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Neuroprotection with Angiotensin Receptor Antagonists

A Review of the Evidence and Potential Mechanisms

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The peptide hormone angiotensin (A)-II, the major effector peptide of the renin-angiotensin system (RAS), is well established to play a pivotal role in the systemic regulation of blood pressure, fluid, and electrolyte homeostasis. Recent biochemical and neurophysiologic studies have documented local intrinsic angiotensin-generating systems in organs and tissues such as the brain, retina, bone marrow, liver, and pancreas. The locally generated angiotensin peptides have multiple and novel actions including stimulating cell growth and anti-proliferative and/or antiapoptotic actions. In the mammalian brain, all components of the RAS are present including angiotensin receptor subtypes 1 (AT1) and 2 (AT2). A-II exerts most of its well defined physiologic and pathophysiologic actions, including those on the central and peripheral nervous system, through its AT1 receptor subtype. While the AT1 receptor is responsible for the classical effects of A-II, it has been found that the AT2 receptor is linked to totally different signalling mechanisms and this has revealed hitherto unknown functions of A-II. AT2 receptors are expressed at low density in many healthy adult tissues, but are upregulated in a variety of human diseases. This receptor not only contributes to stroke-related pathologic mechanisms (e.g. hypertension, atherothrombosis, and cardiac hypertrophy) but may also be involved in post-ischemic damage to the brain. It has been reported that the AT2 receptor regulates several functions of nerve cells, e.g. ionic fluxes, cell differentiation, and neuronal tissue regeneration, and also modulates programmed cell death. In this article, we review the experimental evidence supporting the notion that blockade of brain AT1receptors can be beneficial with respect to stroke incidence and outcome. We further delineate how AT2 receptors could be involved in neuronal regeneration following brain injury such as stroke or CNS trauma. The current review is focussed on some of the new functions arising from the locally formed A-II with particular attention to its emerging neuroprotective role in the brain.

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Fig. 1


  1. 1.

    Tigerstedt R, Bergmann PG. Niere und Kreislauf. Skand Arch Physiol 1898; 8: 223–231.

  2. 2.

    Dzau VJ. Cell biology and genetics of angiotensin in cardiovascular disease. J Hypertens Suppl 1994; 12(4): S3–10.

  3. 3.

    Owens GK, Rabinovitch PS, Schwartz SM. Smooth muscle cell hypertrophy versus hyperplasia in hypertension. Proc Natl Acad Sci U S A 1981; 78(12): 7759–63.

  4. 4.

    Bumpus FM, Catt KJ, Chiu AT, et al. Nomenclature for angiotensin receptors: a report of the Nomenclature Committee of the Council for High Blood Pressure Research. Hypertension 1991; 17(5): 720–1.

  5. 5.

    Unger T, Chung O, Csikos T, et al. Angiotensin receptors. J Hypertens Suppl 1996; 14(5): S95–103.

  6. 6.

    Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993; 45(2): 205–51.

  7. 7.

    Aceto JF, Baker KM. [Sarl]angiotensin II receptor-mediated stimulation of protein synthesis in chick heart cells. Am J Physiol 1990; 258(3 Pt 2): H806–13.

  8. 8.

    Paquet JL, Baudouin-Legros M, Brunelle G, et al. Angiotensin II-induced proliferation of aortic myocytes in spontaneously hypertensive rats. J Hypertens 1990; 8(6): 565–72.

  9. 9.

    Stoll M, Steckelings UM, Paul M, et al. The angiotensin AT2 receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 1995; 95(2): 651–7.

  10. 10.

    Rosenstiel P, Gallinat S, Arlt A, et al. Angiotensin AT2 receptor ligands: do they have potential as future treatments for neurological disease? CNS Drugs 2002; 16(3): 145–53.

  11. 11.

    Zhu YZ, Chimon GN, Zhu YC, et al. Expression of angiotensin II AT2 receptor in the acute phase of stroke in rats. Neuroreport 2000; 11(6): 1191–4.

  12. 12.

    Gallinat S, Yu M, Dorst A, et al. Sciatic nerve transection evokes lasting upregulation of angiotensin AT2 and ATI receptor mRNA in adult rat dorsal root ganglia and sciatic nerves. Brain Res Mol Brain Res 1998; 57(1): 111–22.

  13. 13.

    Lucius R, Gallinat S, Rosenstiel P, et al. The angiotensin II type 2 (AT2) receptor promotes axonal regeneration in the optic nerve of adult rats. J Exp Med 1998; 188(4): 661–70.

  14. 14.

    Ge J, Barnes NM. Alterations in angiotensin AT1 and AT2 receptor subtype levels in brain regions from patients with neurodegenerative disorders. Eur J Pharmacol 1996; 297(3): 299–306.

  15. 15.

    Brechler V, Jones PW, Levens NR, et al. Agonistic and antagonistic properties of angiotensin analogs at the AT2 receptor in PC12W cells. Regul Pept 1993; 44(2): 207–13.

  16. 16.

    Elton TS, Stephan CC, Taylor GR, et al. Isolation of two distinct type I angiotensin II receptor genes. Biochem Biophys Res Commun 1992; 184(2): 1067–73.

  17. 17.

    Yoshida H, Kakuchi J, Guo DF, et al. Analysis of the evolution of angiotensin II type 1 receptor gene in mammals (mouse, rat, bovine and human). Biochem Biophys Res Commun 1992; 186(2): 1042–9.

  18. 18.

    Ernsberger P, Zhou J, Damon TH, et al. Angiotensin II receptor subtypes in cultured rat renal mesangial cells. Am J Physiol 1992; 263(3 Pt 2): F411–6.

  19. 19.

    Siemens IR, Reagan LP, Yee DK, et al. Biochemical characterization of two distinct angiotensin AT2 receptor populations in murine neuroblastoma N1E-115 cells. J Neurochem 1994; 62(6): 2106–15.

  20. 20.

    Volpe M. Treatment of systolic hypertension: spotlight on recent studies with angiotensin II antagonists. J Hum Hypertens 2005; 19(2): 93–102.

  21. 21.

    Unger T, Kaschina E. Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives. Drug Saf 2003; 26(10): 707–20.

  22. 22.

    Camargo MJ, von Lutterotti N, Campbell WG, et al. Control of blood pressure and end-organ damage in maturing salt-loaded stroke-prone spontaneously hypertensive rats by oral angiotensin II receptor blockade. J Hypertens 1993; 11(1): 31–40.

  23. 23.

    Fornes P, Richer C, Vacher E, et al. Losartan’s protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal. J Cardiovasc Pharmacol 1993; 22(2): 305–13.

  24. 24.

    Stier CT, Adler LA, Levine S, et al. Stroke prevention by losartan in stroke-prone spontaneously hypertensive rats. J Hypertens Suppl 1993; 11(3): S37–42.

  25. 25.

    Gohlke P, Linz W, Scholkens BA, et al. Cardiac and vascular effects of long-term losartan treatment in stroke-prone spontaneously hypertensive rats. Hypertension 1996; 28(3): 397–402.

  26. 26.

    Sachinidis A, el-Haschimi K, Ko Y, et al. CV-11974, the active metabolite of TCV-116 (Candesarten), inhibits the synergistic or additive effect of different growth factors on angiotensin II-induced proliferation of vascular smooth muscle cells. Biochem Pharmacol 1996; 52(1): 123–6.

  27. 27.

    Yanagitani Y, Rakugi H, Okamura A, et al. Angiotensin II type 1 receptor-mediated peroxide production in human macrophages. Hypertension 1999; 33(1 Pt 2): 335–9.

  28. 28.

    Blume A, Herdegen T, Unger T. Angiotensin peptides and inducible transcription factors. J Mol Med 1999; 77(3): 339–57.

  29. 29.

    Balla T, Baukal AJ, Eng S, et al. Angiotensin II receptor subtypes and biological responses in the adrenal cortex and medulla. Mol Pharmacol 1991; 40(3): 401–6.

  30. 30.

    Marrero MB, Paxton WG, Schieffer B, et al. Angiotensin II signalling events mediated by tyrosine phosphorylation. Cell Signal 1996; 8(1): 21–6.

  31. 31.

    Gelband CH, Sumners C, Lu D, et al. Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling. Regul Pept 1998; 73(3): 141–7.

  32. 32.

    Akishita M, Ito M, Lehtonen JY, et al. Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influence: fetal vascular growth. J Clin Invest 1999; 103(1): 63–71.

  33. 33.

    Pees C, Unger T, Gohlke P. Effect of angiotensin AT2 receptor stimulation on vascular cyclic GMP production in normotensive Wistar Kyoto rats. Int. Biochem Cell Biol 2003; 35(6): 963–72.

  34. 34.

    Dawson VL, Dawson TM. Nitric oxide in neurodegeneration. Prog Brain Res 1998; 118: 215–29.

  35. 35.

    Jiao H, Cui XL, Torti M, et al. Arachidonic acid mediates angiotensin II effects on p21ras in renal proximal tubular cells via the tyrosine kinase-Shc-Grb2-Sos pathway. Proc Natl Acad Sci U S A 1998; 95(13): 7417–21.

  36. 36.

    Gallinat S, Busche S, Schutze S, et al. AT2 receptor stimulation induces generation of ceramides in PC12W cells. FEBS Lett 1999; 443(1): 75–9.

  37. 37.

    Lehtonen JY, Horiuchi M, Daviet L, et al. Activation of the de novo biosynthesis of sphingolipids mediates angiotensin II type 2 receptor-induced apoptosis. J Bio Chem 1999; 274(24): 16901–6.

  38. 38.

    Huang XC, Richards EM, Sumners C. Angiotensin II type 2 receptor-mediated stimulation of protein phosphatase 2A in rat hypothalamic/brainstem neurona cocultures. J Neurochem 1995; 65(5): 2131–7.

  39. 39.

    Horiuchi M, Hayashida W, Kambe T, et al. Angiotensin type 2 recepto dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phos phatase-1 and induces apoptosis. J Biol Chem 1997; 272(30): 19022–6.

  40. 40.

    Shaw S, Bencherif M, Marrero MB. Angiotensin II blocks nicotine-mediated neuroprotection against beta-amyloid (1–42) via activation of the tyrosine phosphatase SHP-1. J Neurosci 2003; 23(35): 11224–8.

  41. 41.

    de Gasparo M, Catt KJ, Nagami T, et al. International union of pharmacology: XXIII. The angiotensin II receptors. Pharmacol Rev 2000; 52(3): 415–72.

  42. 42.

    Archer FR, Doherty P, Collins D, et al. CAMs and FGF cause a local submembrane calcium signal promoting axon outgrowth without a rise in bulk calciun concentration. Eur J Neurosci 1999; 11(10): 3565–73.

  43. 43.

    Koshimura K, Murakami Y, Sohmiya M, et al. Effects of erythropoietin on neuronal activity. J Neurochem 1999; 72(6): 2565–72.

  44. 44.

    Yu SP, Yeh CH, Sensi SL, et al. Mediation of neuronal apoptosis by enhancement of outward potassium current. Science 1997; 278(5335): 114–7.

  45. 45.

    Jing G, Grammatopoulos T, Ferguson P, et al. Inhibitory effects of angiotensin on NMDA-induced cytotoxicity in primary neuronal cultures. Brain Res Bull 2004; 62(5): 397–403.

  46. 46.

    Horiuchi M, Hayashida W, Akishita M, et al. Stimulation of different subtypes of angiotensin II receptors, AT1 and AT2 receptors, regulates STAT activation by negative crosstalk. Circ Res 1999; 84(8): 876–82.

  47. 47.

    De-Fraja C. STAT signalling in the mature and aging brain. Int J Dev Neurosci 2000; 18(4–5): 439–46.

  48. 48.

    Nouet S, Amzallag N, Li JM, et al. Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP. J Biol Chen 2004; 279(28): 28989–97.

  49. 49.

    Unger T, Badoer E, Ganten D, et al. Brain angiotensin: pathways and pharmacology. Circulation 1988; 77(6 Pt 2): 140–54.

  50. 50.

    Dai WJ, Funk A, Herdegen T, et al. Blockade of central angiotensin AT (1) receptors improves neurological outcome and reduces expression of AP-1 transcription factors after focal brain ischemia in rats. Stroke 1999; 30(11): 2391–8.

  51. 51.

    Lou M, Blume A, Zhao Y, et al. Sustained blockade of brain ATI receptors before and after focal cerebral ischemia alleviates neurologic deficits and reduce: neuronal injury, apoptosis, and inflammatory responses in the rat. J Cereb Blood Flow Metab 2004; 24(5): 536–47.

  52. 52.

    Li J, Culman J, Hörtnagl H, et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB J 2005 Apr; 19(6): 617–9.

  53. 53.

    Sandercock PA, Warlow CP, Jones LN, et al. Predisposing factors for cerebral infarction: the Oxfordshire community stroke project. BMJ 1989; 298(6666): 75–80.

  54. 54.

    Ogata J, Fujishima M, Tamaki K, et al. Stroke-prone spontaneously hypertensive rats as an experimental model of malignant hypertension: I. A light- and electron-microscopic study of the brain. Acta Neuropathol (Berl) 1980; 51(3): 179–84.

  55. 55.

    Mayhan WG, Faraci FM, Heistad DD. Impairment of endothelium-dependent responses of cerebral arterioles in chronic hypertension. Am J Physiol 1987; 253(6 Pt 2): H1435–40.

  56. 56.

    Baumbach GL, Dobrin PB, Hart MN, et al. Mechanics of cerebral arterioles in hypertensive rats. Circ Res 1988; 62(1): 56–64.

  57. 57.

    Smeda JS. Cerebral vascular changes associated with hemorrhagic stroke in hypertension. Can J Physiol Pharmacol 1992; 70(4): 552–64.

  58. 58.

    Vraamark T, Waldemar G, Strandgaard S, et al. Angiotensin II receptor antagonist CV-11974 and cerebral blood flow autoregulation. J Hypertens 1995; 13(7): 755–61.

  59. 59.

    Inada Y, Wada T, Ojima M, et al. Protective effects of candesartan cilexetil (TCV-116) against stroke, kidney dysfunction and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats. Clin Exp Hypertens 1997; 19(7): 1079–99.

  60. 60.

    Vacher E, Richer C, Giudicelli JF. Effects of losartan on cerebral arteries in stroke-prone spontaneously hypertensive rats. J Hypertens 1996; 14(11): 1341–8.

  61. 61.

    Tesfamariam B, Halpern W. Endothelium-dependent and endothelium-independent vasodilation in resistance arteries from hypertensive rats. Hypertension 1988; 11(5): 440–4.

  62. 62.

    Diederich D, Yang ZH, Buhler FR, et al. Impaired endothelium-dependent relaxations in hypertensive resistance arteries involve cyclooxygenase pathway. Am J Physiol 1990; 258(2 Pt 2): H445–51.

  63. 63.

    Mayhan WG, Faraci FM, Heistad DD. Responses of cerebral arterioles to adenosine 5’-diphosphate, serotonin, and the thromboxane analogue U-46619 during chronic hypertension. Hypertension 1988; 12(6): 556–61.

  64. 64.

    Sudhir K, MacGregor JS, Gupta M, et al. Effect of selective angiotensin II receptor antagonism and angiotensin converting enzyme inhibition on the coronary vasculature in vivo: intravascular two-dimensional and Doppler ultrasound studies. Circulation 1993; 87(3): 931–8.

  65. 65.

    Jaiswal N, Diz DI, Tallant EA, et al. The nonpeptide angiotensin II antagonist DuP 753 is a potent stimulus for prostacyclin synthesis. Am J Hypertens 1991; 4(3 Pt 1): 228–33.

  66. 66.

    Bertolino F, Valentin JP, Maffre M, et al. Prevention of thromboxane A2 receptor-mediated pulmonary hypertension by a nonpeptide angiotensin II type 1 receptor antagonist. J Pharmacol Exp Ther 1994; 268(2): 747–52.

  67. 67.

    Ishizaki H, Ohtawa M. Inhibitory effect of the nonpeptide angiotensin II receptor antagonist losartan and its active metabolite, E-3174, on cAMP phosphodiesterase: additional action of the antagonists. Biochem Pharmacol 1994; 48(1): 201–4.

  68. 68.

    Nishimura Y, Ito T, Saavedra JM. Angiotensin II AT (1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 2000; 31(10): 2478–86.

  69. 69.

    Fernandez LA, Caride VJ, Stromberg C, et al. Angiotensin AT2 receptor stimulation increases survival in gerbils with abrupt unilateral carotid ligation. J Cardiovasc Pharmacol 1994; 24(6): 937–40.

  70. 70.

    Engelhorn T, Goerike S, Doerfler A, et al. The angiotensin II type 1 receptor blocker candesartan improves cerebral blood flow, reduces infarct size, and improves neurological outcome after transient cerebral ischemia in rats. J Cereb Blood Flow Metab 2004; 24: 467–74.

  71. 71.

    Groth W, Blume A, Gohlke P, et al. Chronic pretreatment with candesartan improves recovery from focal cerebral ischaemia in rats. J Hypertens 2003; 21(11): 2175–82.

  72. 72.

    Devereux RB, Dahlof B, Kjeldsen SE, et al. Effects of losartan or atenolol in hypertensive patients without clinically evident vascular disease: a substudy of the LIFE randomized trial. Ann Intern Med 2003; 139(3): 169–77.

  73. 73.

    Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353: 611–6.

  74. 74.

    Fernandez LA, Spencer DD, Kaczmar T. Angiotensin II decreases mortality rate in gerbils with unilateral carotid ligation. Stroke 1986; 17: 82–5.

  75. 75.

    Kaliszewski C, Fernandez LA, Wicke JD. Differences in mortality rate between abrupt and progressive carotid ligation in the gerbil: role of endogenous angiotensin II. J Cereb Blood Flow Metab 1988; 8: 149–54.

  76. 76.

    Walther T, Olah L, Harms C, et al. Ischemic injury in experimental stroke depends on angiotensin II. FASEB J 2002; 16(2): 169–76.

  77. 77.

    Kimura B, Sumners C, Phillips MI. Changes in skin angiotensin II receptors in rats during wound healing. Biochem Biophys Res Commun 1992; 187(2): 1083–90.

  78. 78.

    Nio Y, Matsubara H, Murasawa S, et al. Regulation of gene transcription of angiotensin II receptor subtypes in myocardial infarction. J Clin Invest 1995; 95(1): 46–54.

  79. 79.

    Shewan D, Berry M, Cohen J. Extensive regeneration in vitro by early embryonic neurons on immature and adult CNS tissue. J Neurosci 1995; 15(3 Pt 1): 2057–62.

  80. 80.

    Hausmann B, Sievers J, Hermanns J, et al. Regeneration of axons from the adult rat optic nerve: influence of fetal brain grafts, laminin, and artificial basement membrane. J Comp Neurol 1989; 281(3): 447–66.

  81. 81.

    Meffert S, Stoll M, Steckelings UM, et al. The angiotensin II AT2 receptor inhibits proliferation and promotes differentiation in PC12W cells. Mol Cell Endocrinol 1996; 122(1): 59–67.

  82. 82.

    Gallinat S, Csikos T, Meffert S, et al. The angiotensin AT2 receptor down-regulates neurofilament M in PC12W cells. Neurosci Lett 1997; 227(1): 29–32.

  83. 83.

    Stroth U, Meffert S, Gallinat S, et al. Angiotensin II and NGF differentially influence microtubule proteins in PC12W cells: role of the AT2 receptor. Brain Res Mol Brain Res 1998; 53(1–2): 187–95.

  84. 84.

    Laflamme L, Gasparo M, Gallo JM, et al. Angiotensin II induction of neurite outgrowth by AT2 receptors in NG108-15 cells: effect counteracted by the AT1 receptors. J Biol Chem 1996; 271(37): 22729–35.

  85. 85.

    Nijhawan D, Honarpour N, Wang X. Apoptosis in neural development and disease. Annu Rev Neurosci 2000; 23: 73–87.

  86. 86.

    Herdegen T, Skene P, Bahr M. The c-Jun transcription factor-bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci 1997; 20(5): 227–31.

  87. 87.

    Yamada T, Horiuchi M, Dzau VJ. Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci U S A 1996; 93(1): 156–60.

  88. 88.

    Stroth U, Blume A, Mielke K, et al. Angiotensin AT (2) receptor stimulates ERK1 and ERK2 in quiescent but inhibits ERK in NGF-stimulated PC12W cells. Brain Res Mol Brain Res 2000; 78(1–2): 175–80.

  89. 89.

    Kummer JL, Rao PK, Heidenreich KA. Apoptosis induced by withdrawal of trophic factors is mediated by p38 mitogen-activated protein kinase. J Biol Chem 1997; 272(33): 20490–4.

  90. 90.

    Kolesnick RN, Kronke M. Regulation of ceramide production and apoptosis. Annu Rev Physiol 1998; 60: 643–65.

  91. 91.

    Merry DE, Korsmeyer SJ. Bcl-2 gene family in the nervous system. Annu Rev Neurosci 1997; 20: 245–67.

  92. 92.

    Shenoy UV, Richards EM, Huang XC, et al. Angiotensin II type 2 receptor-mediated apoptosis of cultured neurons from newborn rat brain. Endocrinology 1999; 140(1): 500–9.

  93. 93.

    Miura S, Karnik SS. Ligand-independent signals from angiotensin II type 2 receptor induce apoptosis. EMBO J 2000; 19(15): 4026–35.

  94. 94.

    Grammatopoulos TN, Morris K, Bachar C, et al. Angiotensin II attenuates chemical hypoxia-induced caspase-3 activation in primary cortical neuronal cultures. Brain Res Bull 2004; 62(4): 297–303.

  95. 95.

    Heumann R. Neurotrophin signalling. Curr Opin Neurobiol 1994; 4(5): 668–79.

  96. 96.

    Harrington EA, Fanidi A, Evan GI. Oncogenes and cell death. Curr Opin Genet Dev 1994; 4(1): 120–9.

  97. 97.

    Reinecke K, Lucius R, Reinecke A, et al. Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: role of the AT2 receptor and the transcription factor NF-kappaB. FASEB J 2003; 17(14): 2094–6.

  98. 98.

    Iwasaki Y, Chikawa Y, Igarashi O, et al. Trophic effect of olmesartan, a novel AT1R antagonist, on spinal motor neurons in vitro and in vivo. Neurol Res 2002; 24(5): 468–72.

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This review was supported by a generous gift from the “Lampe-Stiftung” (University of Kiel, to H. Wilms and R. Lucius) and a grant from the BMBF (Federal Ministry for Education and Research) to P. Rosenstiel (NGFN pathway mapping).

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Correspondence to Dr Ralph Lucius.

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Wilms, H., Rosenstiel, P., Unger, T. et al. Neuroprotection with Angiotensin Receptor Antagonists. Am J Cardiovasc Drugs 5, 245–253 (2005). https://doi.org/10.2165/00129784-200505040-00004

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  • Losartan
  • Telmisartan
  • Irbesartan
  • Candesartan Cilexetil
  • Olmesartan Medoxomil