Molecular Biotechnology

, Volume 24, Issue 1, pp 27–39 | Cite as

Historical perspective of the renin-angiotensin system

  • John E. HallEmail author


Researchers continue to be fascinated with the renin-angiotensin system (RAS) more than 100 yr after its discovery because of its powerful role in controlling sodium balance, body fluid volumes, and arterial pressure. Development of drugs that block different components of this system has led to powerful treatments for hypertension, heart failure, diabetes, and other diseases. Molecular approaches to studying this system offer new possibilities for better understanding the physiology and pathophysiology of the RAS, and for developing new therapeutic paradigms. Our challenge in the future will be to effectively utilize the technological advances that are taking place in virtually all areas of science, including the RAS, and to translate them into a better understanding of the pathophysiology and treatment of human diseases.

Index Entries

Kidney angiotensin II hypertension sodium excretion 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Aurell, M. (1998) The renin-angiotensin system—The centenary jubilee. Blood Pressure, 7, 71–75.PubMedCrossRefGoogle Scholar
  2. 2.
    Page, I. H. (1987) Hypertension Mechanisms. Grune & Stratton, Orlando, FL.Google Scholar
  3. 3.
    Robertson, J. I. S. (1993) Renin and angiotensin: an historical review, in The Renin-Angiotensin System (Robertson, J. I. S. and Nicholls, M. G., eds.) Gower, London, pp. 1–18.Google Scholar
  4. 4.
    Aurell, M. (1998) Robert Tigerstedt—scientist, teacher and critic, in Renin-Angiotensin (Ulfendahl, H. R. and Aurell. M., eds.) Portland Press, London, pp. 1–12.Google Scholar
  5. 5.
    Skeggs, L. (1986) Current concepts and historical perspectives of renal pressor mechanisms. J. Hypertension, 4, (suppl. 4): S3-S10.Google Scholar
  6. 6.
    Pickering, G. W. (1982) Systemic arterial hypertension., in Circulation of the Blood—Men and Ideas. (Fishman, A.P. and Richards, D.W., eds.) The American Physiological Society, Waverly Press Inc., Baltimore, pp. 487–541.Google Scholar
  7. 7.
    Inagami, T. (1998) A memorial to Robert Tigersteadt—The centennial of renin discovery. Hypertension, 32, 953–957.PubMedGoogle Scholar
  8. 8.
    Tigerstedt, R. and Bergman, P. G. (1898) Niere und kreislauf. Skand. Arch. Physiol. 8, 223–271.Google Scholar
  9. 9.
    Janeway, T.C. (1909) Note on the blood pressure changes following reduction of the renal arterial circulation. Proc. Soc. Exp. Biol. Med., 109, 5–6.Google Scholar
  10. 10.
    Goldblatt, H., et al. (1934) Studies on experimental hypertension. I. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J. Exp. Med., 59, 347–380.CrossRefGoogle Scholar
  11. 11.
    Harrison, T. R., Blalock A., and Mason, M. F. (1937) Effect on blood pressure of injection of kidney extracts of dogs with renal hypertension. Proc. Soc. Exp. Biol., 35, 38.Google Scholar
  12. 12.
    Prinzmetal, M. and Friedman, B. (1937) Pressor effects of kidney extracts from patients and dogs with hypertension. Proc. Soc. Exp. Biol., 35, 122.Google Scholar
  13. 13.
    Fasciolo, J.C., et al. (1938) The blood pressure raising secretion of the ischemic kidney. J. Physiol. 94, 281–290.PubMedGoogle Scholar
  14. 14.
    Houssay, B. A. and Taquini, A. C. (1938) Acción Vasoconstrictora de la sangre venosa del riñon isquemiado. Rev. Soc. Argent. Bio. 14, 5.Google Scholar
  15. 15.
    Kohlstaedt, K.G., Helmer, O., and Page, I.H.(1938) Activation of renin by blood colloids. Proc. Soc. Exp. Biol. Med., 39, 214–215.Google Scholar
  16. 16.
    Muá-áoz, J.M., et al. (1939) Hypertensin: the substance causing renal hypertension. Nature, 144, 980.Google Scholar
  17. 17.
    Page I. H., and Helmer, O.H. (1940) A crystalline pressor substance (angiotonin) resulting from the interaction between renin and renin-activator. J. Exp. Med., 71, 29–42.CrossRefGoogle Scholar
  18. 18.
    Braun-Menéndez, E., et al. (1940) The substance causing renal hypertension. J. Physiol. 98, 283–298.PubMedGoogle Scholar
  19. 19.
    Braun-Menéndez, E., Page I. H. (1958) Suggested revision of nomenclature—angiotensin. Science NE, 127, 242.CrossRefGoogle Scholar
  20. 20.
    Skeggs. L. T., Marsh, W. H., Kahn, J. R., and Shumway, N. P. (1954) The purification of hypertension I. J. Exp. Med., 100, 363.PubMedCrossRefGoogle Scholar
  21. 21.
    Skeggs, L. T., Marsh, W. H., Kahn, J. R., and Shumway, N. P. (1954) The existence of two forms of hypertensin. J. Exp. Med. 29, 275.CrossRefGoogle Scholar
  22. 22.
    Skeggs, L. T., et al. (1956) Preparation and function of the hypertensin-converting enzyme. J. Exp. Med. 103, 295–305.PubMedCrossRefGoogle Scholar
  23. 23.
    Skeggs, L. T., Lentz, K. E., Kahn, J. R., Shumway, N. P., Woods, K. R. (1956) The amino acid sequence of hypertensin II. J. Exp. Med. 104, 193–197.PubMedCrossRefGoogle Scholar
  24. 24.
    Elliott, D. F. and Peart, W. S. (1956) Amino acid sequence in a hypertensin. Nature 177, 527–528.PubMedCrossRefGoogle Scholar
  25. 25.
    Skeggs, L. T., Kahn, J. R., Lentz, K. E., and Shumway, N. T. (1957) The preparation, purification, and amino acid sequence of a polypeptide renin substrate. J. Exp. Med. 106, 439–453.PubMedCrossRefGoogle Scholar
  26. 26.
    Bumpus, F. M. Schwarz, H., and Page, I. H. (1957) Synthesis and pharmacology of the octapeptide angiotonin. Science 125, 3253.CrossRefGoogle Scholar
  27. 27.
    Rittel, W. B., Iselin, B., Kappeler, H., Riniker, B., and Schwyzer, R. (1957) Synthese eines hochwirksamen hypertensin II-amids (L-asparagynl-L-arginyl-L-valyl-L-tyrosyl-L-isoleucyl-L-histidyl-L-prolyl-L-phenylalanin). Helv. Chim. Acta., 40, 614–624.CrossRefGoogle Scholar
  28. 28.
    Gross, R. (1958) Renin und Hypertensin: Physiologische oder pathologische Wirkstroffe? Klinische Wochenschrift 36, 693–706.PubMedCrossRefGoogle Scholar
  29. 29.
    Davis, J. O. (1959) Discussion. Recent Progress in Hormone Research. 15, 298–303.Google Scholar
  30. 30.
    Laragh, H. H., Angers, M., Kelly, W. G., and Lieberman, S. (1960) Hypotensive agents and pressor substances: The effect of epinephrine, norepinephrine, angiotensin II, and others on the secretory rate of aldosterone in man. JAMA 174, 240–243.Google Scholar
  31. 31.
    Genest, J., Nowaczynski, W., Noiw, E. Sandor, T., and Biron, P. (1960) Adrenocortical function in essential hypertension. In Essential Hypertension (Bock, K. D., and Cottier, P. T., eds.) Springer-Verlag, Berlin. pp. 126–146.Google Scholar
  32. 32.
    Mulrow, P. J. and Ganong, W. R. (1961) Stimulation of aldosterone secretion by angiotensin II. Yale J. Biol. Med. 33, 386–395.Google Scholar
  33. 33.
    Simpson, S. A. S. and Tait J.F. (1953) Physiochemical methods of detection of a previously unidentified adrenal hormone. Mem. Soc. Endocrinol. 2, 9–24.Google Scholar
  34. 34.
    Merrill, A., Williams, R. H., and Harrison, TR. (1938) The effects of a pressor substance obtained from the kidneys on the renal circulation of rats and dogs. Am. J. Med., 96, 240–246.Google Scholar
  35. 35.
    Corcoran, A. C. and Page, I. H. (1940) The effects of angiotensin on renal blood flow and glomerular filtration. Am. J. Physiol. 130, 335–339.Google Scholar
  36. 36.
    Goormaghtigh N. (1937) L’Appareil neuromyart(riel juxtaglom(rulaire du rein: ses reactions en pathologie et ses rapports avec le tube urinef(re. C. R. Soc. Biol. (Paris), 124, 293–296.Google Scholar
  37. 37.
    Guyton, A. C. (1963) Theory for autoregulation of glomerular filtration rate and blood flow in each nephron by the juxtaglomerular apparatus. The Physiologist, 6, 194.Google Scholar
  38. 38.
    Thurau, K. (1964) Renal hemodynamics. Am. J. Med., 36: 698–719.PubMedCrossRefGoogle Scholar
  39. 39.
    Vander, A and Miller, R. (1964) Control of renin secretion in the anesthetized dog. Am. J. Physiol. 207, 537–546.PubMedGoogle Scholar
  40. 40.
    Hall, J.E., Guyton, A. C., Jackson, T. E., Coleman, T. G., Lohmeier, T. E., and Trippodo, N. C. (1977) Control of glomerular filtration rate by renin-angiotensin system. Am. J. Physiol., 233, F366-F372.PubMedGoogle Scholar
  41. 41.
    Anderson S, Rennke H. G., and Brenner, B. M. (1986) Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J. Clin. Invest. 77, 77:1993–2000.PubMedGoogle Scholar
  42. 42.
    Ames, R. P., Borkowski, A. J., Sicinski, A., and Laragh, J. H. (1965) Prolonged infusions of angiotensin II and norepinephrine and blood pressure, electrolyte balance, and aldosterone and cortisol secretion in normal man and in cirrhosis with ascites. J. Clin. Invest. 44, 1171–1185.PubMedGoogle Scholar
  43. 43.
    Freeman, R. H., Davis, J. O., Vitale, S. J., and Johnson, J. A. (1973) Intrarenal role of ang2iotensin II. homeostatic regulation of renal blood flow. Circ. Res., 32, 692–698.PubMedGoogle Scholar
  44. 44.
    Hall, J. E., Guyton, A. C., Trippodo, N. C., Lohmeier, T. E., McCaa, R. E., and Cowley, A. W., Jr. (1977) Intrarenal control of electrolyte excretion by angiotensin II. Am. J. Physiol. 233, F538-F544.Google Scholar
  45. 45.
    Kimbrough, H. M., Jr., Vaughn, E. D., Jr, Carey, R.M., and Ayers, C. R. (1977) Effect of intrarenal angiotensin II blockade on renal function in conscious dogs. Circ. Res, 40, 174–178.PubMedGoogle Scholar
  46. 46.
    Hall, J. E., Guyton, A. C., Smith, M. J., Jr., and Coleman, T. G. (1980) Blood pressure and renal function during chronic changes in sodium intake: role of angiotensin. Am. J. Physiol., 239, F271-F280.PubMedGoogle Scholar
  47. 47.
    Harris, P. J. and Young, J. A. (1977) Dose-dependent stimulation and inhibition of proximal tubular sodium reabsorption by angiotensin II in the rat kidney. Pflugers Arch., 367, 295–297.PubMedCrossRefGoogle Scholar
  48. 48.
    Schuster, V. L., Kokko, J. P., Jacobson, H. R. (1984) Angiotensin II directly stimulates sodium transport in rabbit proximal convoluted tubules. J. Clin. Invest. 73, 507–515.PubMedCrossRefGoogle Scholar
  49. 49.
    Guyton, A. C., and Coleman, T. G. (1969) Quantitative analysis of the pathophysiology of hypertension. Circ. Res., 24(Suppl I), 1–19.PubMedGoogle Scholar
  50. 50.
    Starling, E. H. (1909) The fluids of the body, in The Herter Lectures, Keever, Chicago.Google Scholar
  51. 51.
    Goll, R. (1854) Uber den Einfluss des Blutdrucks auf die Harnabsonderung. Z. Natural. Med. 4, 78.Google Scholar
  52. 52.
    Selkurt, E. E., Hall, P. W., and Spencer, M. P. (1949) Effect of graded arterial pressure decrement on renal clearance of creatinine, P-amino hippurate and sodium. Am. J. Physiol. 159, 369–384.PubMedGoogle Scholar
  53. 53.
    Haber, E., Koerner, T. Page, L. B., Kliman, B., and Purnode, A. (1969) Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects. J. Clin. Endocrinol. Metab. 29, 1349–1355.PubMedCrossRefGoogle Scholar
  54. 54.
    Boyd, G. W., Adamson, A. R., Fitz, A. E., and Peart, W.S. (1969) Radio-immunoassay determination of plasma-renin activity. Lancet 1, 213–218.PubMedCrossRefGoogle Scholar
  55. 55.
    Khairallah, P. A., Toth, A., and Bumpus, F. M. (1970) Analogs of angiotensin II. Mechanism of receptor interactions. J. Med. Chem. 13, 181.PubMedCrossRefGoogle Scholar
  56. 56.
    Pals, D. T., Masucci, F.D., Sipos, F., and Denning, G. S. (1971) Specific competitive antagonists of the vascular action of angiotensin II. Circ. Res. 29, 664–672.PubMedGoogle Scholar
  57. 57.
    Brunner, H. R., Gavras, H., Laragh, J. H., and Keenan, R. (1973) Angiotensin-II blockade in man by SAR1-Ala8-angiotensin II for understanding and treatment of high blood-pressure. Lancet 1, 1945–1948.Google Scholar
  58. 58.
    Gavras, H., Brunner, H. R., Vaughn E. D., Jr., and Laragh, J. H. (1973) Angiotensin-sodium interaction in blood pressure maintenance of renal hypertensive and normotensive rats. Science 180, 1369–1372.PubMedCrossRefGoogle Scholar
  59. 59.
    Ferreira, S. H. and Rocha e Silva, M. (1965) Potentiation of bradykinin and eledoisin by BPF (bradykinin-potentiating factor) from Bothrops jararaca venom. Experientia 21, 347–349.PubMedCrossRefGoogle Scholar
  60. 60.
    Bahkle, Y. S. (1968) Conversion of angiotensin I to angiotensin II by cell-free extracts of dog lung. Nature 220, 919–921.CrossRefGoogle Scholar
  61. 61.
    Ondetti, M. A., Williams, N. J. Sabo, E.F., Pluscec, J., Weaver, E.R., and Kocy, O. (1971) Angiotensin-converting enzyme inhibitors from the venom of Bothrops jararaca. Isolation, elucidation of structure and synthesis. Biochemistry 10, 4033–4039.PubMedCrossRefGoogle Scholar
  62. 62.
    Ondetti, M. A., Rubin, B., and Cushman, D. V. (1977) Design of specific inhibitors of angiotensin converting enzyme: new class of orally active anti-hypertensive agents. Science 196, 441–444.PubMedCrossRefGoogle Scholar
  63. 63.
    Furukuwa, Y., Kishimoto, S., and Nishikawa, K. (1982) Hypotensive imidazole derivatives. US Patent 4,340,598 issued to Takeda Chemical industries, Ltd, Osaka, Japan.Google Scholar
  64. 64.
    Wong, P.C., Chiu, A.T., Price, W.A., et al. (1988) Nonpeptide angiotensin II receptor antagonists. I. Pharmacological characterization of 2-n-butyl-4-chloro-1-(2-chlorobenzyl) imidazole-5-acetic acid, sodium salt (S-8307). J. Pharm. Exp. Therap. 247, 1–7.Google Scholar
  65. 65.
    Inagami, T., Murakami, K. (1977) Pure renin: isolation from hog kidney and characterization. J. Biol. Chem. 252, 2978–2983.PubMedGoogle Scholar
  66. 66.
    Corvol, P., Devaux, C., Ito, T., Sicard, P., Duclous, J., and Menard, J. (1977) Large scale purification of hog renin. Circ. Res. 41:612–622.Google Scholar
  67. 67.
    Lin, S-Y. and Goodfriend, T. (1970) Angiotensin receptors. Am. J. Physiology 218, 1319–1328.Google Scholar
  68. 68.
    Ruskin, A. (1956) Classics in Arterial Hypertension. Thomas, Springfield, IL, pp. ix-x.Google Scholar
  69. 69.
    Yanigisawa, M., Kurihara, H., Kimura, S., et al. (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332, 411–415.CrossRefGoogle Scholar
  70. 70.
    Swales, J. D. (1994) Hypertension: the past, the present and the future. In Textbook of Hypertension (Swales, J. D., ed.) Blackwell Scientific Publishers, Oxford, pp. 1–7.Google Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  1. 1.Department of Physiology and BiophysicsUniversity of Mississippi Medical CenterJackson

Personalised recommendations