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Are Local Renin–Angiotensin Systems the Focal Points for Understanding Salt Sensitivity in Hypertension?

  • Edward D. Frohlich
Conference paper

Abstract

Salt has had a prominent role in the history of man. Initially involving social, economic, and political aspects of human endeavor, in more recent decades salt has become extremely important in its role in the pathogenesis of cardiovascular and renal diseases. The magnitude of this relationship is of tremendous significance, affecting the health of billions of people throughout the world. Our laboratory studies in the adult spontaneously hypertensive rat and in its normotensive control Wistar Kyoto rat over the past 30 to 40 years have clearly demonstrated that in addition to elevating arterial pressure slightly, but significantly, long term salt loading produced severe structural and functional derangements of the vital organs. These salt induced changes have resulted in severe fibrosis (with deposition of hydroxyproline, type 1collagen), ischemia of both ventricles (the hypertrophied left as well as the non-hypertrophied right), and impaired diastolic ventricular function in the presence of preserved systolic function. The aorta demonstrated severe fibrosis and impaired distensibility and pulse wave velocity. Furthermore, the kidneys demonstrated severe changes of nephrosclerosis manifested by marked ischemia, fibrosis, small cell infiltration, glomerular sclerosis, increased total arteriolar resistance associated with afferent and efferent glomerular resistances with increased glomerular hydrostatic pressure, and marked proteinuria. The changes are typical of diastolic functional impairment of the heart and end-stage renal disease in patients with end-stage renal disease that were dramatically prevented and/or reversed by either of two angiotensin II (type 1) receptor blocking agents. These salt induced cardiac, vascular and renal structural and functional findings are strikingly similar to the target organ involvements in patients with essential hypertension associated with suppression of the endocrine rennin–angiotensin system mediated through the juxtaglomerular apparatus, We therefore suggest that these disastrous effects of salt loading are mediated through local cardiac, vascular, and renal angiotensin systems in these organs. They are dramatically supported by a large recent multicenter clinical trial involving prehypertensive patients who were maintained on their usual salt loaded diets and were compared with similar patients who received a salt restricted diet. Further studies are in progress to elaborate this attractive and novel mechanism of action.

Keywords

Essential Hypertension Salt Sensitivity Salt Loading Diastolic Ventricular Dysfunction Juxtaglomerular Apparatus 
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.

References

  1. 1.
    Kurlansky M. SALT: A World History. New York: Penguin Books; 2003.Google Scholar
  2. 2.
    Ambard L, Beaujard E. Causes de l’hypertension arterialle. Arch Gen Med. 1904;1:520–533.Google Scholar
  3. 3.
    Stamler J. The INTERSALT Study: background, methods, findings, and implications. Am J Clin Nutr. 1997;65:626S–642S.PubMedGoogle Scholar
  4. 4.
    Dahl LK. Salt intake and salt need. N Engl J Med. 1958;258:1152–1157.PubMedCrossRefGoogle Scholar
  5. 5.
    Dahl LK. Salt and hypertension. Am J Clin Nutr. 1072;25:231–244.Google Scholar
  6. 6.
    Frohlich ED. The salt conundrum: a hypothesis. Hypertension. 2007;50:161–166.PubMedCrossRefGoogle Scholar
  7. 7.
    Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8(Suppl II):127–134.Google Scholar
  8. 8.
    Frohlich ED. In memoriam – Ray Gifford, Jr., MD (1923–2004). Hypertension. 2004;44:109–110.CrossRefGoogle Scholar
  9. 9.
    Frohlich ED. The role of salt in hypertension: The complexity seems to become clearer. Nat Clin Pract Cardiovasc Med. 2008;5:2–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Chrysant SG, Walsh GM, Kem DC, Frohlich ED. Hemodynamic and metabolic evidence of salt sensitivity in spontaneously hypertensive rats. Kidney Int. 1979;15:33–37.PubMedCrossRefGoogle Scholar
  11. 11.
    MacPhee AA, Blakeslley HL, Graci KA, Frohlich ED, Cole FE. Altered cardiac beta-adrenergic receptors in SHR rats receiving salt excess. Clin Sci. 1980;59(Suppl VI):169–170.Google Scholar
  12. 12.
    Frohlich ED, Chien Y, Sosoko S, Pegram BL. Relationships between dietary sodium intake, hemodynamic and cardiac mass in spontaneously hypertensive and normotensive Wistar-Kyoto rats. Am J Physiol. 1993;264:R30–R34.PubMedGoogle Scholar
  13. 13.
    Ahn J, Varagic J, Slama M, Susic D, Frohlich ED. Cardiac structural and functional responses to salt loading in SHR. Am J Physiol (Heart Circ Physiol). 2004;287:H767–H772.CrossRefGoogle Scholar
  14. 14.
    Varagic J, Frohlich ED, Diez J, et al. Myocardial fibrosis, impaired coronary hemodynamics, and biventricular dysfunction in salt-loaded SHR. Am J Physiol (Heart Circ Physiol). 2006;290:H1503–H1509.CrossRefGoogle Scholar
  15. 15.
    Varagic J, Frohlich ED, Susic D, et al. AT-1 receptor antagonism attenuates target organ effects of salt excess in SHRs without affecting pressure. Am J Physiol (Heart Circ Physiol). 2008;294:H853–H868.CrossRefGoogle Scholar
  16. 16.
    Matavelli LC, Zhou X, Varagic J, Susic D, Frohlich ED. Salt loading produces severe renal hemodynamic dysfunction independent of arterial pressure in spontaneously hypertensive rats. Am J Physiol (Heart Circ Physiol). 2007;292:H814–H819.CrossRefGoogle Scholar
  17. 17.
    Trippodo NC, Frohlich ED. Controversies in cardiovascular research: similarities of genetic (spontaneous) hypertension. Man and rat. Circ Res. 1981;48:309–319.PubMedGoogle Scholar
  18. 18.
    Safar ME, Asmar RG, Benetos A, London GM, Levy BI. Sodium, large arteries and diuretic compounds in hypertension. J Hypertens. 1992;10:S133–S136.CrossRefGoogle Scholar
  19. 19.
    Partovian C, Benetos A, Pommies J-P, Mischler W, Safar ME. Effects of a chronic high-salt diet on large artery structure: role of endogenous bradykinin. Am J Physiol. 1998;274:H1423–H1428.PubMedGoogle Scholar
  20. 20.
    Williams JS, Solomon SD, Crivaro M, Conlin PR. Dietary sodium intake modulates myocardium relaxation responsiveness to angiotensin II. Transl Res. 2006;48:49–54.CrossRefGoogle Scholar
  21. 21.
    Du Cailar G, Ribstein J, Mimran A. Dietary sodium and target organ damage in essential hypertension. Am J Hypertens. 2002;15:222–229.PubMedCrossRefGoogle Scholar
  22. 22.
    Susic D, Zhou X, Frohlich ED. Angiotensin blockade prevents salt-induced injury of the renal circulation in spontaneously hypertensive rats. Am J Nephrol.2009;29:639–645.PubMedCrossRefGoogle Scholar
  23. 23.
    Cook NR, Cutler JA, Obarzanek E, et al. Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP). BMJ. 2007;334:885–894.PubMedCrossRefGoogle Scholar
  24. 24.
    Tunstall-Pedoe H, Woodward M, Tavendale R, Rook RA, McCluske MK. Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish Heart Health Study. BMJ. 1997;351:722–729.Google Scholar
  25. 25.
    Toumilehto J, Iousilahti P, Restenyte D, et al. Urinary sodium excretion and cardiovascular mortality in Finland: a prospective study. Lancet. 2001;357:848–851.CrossRefGoogle Scholar
  26. 26.
    Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42:1206–1252.PubMedCrossRefGoogle Scholar
  27. 27.
    International Society of Hypertension Writing Group. International Society of Hypertension (ISH). Statement on blood pressure lowering and stroke prevention. J Hypertens. 2003;21:651–663.CrossRefGoogle Scholar
  28. 28.
    Re RN. Tissue renin angiotensin systems. Med Clin North Am. 2004;88:19–38.PubMedCrossRefGoogle Scholar
  29. 29.
    Re RN. Intracellular renin and the nature of intracrine enzymes. Hypertension. 2003;42:117–122.PubMedCrossRefGoogle Scholar
  30. 30.
    De Mello WC. The pathophysiological implications of an intracellular renin receptor. Circ Res. 2006;99:1285–1286.CrossRefGoogle Scholar
  31. 31.
    Schunkert H, Ingelfinger JR, Jacob H, Jackson B, Bouyounes B, Dzau VJ. Reciprocal feedback regulation of kidney angiotensinogen and renin RNA expressions by angiotensin II. Am J. Physiol. 1992;263(5 Pt 1):E863–E869.PubMedGoogle Scholar
  32. 32.
    Navar LG, Prieto-Carrasquero MC, Kobori H. Regulation of renin in JGA and tubules in hypertension. In: Frohlich ED, Re RN, eds. The Local Cardiac Renin Angiotensin-Aldosterone System. New York: Springer Science + Business Media, Inc; 2005:22–29.Google Scholar
  33. 33.
    Varagic J, Frohlich ED. Hypertension and the multifactorial role of salt. Lab Med. 2005;36:2–5.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Edward D. Frohlich
    • 1
  1. 1.Ochsner Clinic FoundationNew OrleansUSA

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