The Ionic Hypothesis of Aging

Role of Intracellular Ions in the Development of Hypertension and Insulin Resistance
  • Mario Barbagallo
  • Ligia J. Dominguez
  • Anna Licata
  • Lilia Granvillano
  • Maria Adele Alessi
  • Giuseppe Licata
  • Lawrence M. Resnick

Abstract

The clinical association of essential hypertension with metabolic abnormalities, such as hyperinsulinemia, insulin resistance, obesity, altered glucose tolerance and/or frank non-insulin dependent diabetes mellitus (NIDDM) has long been appreciated(1). Each of the above clinical conditions is extremely frequent in the elderly. The association of these different clinical states, that is also common at younger ages, has been termed “Syndrome X” and more recently “Generalized Cardiovascular-Metabolic Disease.”(2,3) Although several hypothesis have been proposed, including a primary role of hyperinsulinemia and insulin resistance, the mechanism(s) of this linkage has not been established. This syndrome complex is frequently associated with target organ involvement, such as left ventricular hypertrophy (LVH) and atherosclerosis of the coronary and peripheral vascular beds.

Keywords

Free Calcium Intracellular Free Calcium Peripheral Insulin Resistance Cytosolic Free Calcium Dehydroepiandrosterone Sulfate 
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.

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References

  1. 1.
    Jarret RJ, Keen H, McCartney M, Fuller JH, Hamilton PJS, Reid D, Rose G.: Glucose tolerance and blood pressure in two population samples. Their relationship to diabetes mellitus and hypertension. Am.J.Epidemiol., 1978, 7: 15–24.Google Scholar
  2. 2.
    Resnick LM: Ionic basis of hypertension, insulin resistance, vascular disease and related disorders. The mechanism of “Syndrome X”. Am.J.Hypertens., 1993, 6: 123S–134S.PubMedGoogle Scholar
  3. 3.
    Barbagallo M., Resnick LM, Calcium and Magnesium in the regulation of smooth muscle function and blood pressure. in: Endocrinology of the Vasculature, JR Sowers editor, Humana Press Inc. NJ, USA, pp. 283-300.Google Scholar
  4. 4.
    Ringer S.: A third contribution regarding the infusion of the inorganic constituents of the blood on the ventricular contraction. J.Physiol., 1883, 222-5.Google Scholar
  5. 5.
    Kuriyama H., Uishi I., Suaky H., Kitamura K., Itoh T.: Factors modifying contraction-relaxation in vascular smooth muscle. Am.J.Physiol., 1982, 243: H641–H662.PubMedGoogle Scholar
  6. 6.
    Borle AB: Control, modulation and regulation of cell calcium. Rev. Physiol. Biochem. Pharmacol., 1981, 90:13–153.PubMedCrossRefGoogle Scholar
  7. 7.
    Rasmussen H.: Calcium messenger system. N.Engl.J.Med., 1986, 314:1094–1107, 1164-1170.PubMedCrossRefGoogle Scholar
  8. 8.
    Eggermont J.A., Vrolix M., Raeymaekers L., Wuytack F., Casteels R.: Ca++ transport ATPases of vascular smooth muscle. Circ.Res., 1988, 62: 266–278.PubMedCrossRefGoogle Scholar
  9. 9.
    Nabel E.G., Berk B.C., Brock T.A., Smith T.W: Na+-Ca++ exchange in cultured vascular smooth muscle cells. Circ.Res., 1988, 62: 486–489.PubMedCrossRefGoogle Scholar
  10. 10.
    Rubin RP: The role of calcium in the release of neurotransmitter substances and hormones. Pharmacol. Rev. 1970; 22: 389–427.PubMedGoogle Scholar
  11. 11.
    Altura BM, Altura BT: Magnesium ions and contractions on vascular smooth muscles: relationship to some vascular diseases. Fed Proc. 1981; 40: 2672–79.PubMedGoogle Scholar
  12. 12.
    Altura BM, Altura BT, Carella A, Turlapaty PDMV: Ca++ coupling in vascular smooth muscle: Mg++ and buffer effects on contractility and membrane Ca++ movements. Can.J.Physiol. 1982; 60: 459–482.CrossRefGoogle Scholar
  13. 13.
    Altura BM, Altura BT: Magnesium and contractions of arterial smooth muscle. Microvasc Res. 1974; 7: 145–155.PubMedCrossRefGoogle Scholar
  14. 14.
    Woods WT, Katholi RE, Urthaler F, James TN: Electrophysiological effects of magnesium on cells in the canine sinus node and false tendon. Circ. Res. 1979; 44: 182–188.PubMedCrossRefGoogle Scholar
  15. 15.
    Turlapaty PDMV, Altura BM: Extracellular magnesium ions control calcium exchange and content of vascular smooth muscle. Eur J Pharmacol. 1978; 52: 421–23.PubMedCrossRefGoogle Scholar
  16. 16.
    Agus ZA, Kalipourie E, Dukes I, Morad M.: Cytosolic magnesium modulates calcium channel activity in mammalian ventricular cells. Am.J.Physiol. 1989; 256: C452–455.PubMedGoogle Scholar
  17. 17.
    Ji BH, Erne P, Kiosky W, Buhler FR, Bolli P.: Magnesium-induced vasodilatation is comparable to that induced by calcium channel blockade. J.Hypertension 1983; 1(suppl.2): 368–71.Google Scholar
  18. 18.
    Altura BM, Altura BT.: Role of magnesium ions in contractility of blood vessels and skeletal muscle. Magnesium Bull. 1981; 3: 102–114.Google Scholar
  19. 19.
    Altura BM, Altura BT, Gebrewold A, Ising H, Guntter T: Magnesium deficiency and hypertension: correlation between magnesium deficient diets and microcircolatory changes in situ. Science 1984; 223: 1315–17.PubMedCrossRefGoogle Scholar
  20. 20.
    Paolisso G, Barbagallo M., Hypertension, Diabetes Mellitus and Insulin Resistance. The role of intracellular magnesium. Am.J. Hypertens., 1997, 10, 346–355.PubMedCrossRefGoogle Scholar
  21. 21.
    Erne P., Bolli P., Burgissen E., Buhler F.: Correlation of platelets calcium with blood pressure: Effects of antihypertensive therapy. N.Engl.J.Med., 1984, 319: 1084–8.CrossRefGoogle Scholar
  22. 22.
    Resnick L.M., Gupta R.K., Bhargava K.K., Gruenspan H., Alderman M.H., Laragh J.H.: Cellular ions in hypertension, diabetes, and obesity: A nuclear magnetic resonance spectroscopic study. Hypertension, 1991, 17:951–957.PubMedCrossRefGoogle Scholar
  23. 23.
    Resnick LM, Gupta RK Sosa RE Corbett ML, Laragh JH. Intracellular free magnesium in erythrocyte of essential hypertension. Proc.Nat.Acad.Sci. USA, 1987, 84: 7663–7667.PubMedCrossRefGoogle Scholar
  24. 24.
    Barbagallo M., Gupta RK, Resnick LM. Cellularions in NIDDM: Relation of calcium to hyperglycemia and cardiac mass. Diabetes Care, 1996, 19, 1393–1398.PubMedCrossRefGoogle Scholar
  25. 25.
    Resnick L.M., Gupta R.K., Gruenspan H., Alderman M.H., Laragh J.H.: Hypertension and peripheral insulin resistance: mediating role of intracellular free magnesium. Am.J.Hypertens., 1990, 3: 373–379.PubMedCrossRefGoogle Scholar
  26. 26.
    Resnick LM, Gupta RK, Di Fabio B, Barbagallo M, Marion R, Laragh JH: Intracellular ionic consequences of dietary salt loading in essential hypertension. J Clin Invest, 1994; 94:1269–76.PubMedCrossRefGoogle Scholar
  27. 27.
    Resnick LM, Gupta RK, Gruenspan H., Laragh JH: Intracellular ion response to glucose tolerance: Relation of hypertension, obesity and insulin resistance. Circulation, 1988, 78(suppl.II): 11–570.Google Scholar
  28. 28.
    Resnick L.M., Barbagallo M., Gupta R.K., Laragh J.H.: Ionic basis of hypertension in diabetes mellitus: role of hyperglycemia. Am.J.Hypertens., 1993, 6: 413–417.PubMedGoogle Scholar
  29. 29.
    Barbagallo M., Shan J., Pang PKT, Resnick LM: Glucose-induced alterations of cytosolic free calcium in cultured rat tail artery vascular smooth muscle cells. J.Clin.Invest., 1995, 95: 763–767.PubMedCrossRefGoogle Scholar
  30. 30.
    Davis FB, Davis PJ, Gerard N, Blas S, MacGillivray S, Gutman S, Feldman J.: The effect of in vivo glucose administration on human Ca-ATPase activity and on enzyme responsiveness in vitro to thyroid hormone and calmodulin. Diabetes, 1985, 34: 639–646.PubMedCrossRefGoogle Scholar
  31. 31.
    Deziel MR, Safeer RS, Blas S, Davis FB, Davis PJ: Hexose-specific inhibition in vitro of human red cell Ca++-ATPase-ATP-ase activity. Biochem.Biophys.Acta, 1992, 1110: 119–122.PubMedCrossRefGoogle Scholar
  32. 32.
    Draznin B., Leitner W., Sussman KE, Sherman N.: Insulin and glucose modulate protein kinase C in rat adipocytes. Biochem.Biophys.Res.Commun., 1988, 156: 570–575.PubMedCrossRefGoogle Scholar
  33. 33.
    Haffner SM, Fong D, Hazude HP, Pugh J.A, Patterson J.K: Hyperinsulinemia, upper body adiposity and cardiovascular risk factors in non diabetics. Metabolism, 1988, 37, 338–345.PubMedCrossRefGoogle Scholar
  34. 34.
    Lucas C.P., Estigarribie J.A., Darza L.L., Reaven G.M.: Insulin and blood pressure in obesity and hypertension. Hypertension, 1985, 7, 702–706.PubMedCrossRefGoogle Scholar
  35. 35.
    Reaven G.M., Hoffman B.B.: A role for insulin in the aetiology and course of hypertension. Lancet, 1987, 2, 435–437.PubMedCrossRefGoogle Scholar
  36. 36.
    Ferrannini E., Buzzigoli G., Bonadonna R., Giorico M.A., Oleggini M., Graziadei L., Pedrinelli R., Brandi L., Bevilacqua S.: Insulin resistance in essential hypertension. N.Engl.J.Med., 1987, 317, 350–357.PubMedCrossRefGoogle Scholar
  37. 37.
    Mathias C.J., daCosta D.F., Fosbraey P., Christensen N.J., Bannister R.: Hypotensive and sedative effect of insulin in autonomic nervous failure. Br.Med.J., 1987, 295, 161–163.CrossRefGoogle Scholar
  38. 38.
    Barbagallo M., Gupta R.K., Resnick LM.: Cellular ionic effects of insulin in normal human red cells: a nuclear magnetic resonance study. Diabetologia, 1993, 36: 146–149.PubMedCrossRefGoogle Scholar
  39. 39.
    Draznin B., Sussman K.E., Eckel R., Kao M., Yost T., Sherman N.A.: Possible role of cytosolic free calcium concentration in mediating insulin resistance of obesity and hyperinsulinemia. J.Clin.Invest., 1988, 82: 1848–1852PubMedCrossRefGoogle Scholar
  40. 40.
    Hoffman J.M., Ishizuka T., Farese R.V.: Interrelated effects of insulin and glucose on diacylglycerol-protein kinase-C signaling in rat adipocytes and soley muscle in vitro and in vivo in diabetic rats. Endocrinology, 128, 2937–2948, 1991.PubMedCrossRefGoogle Scholar
  41. 41.
    Paolisso G., Sgambato S., Passariello N., Giugliano D., Scheen AJ., D’Onofrio F., Lefebvre PJ.: Insulin induces opposite changes in plasma and erythrocyte magnesium concentration in normal man. Diabetologia 1986; 29:644–647.PubMedCrossRefGoogle Scholar
  42. 42.
    Barbagallo M., Gupta RK, Bardicef M, Bardicef O., Resnick LM: Altered ionic effect of insulin in hypertension: Role of basal ion levels in determining insulin responsiveness. J.Clin.Endocrinol.Metab., 1997, 82, 1761–1765.PubMedCrossRefGoogle Scholar
  43. 43.
    Dominguez LJ, Davidoff AJ, Srinivas PR, Standley PR, Walsh MF, Sowers JR: Effects of metformin on tyrosine-kinase activity, glucose transport and intracellular calcium in rat vascular smooth muscle. Endocrinology, 1996, 137, 113–121.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang F., Sowers JR, Ram JL, Standley PR, Peuler JD.: Effect of pioglitazone on L-type calcium channel in vascular smooth muscle. Hypertension, 1994, 24, 170–175.PubMedCrossRefGoogle Scholar
  45. 45.
    Song J., Walsh MF, Igwe R, Ram JL, Barazi M, Dominguez LJ, Sowers JR: Trioglitazone reduces contraction by inhibition of vascular smooth muscle cell Ca++ currents and not endothelial nitric oxide production. Diabetes, 1997, 46, 659–664.PubMedCrossRefGoogle Scholar
  46. 46.
    Shan J., Resnick LM, Liu Q, Wu X, Barbagallo M, Pang PKT: Vascular effect of 17 estradiol in male SD rats. Am.J.Physiol, 1994; 266:H967–H973.PubMedGoogle Scholar
  47. 47.
    Barbagallo M, Shan J, Pang PKT, Resnick LM: Vascular effects of progesterone: role intracellular calcium metabolism. Am J Hypertens, 1995;8(part2):66A.CrossRefGoogle Scholar
  48. 48.
    Orentreich N, Brind JL, Rizer RL, Vogelamn JH: Age changes and sex differences in serum dehydroepian-drosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab, 1984; 59:551–555.PubMedCrossRefGoogle Scholar
  49. 49.
    Yamaji T, Ibayashi H: Plasma dehydroepiandrosterone sulfate in normal and pathological conditions. J Clin Endocrinol Metab, 1969; 29:273–78.PubMedCrossRefGoogle Scholar
  50. 50.
    Marmoston J, Griffith GC, Geller PJ, Fishman EL, Welsch F, Weiner JM: Urinary steroids in the measurement of aging and atherosclerosis. J Am Geriat Soc, 1975; 23:481–492.Google Scholar
  51. 51.
    Barret-Connor E, Khaw KT, Yen SSC: A prospective study of dehydroepiandrosterone sulfate, mortality and cardiovascular disease. N Engl J Med, 1986; 315:1519–24.CrossRefGoogle Scholar
  52. 52.
    Gordon GB, Bush DE, Weishman HF: Reduction of atherosclerosis by administration of dehydroepiandrosterone. J Clin Invest, 1988; 82:712–720.PubMedCrossRefGoogle Scholar
  53. 53.
    Barbagallo M, Shan J, Pang PKT, Resnick LM: DHEAS effects on VSMC cytosolic free calcium and vascular contractility. Hypertension, 1995; 26(part 2): 1065–69.PubMedCrossRefGoogle Scholar
  54. 54.
    Gordon T.: Blood pressure of adults by age and sex, USA 1960–62. National Center for Health Statistics, 1964, PHS publication 1000, series 11, n.4.Google Scholar
  55. 55.
    Kannel W.B.: Blood pressure and the development of cardiovascular disease in the aged. In: Cardiology in Old Age. Caird FL, Dall JLC, Kennedy RD eds. New York, NY, Plenum Press publisher, 1976, 143–175.Google Scholar
  56. 56.
    Andres R.: Aging and diabetes. Med.Clin.North Am., 1971, 55:835–45.PubMedGoogle Scholar
  57. 57.
    DeFronzo R.A.: Glucose intolerance and aging. Evidence for tissue insensitivity to insulin. Diabetes, 1979, 28: 1095–1101.Google Scholar
  58. 58.
    Barbagallo M., Gupta R.K., Resnick L.M. Effect of aging on cellular divalent cations: Relation to hypertension and diabetes. J.Invest. Medicine, 1995, 43, suppl.2: 300A.Google Scholar
  59. 59.
    Barbagallo M., Dominguez LJ, Putignano E., Barbagallo Sangiorgi G., Resnick LM: Effect of aging on intracellular divalent cation metabolism: a link to the increased incidence of hypertension and non-insulin dependent diabetes mellitus in the elderly? Arch. Gerontol. Geriatr., 1996(suppl 5), pp. 233–238.Google Scholar
  60. 60.
    Lansing AI, Alex M, Rosenthal TB.: Calcium and elastin in human atherosclerosis. J.Geront., 1973, 5: 112–117.CrossRefGoogle Scholar
  61. 61.
    Elkeles A: A comparative radiological study of calcified atheromas in males and females over 50 years of age. Lancet, 1957, ii: 714–715.CrossRefGoogle Scholar
  62. 62.
    Fleckenstein A., Frey M., Zorn S., Fleckenstein-Grun G.: Experimental basis of long term therapy of arterial hypertension with calcium antagonists. Am.J.Cardiol., 1995, 56: 3H–14H.CrossRefGoogle Scholar
  63. 63.
    Orimo H., Ouchi Y.: The role of calcium and magnesium in the development of atherosclerosis. Experimental and clinical evidence. Ann.NY.Acad.Sci., 1990, 598: 444–57.CrossRefGoogle Scholar
  64. 64.
    Orrenius S, McConkey DJ, Bellomo G., Nicotera P.: Role of Ca++ in toxic cell killing. Trends Pharmacol. Sci., 1989, 10:281–285.PubMedCrossRefGoogle Scholar
  65. 65.
    Fujita T.: Aging and calcium. Mineral Electrolyte Metab., 1986, 12: 149–156.Google Scholar
  66. 66.
    Kachaturian ZS: Hypothesis on the regulation of cytosol calcium concentration and the aging brain. Neuro-biol. Aging, 1987, 8, 345–346.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Mario Barbagallo
    • 1
  • Ligia J. Dominguez
    • 2
  • Anna Licata
    • 2
  • Lilia Granvillano
    • 1
  • Maria Adele Alessi
    • 1
  • Giuseppe Licata
    • 2
  • Lawrence M. Resnick
    • 3
  1. 1.Department of GeriatricsUniversity of PalermoPalermoItaly
  2. 2.Institute of Internal MedicineUniversity of PalermoItaly
  3. 3.Division of EndocrinologyWayne State UniversityDetroitUSA

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