Skip to main content
SpringerLink
Log in

Salt-induced hypertension in WKY rats: Prevention by α-lipoic acid supplementation

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

There is strong evidence that points to excess dietary salt as a major factor contributing to the development of hypertension. Salt sensitivity is associated with glucose intolerance and insulin resistance in both animal models and humans. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes which bind to vascular calcium channels, increasing cytosolic [Ca2+]i and blood pressure. In an insulin resistant animal model of hypertension, spontaneously hypertensive rats (SHRs), dietary supplementation with lipoic acid lowers tissue aldehydes and plasma insulin levels and normalizes blood pressure. The objective of this study is to examine the effects of a high salt diet on tissue aldehydes, cytosolic [Ca2+]i and blood pressure in WKY rats and to investigate whether dietary supplementation with lipoic acid can prevent a salt induced increase in blood pressure. Starting at 7 weeks of age, WKY rats were divided into three groups of six animals each and treated for 10 weeks with diets as follows: WKY-normal salt (0.7% NaCl); WKY-high salt (8% NaCl); WKY-high salt + lipoic acid (8% NaCl diet + lipoic acid 500 mg/Kg feed). At completion, animals in the high salt group had elevated systolic blood pressure, platelet [Ca2+]i, and tissue aldehyde conjugates compared with the normal salt group and showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary α-lipoic acid supplementation in high salt-treated WKY rats normalized systolic blood pressure and cytosolic [Ca2+]i and aldehydes in liver and aorta. Kidney aldehydes and renal vascular changes were attenuated, but not normalized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. González-Albarrán O, Ruilope LM, Villa E, Robles RG: Salt sensitivity: Concept and pathogenesis. Diabetes Res Clin Pract 39(suppl): S15-S26, 1998

    Google Scholar 

  2. Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS: Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension 8(suppl II): II127-II134, 1986

    Google Scholar 

  3. Kotchen TA, Zhang HY, Covelli M, Blehschmidt N: Insulin resistance and blood pressure in Dahl rats, and in one-kidney, one-clip hypertensive rats. Am J Physiol 261 (Endocrinol Metab 24): E692-E697, 1991

    Google Scholar 

  4. Mori Y, Murakawa Y, Yokoyama J, Tajima N, Ikeda Y, Nobukata H et al.: Effect of highly purified eicosapentaenoic acid ethyl ester in insulin resistance and hypertension in Dahl salt-sensitive rats. Metabolism 48: 1089-1095, 1999

    Google Scholar 

  5. Mondon CE, Reaven GM: Evidence of abnormalities of insulin metabolism in rats with spontaneous hypertension. Metabolism 37: 303-305, 1988

    Google Scholar 

  6. Preuss HG, el Zein M, Knapka J, MacArthy P, Yousufi AK, Gleim GW et al.: Blood pressure responses to sucrose ingestion in four rat strains. Am J Hypertens 5: 244-250, 1992

    Google Scholar 

  7. Ogihara T, Asano T, Ando K, Sakoda H, Anai M, Shojima N et al.: High-salt diet enhances insulin signaling and induces insulin resistance in Dahl salt-sensitive rats. Hypertension 40: 83-89, 2002

    Google Scholar 

  8. Ogihara T, Asano T, Ando K, Chiba Y, Sekine N, Sakoda H et al.: Insulin resistance with enhanced insulin signaling in high-salt diet-fed rats. Diabetes 50: 573-583, 2001

    Google Scholar 

  9. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L et al.: Insulin resistance in essential hypertension. N Eng J Med 313:350-357, 1987

    Google Scholar 

  10. Levy J, Zemel MB, Sowers JR: Role of cellular calcium metabolism in abnormal glucose metabolism, and diabetic hypertension. Am J Med (suppl 6A): 7S-16S, 1989

    Google Scholar 

  11. Reaven GM: Insulin resistance, hyperinsulinemia, and hypertriglyceridemia in the etiology and clinical course of hypertension. Am J Med (suppl 2A): 7S-12S, 1991

    Google Scholar 

  12. Brandt RB, Siegel SA: Methylglyoxal production in human blood. Submolecular biology and cancer. Excerpta Medica, CIBA Foundation Symposium 67: 211-223, 1979

    Google Scholar 

  13. Phillips SA, Mirrlees D, Thornalley PJ: Modification of the glyoxalase system in streptozotocin-induced diabetic rats. Effect of the aldose reductase inhibitor statil. Biochem Pharmacol 46: 805-811, 1993

    Google Scholar 

  14. Leoncini G, Maresca M, Buzzi E: Inhibition of the glycolytic pathway by methylgloxal in human platelets. Cell Biochem Function 7: 65-70, 1989

    Google Scholar 

  15. Lieber CS: Mechanism of ethanol induced hepatic injury. Pharmac Ther 46:1-41, 1990

    Google Scholar 

  16. Sorrell MD, Ruma DJ: The functional implications of acetaldehyde binding to cell constituents. Ann NY Acad Sci 492: 50-70, 1987

    Google Scholar 

  17. Vasdev S, Barrett B, Longerich L, Ford CA: Ethanol-induced hypertension: The role of acetaldehyde. In: N.S. Dhalla (ed). Pathophysiology of Heart Failure. Kluwer Academic Publishers, Norwell, MA, USA, 1996, pp 77-93

    Google Scholar 

  18. Vasdev S, Longerich L, Ford CA: Role of aldehydes in hypertension. In: B.K. Sharma, N. Takeda, N.K. Ganguly, P.K. Singal (eds). Adaptation Biology and Medicine, vol. I. Narosa Publishing House, New Delhi, India, 1997, pp 326-339

    Google Scholar 

  19. Vasdev S, Ford CA, Longerich L, Gadag V, Wadhawan S: Role of aldehydes in fructose induced hypertension. Mol Cell Biochem 181: 1-9, 1998

    Google Scholar 

  20. Vasdev S, Mian T, Ford CA, Longerich L, Parai S: Role of endogenous aldehydes in spontaneously hypertensive and disulfiram-induced hypertensive rats. Nutr Metab Cardiovasc Dis 6: 130-140, 1996

    Google Scholar 

  21. Vasdev S, Ford CA, Parai S, Longerich L, Gadag V: Dietary α-lipoic acid supplementation lowers blood pressure in spontaneously hypertensive rats. J Hypertens 18: 567-573, 2000

    Google Scholar 

  22. Vasdev S, Ford CA, Parai S, Longerich L, Gadag V: Dietary lipoic acid supplementation prevents fructose-induced hypertension in rats. Nutr Metab Cardiovasc Dis 10: 339-346, 2000

    Google Scholar 

  23. Scherrer U, Sartori C: Defective nitric oxide synthesis: A link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity. Euro J Endocrinol 142: 315-323, 2000

    Google Scholar 

  24. Brandwein HJ, Lewicki JA, Murad F: Reversible inactivation of guanylate cyclase by mixed disulfide formation. J Biol Chem 256: 2958-2962, 1981

    Google Scholar 

  25. Degenhardt TP, Thorpe SR, Baynes JW: Chemical modification of proteins by methylglyoxal. Cell Mol Biol 44: 1139-1145, 1998

    Google Scholar 

  26. Sprince H, Parker CM, Smith CG, Gonzales LJ: Protection against acetaldehyde toxicity in the rat by L-cysteine, thiamin and L-2-methylthiazolidine-4-carboxylic acid. Agents Actions 4: 125-129, 1974

    Google Scholar 

  27. Meister A, Anderson ME, Hwang O: Intracellular cysteine and glutathione delivery systems. J Am Col Nutr 5: 137-151, 1986

    Google Scholar 

  28. Packer L, Roy S, Sen CK: α-Lipoic acid: A metabolic antioxidant and potential redox modulator of transcription. Adv Pharmacol 38: 79-101, 1999

    Google Scholar 

  29. Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ et al.: Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittel-Forschung 45: 872-874, 1995

    Google Scholar 

  30. Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ: Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes 104: 284-288, 1996

    Google Scholar 

  31. Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ et al.: The antioxidant α-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. Diabetes 45: 1024-1029, 1996

    Google Scholar 

  32. Henriksen EJ, Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ: Stimulation by α-lipoic acid of glucose transport activity in skelctal muscle of lean and obese zucker rats. Life Sci 61: 805-812, 1997

    Google Scholar 

  33. Busse E, Zimmer G, Schopohl B, Kornhuber B: Influence of α-lipoic acid on intracellular glutathione in vitro and in vivo. Arzneimittel-Forschung 42: 829-831, 1992

    Google Scholar 

  34. Dillard CJ, Tappel AL: Fluorescent damage products of lipid peroxidation. Meth Enzymol 105: 337-341, 1984

    Google Scholar 

  35. Mandal AK, Bell RD, Parker D, Nordquist JA, Lindeman RD: An analysis of the relationship of the malignant lesions of the kidney to hypertension. Microvasc Res 14: 279-292, 1977

    Google Scholar 

  36. Schauenstein E, Esterbauer H, Zollner H: Aldehydes in biological systems. In: J.R. Lagnado (ed). Aldehydes in Biological Systems, Their Natural Occurrence and Biological Activities. Pion Limited, London, 1977, pp 1-7

    Google Scholar 

  37. Bolli P, Erne P. Hulthen UL, Ritz R, Kiowski W, Ji BH et al.: Parallel reduction of calcium-influx-dependent vasoconstriction and platelet-free calcium concentration with calcium entry and β-adrenoceptor blockade. J Cardiovasc Pharmac 6: S996-S1001, 1984

    Google Scholar 

  38. Pollard TD: Electron microscopy of synthetic myosin filaments. J Cell Biol 67:93-104, 1975

    Google Scholar 

  39. Trovati M, Anfossi G, Massucco P, Mattiello L, Costamagna C, Piretto V et al.: Insulin stimulates nitric oxide synthesis in human platelets and, through nitric oxide, increases platelet concentrations of both guanosine-3′, 5′-cyclic monophosphate and adenosine-3′, 5′-cyclic monophosphate. Diabetes 46: 742-749, 1997

    Google Scholar 

  40. Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA: Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 27: 567-574, 1996

    Google Scholar 

  41. Taddei S, Viridus A, Mattei P, Salvetti A: Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension 21: 929-933, 1993

    Google Scholar 

  42. Taddei S, Salvetti A: Direct effects of insulin on the arteriolar tone: Abnormality in insulin-resistant states? Nutr Metab Cardiovasc Dis 6: 178-186, 1996

    Google Scholar 

  43. Ibarra M, Meneses A, Ransanz V, Castillo C, Hong E: Changes in endothelium-dependent vascular responses associated with spontaneous hypertension and age in rats. Arch Med Res 26: S177-S183, 1995

    Google Scholar 

  44. Kahn NN, Acharya K, Bhattacharya S, Acharya R, Mazumder S, Bauman WA et al.: Nitric oxide: The 'second messenger’ of insulin. IUBMB Life 49: 441-450, 2000

    Google Scholar 

  45. Sechi LA, Griffin CA, Giacchetti G, Zingaro L, Catena C, Bartoli E et al.: Abnormalities of insulin receptors in spontaneously hypertensive rats. Hypertension 27: 955-961, 1996

    Google Scholar 

  46. Manning RD, Hu L, Tan DY, Meng S: Role of abnormal nitric oxide systems in salt-sensitive hypertension. Am J Hypertens 14: 68S-73S, 2001

    Google Scholar 

  47. Facchini FS, DoNascimento C, Reaven GM, Yip JW, Ni XP, Humphreys MH: Blood pressure, sodium intake, insulin resistance, and urinary nitrate excretion. Hypertension 33: 1008-1012, 1999

    Google Scholar 

  48. Cubeddu, LX, Alfieri AB, Hoffmann IS, Jimenez E, Roa CM, Cubeddu R et al.: Nitric oxide and salt sensitivity. Am J Hypertens 13: 973-979, 2000

    Google Scholar 

  49. Bragulat E, de la Sierra A, Antonio MT, Coca A: Endothelial dysfunction in salt-sensitive essential hypertension. Hypertension 37: 444-448, 2001

    Google Scholar 

  50. Bragulat E, de la Sierra A: Salt intake, endothelial dysfunction, and salt-sensitive hypertension. J Clin Hypertens 4: 41-46, 2002

    Google Scholar 

  51. Ni Z, Oveisi F, Vaziri ND: Nitric oxide synthase isotype expression in salt-sensitive and salt-resistant Dahl rats. Hypertension 34: 552-557, 1999

    Google Scholar 

  52. Castrop H, Kurtz A: Differential nNOS gene expression in salt-sensitive and salt-resistant Dahl rats. J Hypertens 19: 1223-1231, 2001

    Google Scholar 

  53. Chen PY, Sanders PW: Role of nitric oxide synthesis in salt-sensitive hypertension in Dahl/Rapp rats. Hypertension 22: 812-818, 1993

    Google Scholar 

  54. Ni Z, Vaziri ND: Effect of salt loading on nitric oxide synthase expression in normotensive rats. AM J Hypertens 14: 155-163, 2001

    Google Scholar 

  55. Zimmer G, Mainka L, Krüger E: Diydrolipoic acid activates oligomycin-sensitive thiol groups and increases ATP synthesis in mitochondria. Arch Biochem Biophys 288: 609-613, 1991

    Google Scholar 

  56. Hofmann M, Mainka P, Tritshler H, Fuchs J, Zimmer G: Decrease of red cell membrane fluidity and-SH groups due to hyperglycemic conditions is counteracted by α-lipoic acid. Arch Biochem Biophys 324: 85-92, 1995

    Google Scholar 

  57. Sen CK, Roy S, Packer L: Involvement of intracellular Ca2+ in oxidant-induced NF-κB activation. FEBS Lett 385: 58-62, 1996

    Google Scholar 

  58. Chen PY, Sanders PW: L-Arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats. J Clin Invest 88: 1559-1567, 1991

    Google Scholar 

  59. Chen PY, St. John PL, Kirk KA, Abrahamson DR, Sanders PW: Hypertensive nephrosclerosis in the Dahl/Rapp rat. Lab Invest 68: 174-184, 1993

    Google Scholar 

  60. Vasdev S, Ford CA, Longerich L, Parai S, Gadag V, Wadhawan S: Aldehyde induced hypertension in rats: Prevention by N-acetyl cysteine. Artery 23: 10-36, 1998

    Google Scholar 

  61. Thornalley PJ: Modification of the glyoxalase system in disease processes and prospects for therapeutic strategies. Biochem Soc Trans 21: 531-534, 1993

    Google Scholar 

  62. Han D, Handelman G, Marcocci L, Sen CK, Roy S, Kobuchi H et al.: Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors 6: 321-338, 1997

    Google Scholar 

  63. Janero DR, Burghardt B: Cardiac membrane vitamin E and malon-dialdehyde levels in heart muscle of normotensive and spontaneously-hypertensive rats. Lipids 24: 33-38, 1989

    Google Scholar 

  64. Uysal M, Bulur H, Sener D, Öz H: Lipid peroxidation in patients with essential hypertension. Int J Clin Pharmacol Ther Toxicol 24: 474-476, 1986

    Google Scholar 

  65. Packer L: ±-Lipoic acid: A metabolic antioxidant which regulates NF-κB signal transduction and protects against oxidative injury. Drug Metab Rev 30: 245-275, 1998

    Google Scholar 

  66. Natraj CV, Gandhi VM, Menon KKG: Lipoic acid and diabetes. Effect of dihydrolipoic acid administration in diabetic rats and rabbits. J Biosci 6: 37-46, 1984

    Google Scholar 

  67. Randle PJ: Alpha-ketoacid dehydrogenase complexes and respiratory fuel utilization in diabetes. Diabetologia 28: 479-484, 1985

    Google Scholar 

  68. Wagh SS, Natraj CV, Menon KKG: Mode of action of lipoic acid in diabetes. J Biosci 11: 59-74, 1987

    Google Scholar 

  69. Estrada DE, Ewart HS, Tsakiridis T, Volchuk A, Ramlal T, Tritschler H et al.: Stimulation of glucose uptake by the natural coenzyme α-lipoic acid/thioctic acid. Diabetes 45: 1798-1804, 1996

    Google Scholar 

  70. Haugaard N, Haugaard ES: Stimulation of glucose utilization by thioctic acid in rat diaphragm incubated in vitro. Biochim Biophys Acta 222: 583-586, 1970

    Google Scholar 

  71. Singh HPP, Bowman RH: Effect of DL-α-lipoic acid on the citrate concentration and phosphofructokinase activity of perfused hearts from normal and diabetic rats. Biochem Biophys Res Com 41: 555-561, 1970

    Google Scholar 

  72. Kenny JJ: Has it been given a fair shake? Or is it a serial killer? Communicating Food for Health Newsletter 1-20, 1999

Download references

Author information

Authors and Affiliations

  1. Department of Medicine and Laboratory Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, Newfoundland, Canada, A1B 3V6

    Sudesh Vasdev, Vicki Gill & Sushil Parai

  2. Division of Community Health, Health Sciences Centre, Memorial University of Newfoundland, St. John's, Newfoundland, Canada, A1B 3V6

    Linda Longerich & Veeresh Gadag

Authors
  1. Sudesh Vasdev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vicki Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linda Longerich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sushil Parai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Veeresh Gadag
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vasdev, S., Gill, V., Longerich, L. et al. Salt-induced hypertension in WKY rats: Prevention by α-lipoic acid supplementation. Mol Cell Biochem 254, 319–326 (2003). https://doi.org/10.1023/A:1027354005498

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1027354005498

Search

Navigation