrossRefGoogle Scholar
  12. 12.
    Schedi HP, Miller DL, Paper JM, et al. Calcium and sodium transport and vitamin D metabolism in the spontaneously hypertensive rat. J Clin Invest 1984;73:980–986.CrossRefGoogle Scholar
  13. 13.
    Schedi HP, Miller DL, Horst RL, et al. Intestinal calcium transport in the spontaneously hypertensive rat: response to calcium depletion. Am J Physiol 1986; 250:G412–412G419.Google Scholar
  14. 14.
    Hsu CH, Yang CS, Patel SR, Stevens MG. Calcium and vitamin D metabolism in spontaneously hypertensive rats. Am J Physiol 1987;253:F712–F718.PubMedGoogle Scholar
  15. 15.
    Young EW, Patel SR, Hsu CH. Plasma 1,25(OH)2 vitamin D3 response to parathyroid hormone, cyclic AMP, and phosphorus depletion in the spontaneously hypertensive rat. J Lab Clin Med 1986;6:562–566.Google Scholar
  16. 16.
    Lucas PA, Lacour B, McCarron DA, Drueke T. Disturbances of acid-base balance in the young spontaneously hypertensive rat. Clin Sci 1987;73:211–215.PubMedGoogle Scholar
  17. 17.
    Eby B, Salvi D, Lau K. Pathophysiology and consequence of reduced PO4 excretion in the spontaneously hypertensive rat. Proc First Annu Mtg Soc Hypertens 1986;2929A.Google Scholar
  18. 18.
    Jacobs WR, Brazy PC, Mandel LJ. Fura-2 measurements of intracellular free calcium (Caf) in renal cortical tubules from SHR and WKY rats. Kidney Int 1987;31:350.Google Scholar
  19. 19.
    Llibre J, LaPointe M, Batlle DC. Fura-2 measurements at cytosolic cell Ca2+ in renal proximal tubules and circulating lymphocytes of rats with genetic hypertension. Kidney Int 1987;31:302.Google Scholar
  20. 20.
    Ayachi S. Increased dietary calcium lowers blood pressure in the spontaneously hypertensive rat. Metabolism 1979;28:1234–1238.PubMedCrossRefGoogle Scholar
  21. 21.
    Hsu CH, Chen PS, Caldwell RM. Renal phosphate excretion in spontaneously hypertensive and Wistar Kyoto rats. Kidney Int 1984;25:789–795.CrossRefGoogle Scholar
  22. 22.
    Hsu CH, Patel S, Young EW. Calcemic response to parathyroid hormone in spontaneously hypertensive rats: role of calcitriol. J Lab Clin Med 1987;110:682–689.PubMedGoogle Scholar
  23. 23.
    McCarron DA. Impaired nephrogenous cAMP response in the spontaneously hypertensive rat. Kidney Int 1983;23:106.Google Scholar
  24. 24.
    Kurtz TW, Morris RC. Dietary chloride as a determinant of disordered calcium metabolism in salt-dependent hypertension. Life Sci 1985;36: 921–929.PubMedCrossRefGoogle Scholar
  25. 25.
    Cirillo M, Galletti F, Corrado MF, Strazzulo P. Disturbances of renal and erythrocyte calcium handling in the Milan hypertensive strain. J Hypertens 1986;4:443–449.PubMedCrossRefGoogle Scholar
  26. 26.
    Umemura S, Smythe DD, Pettinger WA. Renal adenylate cyclase in Dahl and DOC-Na hypertensive rats: defective response to parathyroid hormone with calcium leak. J Hypertens 1986;4:S291–S293.CrossRefGoogle Scholar
  27. 27.
    Bianchi G, Ferrari P, Salvati P, et al. A renal abnormality in the Milan hypertensive of rats and humans predisposed to essential hypertension. J Hypertens 1986;4:533–536.Google Scholar
  28. 28.
    Toraason MA, Wright GL. Transport of calcium by duodenum of spontaneously hypertensive rat. Am J Physiol 1981; 241:G344–G347.PubMedGoogle Scholar
  29. 29.
    McCarron DA, Lucas PA, Shneidman RS, Drueke T. Blood pressure development of the spontaneously hypertensive rat following concurrent manipulation of the dietary Ca2+ and Na+: relation to intestinal Ca2+ fluxes. J Clin Invest 1985;76:1147–1154.PubMedCrossRefGoogle Scholar
  30. 30.
    McCarron DA, Lucas P, Lacour B, Drueke T. Ca2+ efflux rate constant in isolated SHR enterocytes. Kidney Int 1986;29:252.Google Scholar
  31. 31.
    Drueke T, Lucas PA, Bourgouin P, et al. Changes in calcitriol status and related parameters in the young hypertensive rat (SHR). Kidney Int 1988;33:294.Google Scholar
  32. 32.
    Metz JA, Karanja N, McCarron DA. Characterization of bone calcium, magnesium, and density in the spontaneously hypertensive rat: differential effects of dietary calcium and sodium, (submitted).Google Scholar
  33. 33.
    Izawa Y, Sagara K, Kadota T, Makita T. Bone disorders in spontaneously hypertensive rat. Calcif Tissue Int 1985; 37:605–607.PubMedCrossRefGoogle Scholar
  34. 34.
    Blaustein MP. Sodium ions, calcium ions, blood pressure regulation and hypertension: a reassessment and a hypothesis. Am J Physiol 1977;232: C165–C173.PubMedGoogle Scholar
  35. 35.
    Erne P, Bolli P, Burgisser E, Buhler FR. Correction of platelet calcium with blood pressure: effect of antihypertensive therapy. N Engl J Med 1984;310, 1084–1088.PubMedCrossRefGoogle Scholar
  36. 36.
    Brushi G, Brushi ME, Caroppo M, Orlandini G, Spaggiari M, Cavatorta A. Cytoplasmic free [Ca2+] is increased in the platelets of spontaneously hypertensive rats and essential hypertensive patients. Clin Sci 1985; 68:179–184.Google Scholar
  37. 37.
    Le Quan Sang KH, Montenay-Garestier T, Devynck MA. Platelet cytosolic free calcium concentration in essential hypertension. Nouv Rev Fr Hematol 1985;27:279–283.PubMedGoogle Scholar
  38. 38.
    Le Quan Sang KH, Devynck MA. Increased platelet cytosolic free calcium concentration in essential hypertension. J Hypertens 1986;4:567–574.PubMedCrossRefGoogle Scholar
  39. 39.
    Lechi A, Lechi C, Bonadonna G, et al. Increased basal and thrombin-induced free calcium in platelets of essential hypertensive patients. Hypertension 1987;9:230–235.PubMedGoogle Scholar
  40. 40.
    Baba A, Fukuda K, Kuchii M, et al. Intracellular free calcium concentration, Ca++ channel and calmodulin level in experimental hypertension in rats. Jpn Circ J 1987;51:1216–1222.PubMedCrossRefGoogle Scholar
  41. 41.
    Larsen FL, Katz S, Roufogallis BD, Brooks DE. Physiologic shear stresses enhance the Ca2+ permeability of human erythrocytes. Nature (London) 1981;294:667–668.PubMedCrossRefGoogle Scholar
  42. 42.
    Brushi G, Brushi ME, Caroppo M, Orlandini G, Pavarani C, Cavatorta A. Intracellular free [Ca2+] in circulating lymphocytes of spontaneously hypertensive rats. Life Sci 1984;35:535–542.CrossRefGoogle Scholar
  43. 43.
    Bukoski RD, Pressley MS, McCarron DA. Intracellular Ca2+ ([Ca]i) measured in single aortic myocytes from spontaneously hypertensive (SH) and normotensive Wistar Kyoto (WK) rats using fura-2. Am J Hypertens (in press).Google Scholar
  44. 44.
    Sugiyama T, Yoshizumi M, Takaku F, et al. The elevation of the cytoplasmic calcium ions in vascular smooth muscle cells in SHR. Measurement of the free calcium ions in single living cells by laser microfluorospectrometry. Biochem Biophys Res Comm 1986;141:340–345.PubMedCrossRefGoogle Scholar
  45. 45.
    Nabika T, Velletri PA, Beaven MA, Endo J, Lovenberg W. Vasopressin-induced calcium increases in smooth muscle cells from spontaneously hypertensive rats. Life Sci 1985;37:579–584.PubMedCrossRefGoogle Scholar
  46. 46.
    Bhalla RC, Webb RC, Ashley T, Brock T. Calcium fluxes, calcium binding and adenosine 3′,5′-monophosphate dependent protein kinase activity in aorta of spontaneously hypertensive and Wistar normotensive rats. Mol Pharmacol 1978;14:468–477.PubMedGoogle Scholar
  47. 47.
    Shibata S, Kochii M, Taniguchi T. Calcium fluxes and binding in the aortic smooth muscle from the spontaneously hypertensive rat. Blood Vess 1975;12:279–289.Google Scholar
  48. 48.
    Zsoter TT, Wetchinsky C, Henein NF, Ho LC. Calcium kinetics of the aorta of spontaneously hypertensive rat. Cardiovasc Res 1977;11:353–357.PubMedCrossRefGoogle Scholar
  49. 49.
    Cauvin C, van Breemen C. Altered 45Ca fluxes in isolated mesenteric resistance vessels from SHR. Fed Proc 1985; 44:1008.Google Scholar
  50. 50.
    Cauvin C, Hwang BS, Yamamoto M, van Breemen C. Effects of dihydropyuridines on tension and calcium-45 influx in isolated mesenteric resistance vessels from spontaneously hypertensive and normotensive rats. Am J Cardiol 1987; 59: 116B–122B.PubMedCrossRefGoogle Scholar
  51. 51.
    Mulvany MJ, Nyborg N. An increased calcium sensitivity of mesenteric resistance vessels in young and adult spontaneously hypertensive rats. Br J Pharmacol 1980;71:585–596.PubMedGoogle Scholar
  52. 52.
    Kozniewska E. Enhanced reactivity towards flunazinine in cerebrovascular bed of spontaneously hypertensive rats. Experientia 1988;44:221–222.PubMedCrossRefGoogle Scholar
  53. 53.
    Lacour B, Roullet CM, Lucas PA, McCarron DA, Drueke T. Impaired calcium efflux in enterocytes of spontaneously hypertensive rat (SHR). Kidney Int 1988;33:300.Google Scholar
  54. 54.
    Aoki K Yamashita Y, Tornita N, Tazumi K, Hotta K. ATPase activity and Ca2+ binding ability of subcellular membrane of arterial smooth muscle in spontaneously hypertensive rat. Jpn Heart J 1974;15:180–181.PubMedCrossRefGoogle Scholar
  55. 55.
    Webb RC, Bhalla RC. Altered calcium sequestration by subcellular fractions of vascular smooth muscle from spontaneously hypertensive rats. J Mol Cell Cardiol 1976;8:651–661.PubMedCrossRefGoogle Scholar
  56. 56.
    Kwan CY, Belbeck L, Daniel EE. Abnormal biochemistry of vascular smooth muscle plasma membrane isolated from hypertensive rats. Mol Pharmacol 1980;77:137–140.Google Scholar
  57. 57.
    Kwan CY, Daniel EE. Arterial muscle abnormalities of hydralazine treated spontaneously hypertensive rats. Eur J Pharmacol 1982;82:1878–1890.CrossRefGoogle Scholar
  58. 58.
    Higaki J, Ogihara T, Kumahara Y, Bravo EL. Calmodulin levels in hypertensive rats. Clin Sci 1985;68:407–410.PubMedGoogle Scholar
  59. 59.
    Pokudin NI, Orlov SN, Ryashsky GG, Menshikov NY, Tkachuk VA, Postnov YV. Isolation and characteristics of calmodulin from the brain of rats with spontaneous genetic hypertension. Kardiologiya 1985;25:72–77.PubMedGoogle Scholar
  60. 60.
    Huang SL, Wen YI, Kripranycz DB, et al. Abnormality of calmodulin activity in hypertension. Evidence of the presence of an activator. J Clin Invest (in press).Google Scholar
  61. 61.
    Kowarski S, Cowen LA, Schachter D. Decreased content of integral membrane calcium-binding protein (IMCAL) in tissues of the spontaneously hypertensive rat. Proc Natl Acad Sci USA 1986;83:1097–1100.PubMedCrossRefGoogle Scholar
  62. 62.
    Nojima H, Kishi K, Sokabe H. Organization of calmodulin genes in the spontaneously hypertensive rat. J Hypertens 1986;4(Suppl 3):S275–S277.Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Ramachandra M. Rao
    • 1
  • Eric W. Young
    • 1
  • David A. McCarron
    • 1
  1. 1.Division of Nephrology and Hypertension Institute for Nutrition and Cardiovascular ResearchOregon Health Sciences UniversityPortlandUSA

Personalised recommendations