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Pathologic consequences of increased angiotensin II activity

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Summary

Advances in molecular medicine and pharmacology have allowed clinicians to critically reassess the reninangiotensin system. Angiotensin II (AII) participates in the control of cardiovascular function and electrolyte balance, and plays a part in the regulation of cellular oncogenes and the expression of growth factors. The expression of the proteins of the renin-angiotensin system in organs other than the kidneys suggests that these diverse actions are associated with the peptide in the local environment. Tissue reninangiotensin activity has prompted the investigation of alternate pathways for the production of AII and characterization of novel forms of angiotensin peptides that counteract the vasoconstrictor and proliferative actions of AII. The heptapeptide angiotensin-(1–7) appears to be critically involved in regulating the angiotensinogen activity of AII through stimulation of vasodilator prostaglandins and release of nitric oxide. Study in this area has been accelerated by the identification of receptors that convey the actions of angiotensin peptides at the cellular level and the pharmacologic characterization of agents that inhibit the ability of AII to bind to target receptors. The introduction of a new class of orally active AII-receptor blockers has provided a specific test of the role of AII in the development of essential hypertension and the potential for improved therapy for hypertension and cardiac and vascular sequelae.

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References

  1. Ondetti MA, Cushman DW. Enzymes of the renin angiotensin system and their inhibitors. Annu Rev Biochem 1982;51:238–252.

    Google Scholar 

  2. Page IH. The mosaic theory of arterial hypertension—its interpretation. Perspect Biol Med 1967;10:3–33.

    Google Scholar 

  3. Bonnardeaux A, Davies E, Jeunemaitre X, et al. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 1994;24:63–69.

    Google Scholar 

  4. Charru A, Jeunemaitre X, Soubrier F, Corvol P, Chatellier G. Hypergene: A clinical and genetic database for genetic analysis of human hypertension. J Hypertens 1994; 12:981–985.

    Google Scholar 

  5. Harrap SB, Davidson HR, Connor JM, et al. The angiotensin I converting enzyme gene and predisposition to high blood pressure. Hypertension 1993;21:455–460.

    Google Scholar 

  6. Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al. Molecular basis of human hypertension: Role of angiotensinogen. Cell 1992;71:169–180.

    Google Scholar 

  7. Ferrario CM. The renin-angiotensin system: Importance in physiology and pathology. In: Saruta T, Arakawa K, Kokubu T, eds. ACE inhibitors: Innovative clinical applications. Japan: Medical Tribune, 1990:66–79.

    Google Scholar 

  8. Ferrario CM, Barnes KL, Block CH, et al. Pathways of angiotensin formation and function in the brain. Hypertension 1990;15(Suppl I):I13-I19.

    Google Scholar 

  9. Ferrario CM, Chappell MC. A new myocardial conversion of angiotensin I. Curr Opin Cardiol 1994;9:520–526.

    Google Scholar 

  10. Urata H, Strobel F, Ganten D. Widespread tissue distribution of human chymase. J Hypertens 1994;12(Suppl): S17-S22.

    Google Scholar 

  11. Ferrario CM. Biological roles of angiotensin-(1–7). Hypertens Res 1992;15:61–66.

    Google Scholar 

  12. Nakamoto H, Ferrario CM, Fuller SB, Robaczwski DL, Winicov E, Dean RH. Angiotensin-(1–7) and nitric oxide interaction in renovascular hypertension. Hypertension 1995;25:796–802.

    Google Scholar 

  13. Freeman EJ, Chisolm GM, Ferrario CM, Tallant EA. Angiotensin-1(1–7) [Ang-(1–7)] inhibits vascular smooth muscle cell growth (abstract). Hypertension 1995;22:414.

    Google Scholar 

  14. Benter IF, Diz DI, Ferrario CM. Cardiovascular actions of angiotensin-(1–7). Peptides 1993;14:679–684.

    Google Scholar 

  15. Benter IF, Ferrario CM, Morris M, Diz DI. Antihypertensive actions of angiotensin-(1–7) in spontaneously hypertensive rats. Am J Physiol 1995;269(1 Pt 2): H313-H319.

    Google Scholar 

  16. Moriguchi A, Tallant EA, Matsumura K, et al. Opposing actions of angiotensin-(1–7) and angiotensin II in the brain of transgenic hypertensive rats. Hypertension 1995;25: 1260–1265.

    Google Scholar 

  17. DelliPizzi A, Hilchey SD, Bell-Quilley CP. Natriuretic actions of angiotensin-(1–7). Br J Pharmacol 1994;111:1–3.

    Google Scholar 

  18. Andreatta-Van Leyen S, Romero MF, Khosla MC, Douglas JG. Modulation of phospholipase A2 activity and sodium transport by angiotensin-(1–7). Kidney Int 1993;44: 932–936.

    Google Scholar 

  19. Botelho LMO, Block CH, Khosla MC, Santos RAS. Plasma angiotensin (1–7) immunoreactivity is increased by salt load, water deprivation, and hemorrhage. Peptides 1994; 15:723–729.

    Google Scholar 

  20. Heyne N, Beer W, Muhlbauer B, Osswald H. Renal response to angiotensin-(1–7) in anesthetized rats (abstract). Kidney Int 1995;47:975–976.

    Google Scholar 

  21. Welches WR, Brosnihan KB, Ferrario CM. A comparison of the properties, and enzymatic activity of three angiotensin processing enzymes: Angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11. Life Sci 1993;52:1461–1480.

    Google Scholar 

  22. Ferrario CM. Renin-angiotensin system: Importance in physiology and pathology. J Cardiovasc Pharmacol 1990; 15(Suppl 3):S1-S5.

    Google Scholar 

  23. Ferrario CM, Jaiswal N, Yamamoto K, Diz DI, Schiavone MT. Hypertensive mechanisms and converting enzyme inhibitors. Clin Cardiol 1991;14(Suppl IV):IV56-IV62.

    Google Scholar 

  24. Ferrario CM, Schiavone MT. The renin angiotensin system: Importance in physiology and pathology. Cleve Clin J Med 1989;56:439–446.

    Google Scholar 

  25. Ferrario CM, Averill DB. The importance of angiotensin in the brain. In: Mornex R, Gaffial C, Leclere J, eds. Progress in Endocrinology. Lancs, England: Parthenon, 1993: 482–486.

    Google Scholar 

  26. Welches WR, Santos RAS, Chappell MC, Brosnihan KB, Greene LJ, Ferrario CM. Evidence that prolyl endopeptidase participates in the processing of brain angiotensin. J Hypertens 1991;9:631–638.

    Google Scholar 

  27. Hanesworth JM, Sardinia MF, Krebs LT, Hall KL, Harding JW. Elucidation of a specific binding site for angiotensin II (3–8), angiotensin IV, in mammalian heart membranes. J Pharmacol Exp Ther 1993;266:1036–1042.

    Google Scholar 

  28. Sardinia MF, Hanesworth JM, Krebs LT, Harding JW. AT4 receptor binding characteristics: D-amino acid and glycine-substituted peptides. Peptides 1993;14:949–954.

    Google Scholar 

  29. Swanson GN, Hanesworth JM, Sardinia MF, et al. Discovery of a distinct binding site for angiotensin II (3–8), a putative angiotensin IV receptor. Regul Pept 1992;40: 409–419.

    Google Scholar 

  30. Griendling KK, Berk BC, Socorro L, Tsuda T, Delafontaine P, Alexander RW. Secondary signalling mechanisms in angiotensin II stimulated vascular smooth muscle cells. Clin Exp Pharmacol Physiol 1988;15:105–112.

    Google Scholar 

  31. Jaiswal N, Tallant EA, Diz DI, Khosla MC, Ferrario CM. Subtype 2 angiotensin receptors mediate prostaglandin synthesis in human astrocytes. Hypertension 1991;17: 1115–1120.

    Google Scholar 

  32. Jaiswal N, Diz DI, Tallant EA, Khosla MC, Ferrario CM. Characterization of angiotensin receptors mediating prostaglandin synthesis in C6 glioma cells. Am J Physiol 1991; 260:R1000-R1006.

    Google Scholar 

  33. Timmermans PBMWM, Benfield P, Chiu AT, Herblin WF, Wong PC, Smith RD. Angiotensin II receptors and functional correlates. Am J Hypertens 1992;5:221S-235S.

    Google Scholar 

  34. Timmermans PBMWM, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993;45:205–251.

    Google Scholar 

  35. Ichiki T, Inagami T. Expression, genomic organization, and transcription of the mouse angiotensin II type 2 receptor gene. Circ Res 1995;76:693–700.

    Google Scholar 

  36. Ichiki T, Inagami T. Transcriptional regulation of the mouse angiotensin II type 2 receptor gene. Hypertension 1995;25:720–725.

    Google Scholar 

  37. Nakajima M, Horiuchi M, Morishita R, Yamada T, Pratt RE, Dzau VJ. Growth inhibitory function of type 2 angiotensin II receptor: Gain of function study by in vivo gene transfer (abstract). Hypertension 1994;24:379.

    Google Scholar 

  38. Tsutsumi K, Stromberg C, Viswanathan M, Saavedra JM. Angiotensin-II receptor subtypes in fetal tissues of the rat: Autoradiography, guanine nucleotide sensitivity, and association with phosphoinositide hydrolysis. Endocrinology 1993;129:1075–1082.

    Google Scholar 

  39. Kaplan NM. Clinical Hypertension, 4th ed. Baltimore, MD: Williams & Wilkins, 1986.

    Google Scholar 

  40. Laragh JH, Brenner BM. Hypertension Pathophysiology, Diagnosis, and Management, 2nd ed. New York: Raven Press, 1995:1–1720.

    Google Scholar 

  41. Ferrario CM, Averill DB. Do primary dysfunctions in neural control of arterial pressure contribute to hypertension? Hypertension 1991;18(Suppl 1):138–151.

    Google Scholar 

  42. Von Lutterotti N, Catanzaro DF, Sealey JE, Laragh JH. Renin is not synthesized by cardiac and extrarenal vascular tissues. Circulation 1994;89:458–470.

    Google Scholar 

  43. Abboud FM. The sympathetic system in hypertension. Hypertension 1982;4(Suppl II):208–225.

    Google Scholar 

  44. Kang PM, Landau AJ, Eberhardt RT, Frishman WH. Angiotensin II receptor antagonists: A new approach to blockade of the renin-angiotensin system. Am Heart J 1994;127:1388–1401.

    Google Scholar 

  45. Moncada S. The L-arginine: Nitric oxide pathway, cellular transduction and immunological roles. Adv Second Messenger Phosphoprotein Res 1993;28:97–99.

    Google Scholar 

  46. Moncada S, Palmer RMJ, HIggs EA. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109–141.

    Google Scholar 

  47. Dusting GJ, Moncada S, Vane JR. Prostacyclin: Its biosynthesis, actions, and clinical potential. In: Oates JA, ed. Prostaglandins and the Cardiovascular System. New York: Raven Press, 1982:59–106.

    Google Scholar 

  48. Laragh JH. Conceptual diagnostic and therapeutic dimensions of renin-system profiling of hypertensive disorders and of congestive heart failure: Four new research frontiers. In: Doyle AE, Bearn AG, eds. Hypertension and the Angiotensin System: Therapeutic Approaches. New York: Raven Press, 1984:47–72.

    Google Scholar 

  49. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098–1104.

    Google Scholar 

  50. Cowley AWJr, Roman RJ. The pressure-diuresisnatriuresis mechanism in normal and hypertensive states. In: Zanchetti A, Tarazi RC, eds. Handbook of Hypertension, Vol. 8: Pathophysiology of Hypertension-Regulatory Mechanisms. London: Elsevier Science, 1986: 295–314.

    Google Scholar 

  51. Brenner BM, Anderson S. The interrelationships among filtration surface area, blood pressure, and chronic renal disease. J Cardiovasc Pharmacol 1992;19:S1-S5.

    Google Scholar 

  52. Laragh JH. The renin system and four lines of hypertension research: Nephron heterogeneity, the calcium connection, the prorenin vasodilator limb, and plasma renin and heart attack. Hypertension 1992;20:267–279.

    Google Scholar 

  53. McCubbin JW, Page IH. Neurogenic component of chronic renal hypertension. Science 1963;139:210–215.

    Google Scholar 

  54. Ferrario CM, Barnes KL, Szilagyi JE, Brosnihan KB. Physiological and pharmacological characterization of the area postrema pressor pathways in the normal dog. Hypertension 1979;1:235–245.

    Google Scholar 

  55. Ferrario CM. Central nervous system mechanisms of blood pressure control in normotensive and hypertensive states. Chest 1983;83(Suppl):331–335.

    Google Scholar 

  56. Ferrario CM. Neurogenic actions of angiotensin II. Hypertension 1983;5(Suppl V):V73-V79.

    Google Scholar 

  57. Dzau VJ, Re R. Tissue angiotensin system in cardiovascular medicine. Circulation 1994;89:493–498.

    Google Scholar 

  58. Dzau VJ. Local expression and pathophysiological role of renin-angiotensin in the blood vessels and heart. Basic Res Cardiol 1993;88:1–14.

    Google Scholar 

  59. Skidgel RA, Jackman HL, Erdos EG. Metabolism of substance P and bradykinin by human neutrophils. Biochem Pharmacol 1991;41:1335–1344.

    Google Scholar 

  60. Erdos EG. Angiotensin I converting enzyme and the changes in our concepts through the years. Hypertension 1990;16:363–370.

    Google Scholar 

  61. Fletcher AE, Palmer AJ, Bulpitt CJ. Cough with angiotensin converting enzyme inhibitors: How much of a problem? J Hypertens 1994;12(Suppl):S43-S47.

    Google Scholar 

  62. Lacourciere Y, Lefebvre J, Nakhle G, Faison EP, Snavely DB, Nelson EB. Association between cough and angiotensin converting enzyme inhibitors versus angiotensin II antagonists: The design of a prospective, controlled study. J Hypertens 1994;12(Suppl 2):S49-S53.

    Google Scholar 

  63. Kohara K, Brosnihan KB, Ferrario CM. Angiotensin-(1–7) in the spontaneously hypertensive rat. Peptides 1993;14: 883–891.

    Google Scholar 

  64. Ferrario CM, Milsted A, Santos RAS. Renin, converting enzyme and angiotensin peptides: A review. In: Keane WF, ed. A Focus on the Clinical Effects of a Long-Acting ACE Inhibitor/Hypertension. New York: Raven Press, 1990:1–20.

    Google Scholar 

  65. Admiraal PJJ, Derkx, Danser AHJ, Pieterman H, Schalekamp MADH. Metabolism and production of angiotensin I in different vascular beds in subjects with hypertension. Hypertension 1990;15:44–55.

    Google Scholar 

  66. Juillerat L, Nussberger J, Menard J, et al. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension 1990;16:564–572.

    Google Scholar 

  67. Nussberger J, Brunner DB, Waeber B, Brunner HR. Specific measurement of angiotensin metabolites and in vitro generated angiotensin II in plasma. Hypertension 1986;8: 476–482.

    Google Scholar 

  68. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res 1990;66:883–890.

    Google Scholar 

  69. Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem 1990;265:22348–22357.

    Google Scholar 

  70. Urata H, Boehm KD, Philip A, et al. Cellular localization and regional distribution of an angiotensin II-forming chymase in the heart. J Clin Invest 1993;91:1269–1281.

    Google Scholar 

  71. Kinoshita A, Urata H, Bumpus FM, Husain A. Multiple determinants for the high substrate specificity of an angiotensin II-forming chymase from the human heart. J Biol Chem 1991;266:19192–19197.

    Google Scholar 

  72. Chappell MC, Welches WR, Brosnihan KB, Ferrario CM. Inhibition of angiotensin converting enzyme by the metal-loendopeptidase 3.4.24.15 inhibitor c-phenylpropyl-alanyl-alanyl-phenylalanyl-p-aminobenzoate. Peptides 1992;13: 943–946.

    Google Scholar 

  73. Cachofeiro V, Sakakibara T, Nasjletti A. Kinins, nitric oxide, and the hypotensive effect of captopril and ramiprilat in hypertension. Hypertension 1992;19:138–145.

    Google Scholar 

  74. Carretero OA, Orstavik TB, Rabito SF, Scicli AG. Interference of converting enzyme inhibitors with the kalli-krein-kinin system. Clin Exp Hypertens 1983;A5:1277–1285.

    Google Scholar 

  75. Beierwaltes WH, Carretero OA. Kinin antagonist reverses converting enzyme inhibitor-stimulated vascular prostaglandin I2 synthesis. Hypertension 1989;13:754–758.

    Google Scholar 

  76. Bumpus FM. Angiotensin I and II; some early observations made at the Cleveland Clinic Foundation and recent discoveries relative to angiotensin II formation in human heart. Hypertension 1991;18:122–125.

    Google Scholar 

  77. Wexler RR, Carini DJ, Duncia JV, et al. Rationale for the chemical development of angiotensin II receptor antagonists. Am J Hypertens 1992;5:209S-220S.

    Google Scholar 

  78. Dostal DE, Baker KM. Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart. Mediation by the AT receptor. Am J Hypertens 1992;5:276–280.

    Google Scholar 

  79. Dahlof B. The importance of the renin-angiotensin system in reversal of left ventricular hypertrophy. J Hypertens 1993;11(Suppl 3):S29-S35.

    Google Scholar 

  80. Stier CTJr, Adler LA, Levine S, Chander PN. Stroke prevention by losartan in stroke-prone spontaneously hypertensive rats. J Hypertens 1993;11(Suppl 3):S37-S42.

    Google Scholar 

  81. Gansevoort RT, de Zeeuw D, Shahinfar S, Redfield A, de Jong PE. Effects of the angiotensin II antagonist losartan in hypertensive patients with renal disease. J Hypertens 1994;12(Suppl 2):S37-S42.

    Google Scholar 

  82. Averill DB, Tsuchihashi T, Khosla MC, Ferrario CM. Losartan, nonpeptide angiotensin II-type 1 (AT1) receptor antagonist, attenuates pressor and sympathoexcitatory response evoked by angiotensin II and L-glutamate in rostral ventrolateral medulla. Brain Res 1994;665: 245–252.

    Google Scholar 

  83. Kumagai H, Averill DB, Khosla MC, Ferrario CM. Role of nitrix oxide and angiotensin II in the regulation of sympathetic nerve activity in spontaneously hypertensive rats. Hypertension 1993;21:476–484.

    Google Scholar 

  84. Brunner HR, Nussberger J, Waeber B. Angiotensin II blockade compared with other pharmacological methods of inhibiting the renin-angiotensin system. J Hypertens 1993; 11(Suppl 3):S53-S58.

    Google Scholar 

  85. Moriguchi A, Ferrario CM, Brosnihan KB, Ganten D, Morris M. Differential regulation of central vasopressin in transgenic rats harboring the mouse Ren-2 gene. Am J Physiol 1994;267:R786-R791.

    Google Scholar 

  86. Moriguchi A, Brosnihan KB, Kumagai H, Ganten D, Ferrario CM. Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene. Am J Physiol 1994;266: R1273-R1278.

    Google Scholar 

  87. Stoll M, Steckelings UM, Bottari SP, Metzger R, Unger TH. Role of angiotensin II receptor subtypes in endothelial growth regulation (abstract). J Hypertens 1994;12:S72.

    Google Scholar 

  88. Pratt RE, Wang D, Hein L, Dzau VJ. The AT2 isoform of the angiotensin receptor mediates myointimal hyperplasia following vascular injury (abstract). Hypertension 1992;20: 432.

    Google Scholar 

  89. Benter IF, Ferrario CM, Morris M, Diz D. Chronic intravenous angiotensin-(1–7) infusions activate antihypertensive mechanisms in spontaneously hypertensive rats (abstract). Am J Hypertens 1994;7:94A.

    Google Scholar 

  90. Chappell MC, Tallant EA, Brosnihan KB, Ferrario CM. Processing of angiotensin peptides by NG108–15 neuroblastoma X glioma hybrid cell line. Peptides 1990;11: 375–380.

    Google Scholar 

  91. Burnier M, Waeber B, Brunner HR. The advantages of angiotensin II antagonism. J Hypertens 1994;12:S7-S15.

    Google Scholar 

  92. Brunner HR, Christen Y, Munafo A, Lee RJ, Waeber B, Nussberger J. Clinical experience with angiotensin II receptor antagonists. Am J Hypertens 1992;5:243S-246S.

    Google Scholar 

  93. Nelson E, Arcuri K, Ikeda L, Snavely D, Sweet C. Efficacy and safety of losartan in patients with essential hypertension (abstract). Am J Hypertens 1992;5:19A.

    Google Scholar 

  94. Christen Y, Waeber B, Nussberger J, et al. Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal volunteers; inhibition of pressor response to exogenous angiotensin I and II. Circulation 1991;83:1333–1342.

    Google Scholar 

  95. Munafo A, Christen Y, Nussberger J, et al. Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist. Clin Pharmacol Ther 1992;51:513–521.

    Google Scholar 

  96. Tsunoda K, Abe K, Hagino R, et al. Hypotensive effect of losartan, a nonpeptide angiotensin II receptor antagonist, in essential hypertension. Am J Hypertens 1993;6: 29–32.

    Google Scholar 

  97. Weber MA. Clinical experience with the angiotensin II receptor antagonist losartan. Am J Hypertens 1992;5: 247S-251S.

    Google Scholar 

  98. Fitzpatrick MA, Rademaker MT, Charles CJ, Yandle TG, Espiner EA, Ikram H. Angiotensin II receptor antagonism in ovine heart failure: Acute hemodynamic, hormonal, and renal effects. Am J Physiol 1992;263: H250-H256.

    Google Scholar 

  99. Dickstein K, Gottlieb S, Fleck E, et al. Hemodynamic and neurohumoral effects of the angiotensin II antagonist losartan in patients with heart failure. J Hypertens 1994; 12(Suppl 2):S31-S35.

    Google Scholar 

  100. Lacourciere Y, Lefebvre J, Nakhle G, Faison EP, Snavely DB, Nelson EB. Association between cough and angiotensin converting enzyme inhibitors versus angiotensin II antagonists: The design of a prospective, controlled study. J Hypertens 1994;12(Suppl 2):S49-S53.

    Google Scholar 

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  1. Hypertension Center, Bowman Gray/Baptist Hospital Medical Center of Wake Forest University, Winston-Salem, North Carolina

    Carlos M. Ferrario & John M. Flack

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Ferrario, C.M., Flack, J.M. Pathologic consequences of increased angiotensin II activity. Cardiovasc Drug Ther 10, 511–518 (1996). https://doi.org/10.1007/BF00050990

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