Advertisement

Prehypertension and the Renin-Angiotensin-Aldosterone System

  • Elena Kaschina
  • Thomas Unger
Chapter
Part of the Updates in Hypertension and Cardiovascular Protection book series (UHCP)

Abstract

The renin-angiotensin-aldosterone system (RAAS) represents one of the most important contributors to vascular, cardiac, and renal pathology. Its major effector peptides, notably the octapeptide angiotensin II (AngII), induce vasoconstriction (directly and indirectly via sympathetic activation and vasopressin release) and participate in processes of vascular and cardiac hypertrophy, remodeling, inflammation, and fibrosis, directly through action on the angiotensin AT1 receptor and indirectly through aldosterone stimulation. In addition, the RAAS engenders renal salt retention and is involved in various renal pathologies. By the above mechanisms, the RAAS contributes to the development and maintenance of arterial hypertension. RAAS-induced vascular, cardiac, and renal pathologies occur already in the prehypertensive state, i.e., before overt hypertension has developed. Recently, a so-called protective arm of the renin-angiotensin system (RAS) has been described including angiotensin-converting enzyme 2 (ACE2), the angiotensin AT2 receptor, and the Ang 1–7/Mas receptor system. The “protective RAS” appears to represent an intrinsic opponent of the classical “harmful RAS,” and stimulation of this system may become an important therapeutic approach in individuals at cardiovascular risk.

Inhibitors of the “harmful” RAAS (ACE inhibitors, AT1 receptor, and aldosterone receptor antagonists) have been successfully introduced into the clinic with a broad spectrum of indications, particularly as antihypertensive agents. The TROPHY study with the AT1 receptor blocker, candesartan, and in the PHARAO study with the ACE inhibitor, ramipril, have provided evidence that the natural course from prehypertension to hypertension can be delayed, supporting the idea that in certain patient populations at risk, chronic antihypertensive treatment with an inhibitor of the RAS started already in the prehypertensive phase may exert protection by preventing the onset of high blood pressure disease.

Keywords

Prehypertension Renin-angiotensin system Aldosterone Angiotensin receptors Protective RAS 

References

  1. 1.
    Unger T. The angiotensin type 2 receptor: variations on an enigmatic theme. J Hypertens. 1999;17(12 Pt 2):1775–86.CrossRefGoogle Scholar
  2. 2.
    Kaschina E, Unger T. Angiotensin AT1/AT2 receptors: regulation, signalling and function. Blood Press. 2003;12:70–88.CrossRefGoogle Scholar
  3. 3.
    Namsolleck P, Recarti C, Foulquier S, Steckelings UM, Unger T. AT(2) receptor and tissue injury: therapeutic implications. Curr Hypertens Rep. 2014;16:416.CrossRefGoogle Scholar
  4. 4.
    Leonhardt J, Villela DC, Teichmann A, Münter LM, Mayer MC, Mardahl M, et al. Evidence for heterodimerization and functional interaction of the angiotensin type 2 receptor and the receptor MAS. Hypertension. 2017;69(6):1128–35.CrossRefGoogle Scholar
  5. 5.
    Peralta CA, Adeney KL, Shlipak MG, Jacobs D Jr, Duprez D, Bluemke D, et al. Structural and functional vascular alterations and incident hypertension in normotensive adults: the Multi-Ethnic Study of Atherosclerosis. Am J Epidemiol. 2010;171:63–71.CrossRefGoogle Scholar
  6. 6.
    Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev. 2006;86(3):747–803.CrossRefGoogle Scholar
  7. 7.
    Harrap SB, Van der Merwe WM, Griffin SA, Macpherson F, Lever AF. Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term. Hypertension. 1990;16:603–14.CrossRefGoogle Scholar
  8. 8.
    Lundie MJ, Friberg P, Kline RL, Adams MA. Long-term inhibition of the renin-angiotensin system in genetic hypertension: analysis of the impact on blood pressure and cardiovascular structural changes. J Hypertens. 1997;15:339–48.CrossRefGoogle Scholar
  9. 9.
    Lee RM, Berecek KH, Tsoporis J, McKenzie R, Triggle CR. Prevention of hypertension and vascular changes by captopril treatment. Hypertension. 1991;17:141–50.CrossRefGoogle Scholar
  10. 10.
    Unger T, Mattfeldt T, Lamberty V, Bock P, Mall G, Linz W, Schölkens BA, Gohlke P. Effect of early onset angiotensin converting enzyme inhibition on myocardial capillaries. Hypertension. 1992;20:478–82.CrossRefGoogle Scholar
  11. 11.
    Wu JN, Berecek KH. Prevention of genetic hypertension by early treatment of spontaneously hypertensive rats with the angiotensin converting enzyme inhibitor captopril. Hypertension. 1993;22:139–46.CrossRefGoogle Scholar
  12. 12.
    Unger T, Rettig R. Development of genetic hypertension. Is there a “critical phase”? Hypertension. 1990;16(6):615.CrossRefGoogle Scholar
  13. 13.
    Schiffrin EL, Deng LY, Larochelle P. Effects of a beta-blocker or a converting enzyme inhibitor on resistance arteries in essential hypertension. Hypertension. 1994;23:83–91.CrossRefGoogle Scholar
  14. 14.
    Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al. Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;20(354):1685–97.CrossRefGoogle Scholar
  15. 15.
    Lüders S, Schrader J, Berger J, Unger T, Zidek W, Böhm M, et al. The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure: a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens. 2008;26:1487–96.CrossRefGoogle Scholar
  16. 16.
    Balt JC, Mathy MJ, Pfaffendorf M, van Zwieten PA. Sympatho-inhibitory properties of various AT1 receptor antagonists. J Hypertens Suppl. 2002;20:S3–11.CrossRefGoogle Scholar
  17. 17.
    Hahn AW, Regenass S, Kern F, Bühler FR, Resink TJ. Expression of soluble and insoluble fibronectin in rat aorta: effects of angiotensin II and endothelin-1. Biochem Biophys Res Commun. 1993;192:189–97.CrossRefGoogle Scholar
  18. 18.
    Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74:1141–8.CrossRefGoogle Scholar
  19. 19.
    Zafari AM, Ushio-Fukai M, Akers M, Yin Q, Shah A, Harrison DG, Taylor WR, Griendling KK. Novel role of NADH/NADPH oxidase-derived hydrogen peroxide in angiotensin 11-induced hypertrophy of rat smooth muscle cells. Hypertension. 1998;32:488–95.CrossRefGoogle Scholar
  20. 20.
    Montezano AC, Touyz RM. Reactive oxygen species, vascular Noxs, and hypertension: focus on translational and clinical research. Antioxid Redox Signal. 2014;20:164–82.CrossRefGoogle Scholar
  21. 21.
    Robert Li Y. Free radical biomedicine: principles, clinical correlations, and methodologies: Bentham eBooks; 2012.  https://doi.org/10.2174/97816080532231120101.Google Scholar
  22. 22.
    Lacolley P, Regnault V, Nicoletti A, Li Z, Michel JB. The vascular smooth muscle cell in arterial pathology: a cell that can take on multiple roles. Cardiovasc Res. 2012;15(95):194–204.CrossRefGoogle Scholar
  23. 23.
    Culman J, Baulmann J, Blume A, Unger T. The renin-angiotensin system in the brain: an update. J Renin Angiotensin Aldosterone Syst. 2001;2:96–102.CrossRefGoogle Scholar
  24. 24.
    Burrell LM, Phillips PA, Risvanis J, Aldred KL, Hutchins AM, Johnston CI. Attenuation of genetic hypertension after short-term vasopressin V1A receptor antagonism. Hypertension. 1995;26:828–34.CrossRefGoogle Scholar
  25. 25.
    Burrell LM, Risvanis J, Dean RG, Patel SK, Velkoska E, Johnston CI. Age-dependent regulation of renal vasopressin V(1A) and V2 receptors in rats with genetic hypertension: implications for the treatment of hypertension. J Am Soc Hypertens. 2013;7:3–13.CrossRefGoogle Scholar
  26. 26.
    Bussien JP, Waeber B, Nussberger J, Schaller MD, Gavras H, Hofbauer K, et al. Does vasopressin sustain blood pressure of normally hydrated healthy volunteers? Am J Physiol. 1984;246(1 Pt 2):H143–7.Google Scholar
  27. 27.
    Waeber B, Nussberger J, Hofbauer KG, Nicod P, Brunner HR. Clinical studies with a vascular vasopressin antagonist. J Cardiovasc Pharmacol. 1986;8(Suppl 7):S111–6.CrossRefGoogle Scholar
  28. 28.
    Gross F. Renin and hypertension, physiological or pathological agents? Klin Wochenschr. 1958;36:693–706.CrossRefGoogle Scholar
  29. 29.
    Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens. 1999;12(12 Pt 3):205–13.CrossRefGoogle Scholar
  30. 30.
    Tomaschitz A, Pilz S, Ritz E, Obermayer-Pietsch B, Pieber TR. Aldosterone and arterial hypertension. Nat Rev Endocrinol. 2010;6:83–93.CrossRefGoogle Scholar
  31. 31.
    Vasan RS, Evans JC, Larson MG, Wilson PWF, Meigs JB, Rifai N, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004;351:33–41.CrossRefGoogle Scholar
  32. 32.
    Connell JMC, Davies E. The new biology of aldosterone. J Endocrinol. 2005;186(1):1–20.CrossRefGoogle Scholar
  33. 33.
    Schrier RW, Masoumi A, Elhassan E. Aldosterone: role in edematous disorders, hypertension, chronic renal failure, and metabolic syndrome. Clin J Am Soc Nephrol. 2010;5:1132–40.CrossRefGoogle Scholar
  34. 34.
    Briet M, Schiffrin EL. Treatment of arterial remodeling in essential hypertension. Curr Hypertens Rep. 2013;15:3–9.CrossRefGoogle Scholar
  35. 35.
    Lemarié CA, Paradis P, Schiffrin EL. New insights on signaling cascades induced by cross talk between angiotensin II and aldosterone. J Mol Med. 2008;86:673–8.CrossRefGoogle Scholar
  36. 36.
    Baumann M, Megens R, Bartholome R, Dolff S, van Zandvoort M, Smits J, Sruijker-Boudier HA, De Mey J. Prehypertensive renin-angiotensin-aldosterone system blockade in spontaneously hypertensive rats ameliorates the loss of long-term vascular function. Hypertens Res. 2007;30:853–61.CrossRefGoogle Scholar
  37. 37.
    Unger T, Steckelings UM, dos Santos RAS, editors. The protective arm of the renin angiotensin system—functional aspects and therapeutic implications. 1st ed. London: Academic Press, Elsevier; 2015.Google Scholar
  38. 38.
    Iwai M, Horiuchi M. Devil and angel in the renin-angiotensin system: ACE-angiotensin II AT1 receptor axis vs. ACE2 angiotensin-(1-7)-Mas receptor axis. Hypertens Res. 2009;32:533–6.CrossRefGoogle Scholar
  39. 39.
    Rentzsch B, Todiras M, Iliescu R, Popova E, Campos LA, Oliveira ML, et al. Transgenic angiotensin-converting enzyme 2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function. Hypertension. 2008;52:967–73.CrossRefGoogle Scholar
  40. 40.
    Santos RA, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin-angiotensin system. J Endocrinol. 2013;216:R1–R17.CrossRefGoogle Scholar
  41. 41.
    Sampaio WO, Souza dos Santos RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL, Touyz RM. Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension. 2007;49:185–92.CrossRefGoogle Scholar
  42. 42.
    Bodiga S, Zhong JC, Wang W, Basu R, Lo J, Liu GC, et al. Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47(phox) NADPH oxidase subunit. Cardiovasc Res. 2011;91:151–61.CrossRefGoogle Scholar
  43. 43.
    Durik M, Sevá Pessôa B, Roks AJ. The renin-angiotensin system, bone marrow and progenitor cells. Clin Sci (Lond). 2012;123:205–23.CrossRefGoogle Scholar
  44. 44.
    Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, et al. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003;100:8258–63.CrossRefGoogle Scholar
  45. 45.
    Kostenis E, Milligan G, Christopoulos A, Sanchez-Ferrer CF, Heringer-Walther S, Sexton PM, et al. G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor. Circulation. 2005;111:1806–13.CrossRefGoogle Scholar
  46. 46.
    Villela D, Leonhardt J, Patel N, Joseph J, Kirsch S, Hallberg A, et al. Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison. Clin Sci. 2015;128:227–34.CrossRefGoogle Scholar
  47. 47.
    Singh Y, Singh K, Sharma PL. Effect of combination of renin inhibitor and Mas-receptor agonist in DOCA-salt-induced hypertension in rats. Mol Cell Biochem. 2013;373:189–94.CrossRefGoogle Scholar
  48. 48.
    Patel JM, Martens JR, Li YD, Gelband CH, Raizada MK, Block ER. Angiotensin IV receptor-mediated activation of lung endothelial NOS is associated with vasorelaxation. Am J Physiol. 1998;275(6 Pt 1):L1061–8.Google Scholar
  49. 49.
    Vinh A, Widdop RE, Drummond GR, Gaspari TA. Chronic angiotensin IV treatment reverses endothelial dysfunction in ApoE-deficient mice. Cardiovasc Res. 2008;77:178–87.CrossRefGoogle Scholar
  50. 50.
    De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000;52:415–72.Google Scholar
  51. 51.
    Zhang H, Han GW, Batyuk A, Ishchenko A, White KL, Patel N, et al. Structural basis for selectivity and diversity in angiotensin II receptors. Nature. 2017;544:327–32.CrossRefGoogle Scholar
  52. 52.
    Gohlke P, Pees C, Unger T. AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension. 1998;31:349–55.CrossRefGoogle Scholar
  53. 53.
    Fischer TA, Singh K, O’Hara DS, Kaye DM, Kelly RA. Role of AT1 and AT2 receptors in regulation of MAPKs and MKP-1 by ANG II in adult cardiac myocytes. Am J Physiol. 1998;275:H906–16.Google Scholar
  54. 54.
    Nouet S, Nahmias C. Signal transduction from the angiotensin II AT2 receptor. Trends Endocrinol Metab. 2000;11:1–6.CrossRefGoogle Scholar
  55. 55.
    AbdAlla S, Lother H, Abdel-tawab AM, Quitterer U. The angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol Chem. 2001;276:39721–6.CrossRefGoogle Scholar
  56. 56.
    Gao J, Zhang H, Le KD, Chao J, Gao L. Activation of central angiotensin type 2 receptors suppresses norepinephrine excretion and blood pressure in conscious rats. Am J Hypertens. 2011;24:724–30.CrossRefGoogle Scholar
  57. 57.
    Inagami T, Eguchi S, Numaguchi K, Motley ED, Tang H, Matsumoto T, Yamakawa T. Cross-talk between angiotensin II receptors and the tyrosine kinases and phosphatases. J Am Soc Nephrol. 1999;10(Suppl 11):S57–61.Google Scholar
  58. 58.
    Wiemer G, Schölkens BA, Wagner A, Heitsch H, Linz W. The possible role of angiotensin II subtype AT2 receptors in endothelial cells and isolated ischemic rat hearts. J Hypertens Suppl. 1993;11:S234–5.CrossRefGoogle Scholar
  59. 59.
    Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J Clin Invest. 1997;99:1926–35.CrossRefGoogle Scholar
  60. 60.
    Kraehling JR, Sessa WC. Contemporary approaches to modulating the nitric oxide-cGMP pathway in cardiovascular disease. Circ Res. 2017;120:1174–82.CrossRefGoogle Scholar
  61. 61.
    Siragy HM, Inagami T, Ichiki T, Carey RM. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci U S A. 1999;96:6506–10.CrossRefGoogle Scholar
  62. 62.
    Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest. 1999;104:925–93.CrossRefGoogle Scholar
  63. 63.
    Batenburg WW, Garrelds IM, Bernasconi CC, Juillerat-Jeanneret L, van Kats JP, Saxena PR, Danser AH. Angiotensin II type 2 receptor-mediated vasodilation in human coronary microarteries. Circulation. 2004;109:2296–301.CrossRefGoogle Scholar
  64. 64.
    Savoia C, Touyz RM, Volpe M, Schiffrin EL. Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients. Hypertension. 2007;49:341–6.CrossRefGoogle Scholar
  65. 65.
    Widdop RE, Jones ES, Hannan RE, Gaspari TA. Angiotensin AT2 receptors: cardiovascular hope or hype? Br J Pharmacol. 2003;140:809–24.CrossRefGoogle Scholar
  66. 66.
    Steckelings UM, Paulis L, Namsolleck P, Unger T. AT2 receptor agonists: hypertension and beyond. Curr Opin Nephrol Hypertens. 2012;21:142–6.CrossRefGoogle Scholar
  67. 67.
    Wan Y, Wallinder C, Plouffe B, Beaudry H, Mahalingam AK, Wu X, et al. Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist. J Med Chem. 2004;47:5995–6008.CrossRefGoogle Scholar
  68. 68.
    Paulis L, Becker STR, Lucht K, Schwengel K, Slavic S, Kaschina E, et al. Direct angiotensin II type 2 receptor stimulation in Nω-nitro-L-arginine-methyl ester-induced hypertension: the effect on pulse wave velocity and aortic remodeling. Hypertension. 2012;59:485–92.CrossRefGoogle Scholar
  69. 69.
    Rehman A, Leibowitz A, Yamamoto N, Rautureau Y, Paradis P, Schiffrin EL. Angiotensin type 2 receptor agonist compound 21 reduces vascular injury and myocardial fibrosis in stroke-prone spontaneously hypertensive rats. Hypertension. 2012;59(2):291–9.CrossRefGoogle Scholar
  70. 70.
    Hrenák J, Arendášová K, Rajkovičová R, Aziriová S, Repová K, Krajčírovičová K, et al. Protective effect of captopril, olmesartan, melatonin and compound 21 on doxorubicin-induced nephrotoxicity in rats. Physiol Res. 2013;62(Suppl 1):S181–9.Google Scholar
  71. 71.
    Matavelli LC, Huang J, Siragy HM. Angiotensin AT2 receptor stimulation inhibits early renal inflammation in renovascular hypertension. Hypertension. 2011;57:308–13.CrossRefGoogle Scholar
  72. 72.
    Begorre MA, Dib A, Habchi K, Guihot AL, Bourreau J, Vessieres E, et al. Microvascular vasodilator properties of the angiotensin 2 receptor in a mouse model of type 1 diabetes. Sci Rep. 2017;7:45625.CrossRefGoogle Scholar
  73. 73.
    Sales VL, Sukhova GK, Lopez-Ilasaca MA, Libby P, Dzau VJ, Pratt RE. Angiotensin type 2 receptor is expressed in murine atherosclerotic lesions and modulates lesion evolution. Circulation. 2005;112:3328–36.CrossRefGoogle Scholar
  74. 74.
    Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W, Morishita R, Zhang L, et al. The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci U S A. 1995;92:10663–7.CrossRefGoogle Scholar
  75. 75.
    Iwai M, Chen R, Li Z, Shiuchi T, Suzuki J, Ide A, et al. Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice. Circulation. 2005;112:1636–43.CrossRefGoogle Scholar
  76. 76.
    Kaschina E, Scholz H, Steckelings UM, Sommerfeld M, Kemnitz UR, Artuc M, Schmidt S, Unger T. Transition from atherosclerosis to aortic aneurysm in humans coincides with an increased expression of RAS components. Atherosclerosis. 2009;205:396–403.CrossRefGoogle Scholar
  77. 77.
    Meltzer JI. A specialist in clinical hypertension critiques the TROPHY trial. Am J Hypertens. 2006;19:1098–100.CrossRefGoogle Scholar
  78. 78.
    Julius S, Kaciroti N, Egan BM, Nesbitt S, Michelson EL. Trial of Preventing Hypertension (TROPHY) Investigators. TROPHY study: outcomes based on the Seventh Report of the Joint National Committee on Hypertension definition of hypertension. J Am Soc Hypertens. 2008;2:39–43.CrossRefGoogle Scholar
  79. 79.
    Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363(9426):2022–31.CrossRefGoogle Scholar
  80. 80.
    Kjeldsen SE, Narkiewicz K, Hedner T. An American TROPHY in the prevention of hypertension. Blood Press. 2006;15:132–4.CrossRefGoogle Scholar
  81. 81.
    Qureshi AI, Suri MF, Kirmani JF, Divani AA. Prevalence and trends of prehypertension and hypertension in United States: National Health and Nutrition Examination Surveys 1976 to 2000. Mred Sci Monit. 2005;11:CR403–9.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center for Cardiovascular Research (CCR)Charité—Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of PharmacologyBerlinGermany
  2. 2.CARIM—School for Cardiovascular DiseasesMaastricht UniversityMaastrichtThe Netherlands

Personalised recommendations