Current Hypertension Reports

, Volume 14, Issue 3, pp 202–208

The Role of Angiotensin II Receptors in Stroke Protection



The hypothesis that angiotensin II (Ang II) might have a stroke-protective role was first proposed by Brown and Brown about 25 years ago. Their hypothesis was generated from the results of the first Medical Research Council trial in patients with mild to moderate hypertension, which showed that patients treated with the diuretic bendrofluazide had a 70% decrease in strokes compared with those treated with the β-blocker propranolol for similar blood pressure reduction. This hypothesis, which remained dormant for many years, was recently resurrected by several experimental studies that showed that the brain possesses its own renin-angiotensin system (RAS) similar to the one existing in the systemic circulation. These studies also showed that the brain RAS plays an important role in stroke prevention and neuronal protection through its active peptide Ang II. In addition, these studies demonstrated that the beneficial effects of Ang II are mediated through stimulation of its subtype 2 receptors, and possibly through stimulation of the subtype 4 receptors by Ang IV, a metabolite of Ang II. Drugs that selectively block the Ang II subtype 1 receptors, such as the angiotensin receptor blockers, have shown superior protection against strokes and neuronal damage than drugs that decrease the generation of Ang II, such as the angiotensin-converting enzyme inhibitors and β-blockers. In this review, the role of the Ang II receptors and their mechanism of action regarding stroke prevention are discussed in view of the evidence from experimental and clinical studies.


Renin-angiotensin system (RAS) Angiotensin Receptors AT1 AT2 AT4 Angiotensin receptor blockers (ARBs) Stroke Prevention Experimental studies Clinical trials Blood pressure 


  1. 1.
    Brown MJ, Brown J. Does angiotensin II protect against strokes? Lancet. 1986;2:427–9.PubMedCrossRefGoogle Scholar
  2. 2.
    The Medical Research Working Party. The MRC trial of treatment of mild hypertension: principal results. BMJ. 1985;291:97–104.CrossRefGoogle Scholar
  3. 3.
    Chrysant SG. The pathophysiologic role of the brain renin-angiotensin system in stroke protection: clinical implications. J Clin Hypertens. 2007;9:454–9.CrossRefGoogle Scholar
  4. 4.
    Faure S, Bureau A, Oudart N, et al. Protective effect of candesartan in experimental ischemic stroke in the rat mediated by AT2 and AT4 receptors. J Hypertens. 2008;26:2008–15.PubMedCrossRefGoogle Scholar
  5. 5.
    Fisher-Ferraro C, Nahmod VE, Goldstein DJ, Finkielman S. Angiotensin and rennin in the rat and dog brains. J Exp Med. 1971;133:353–61.CrossRefGoogle Scholar
  6. 6.
    Unger T, Badoer E, Ganten D, Lang RE, Retig R. Brain angiotensin: pathways and pharmacology. Circulation. 1988;77(Part 2):140–54.Google Scholar
  7. 7.
    Mergenthaler P, Dimagl U, Meisel A. Pathophysiology of stroke: lessons from animal models. Metab Brain Dis. 2004;19:151–67.PubMedCrossRefGoogle Scholar
  8. 8.
    Astrup J, Siesjo BK, Symon L. Threshold in cerebral ischemia-the ischemic penumbra. Stroke. 1981;12:723–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Ginsberg MD. Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection. The 2002 Thomas Willis lecture. Stroke. 2003;34:214–23.PubMedCrossRefGoogle Scholar
  10. 10.
    Wilms H, Rosenstiel P, Deusscl G, Lucius R. Neuroprotection with angiotensin receptor antagonists: a review of the evidence and potential mechanisms. Am J Cardiovasc Drugs. 2005;5:245–53.PubMedCrossRefGoogle Scholar
  11. 11.
    Chrysant SG. Vascular remodeling: the role of angiotensin converting enzyme inhibitors. Am Heart J. 1998;135:S21–30.PubMedCrossRefGoogle Scholar
  12. 12.
    Vacher E, Richer C, Giudicelli JF. Effects of losartan on cerebral arteries in stroke-prone spontaneously hypertensive rats. J Hypertens. 1996;14:1341–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Dai WJ, Funk A, Herdegen T, Unger T, Culman J. 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;30:2391–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Engelhorn T, Goerike S, Doefler A, et al. The angiotensin II type 1 receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats. J Cerebral Blood Flow Metab. 2004;24:467–74.CrossRefGoogle Scholar
  15. 15.
    Brdon J, Kaiser S, Hageman F, et al. Comparison between early and delayed systemic treatment with candesartan of rats after ischemic stroke. J Hypertens. 2007;25:187–98.PubMedCrossRefGoogle Scholar
  16. 16.
    Allen AM, Zhuo J, Mendelsohn FA. Localization of angiotensin AT1 and AT2 receptors. J Am Soc Nephrol. 1999;10:S23–9.PubMedGoogle Scholar
  17. 17.
    Millan MA, Jacobowitz DM, Aguillera C, Catt KJ. Differential distribution of AT1 and AT2 angiotensin II receptor subtypes in the rat brain during development. Proc Natl Acad Sci USA. 1991;88:11440–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Steckelings UM, Kaschina E, Unger T. The AT2 receptor—a matter of love and hate. Peptides. 2005;26:1401–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Thone-Reineke C, Steckelings UM, Unger T. Angiotensin receptor blockers and cerebral protection in stroke. J Hypertens. 2006;24:S115–21.CrossRefGoogle Scholar
  20. 20.
    Li J, Culman J, Hortnagl H, et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB J. 2005;19:617–9.PubMedGoogle Scholar
  21. 21.
    Wright JW, Harding JW. Brain angiotensin receptor subtypes in the control of physiological and behavioral responses. Neurosci Biobehav Rev. 1994;18:21–53.PubMedCrossRefGoogle Scholar
  22. 22.
    Braszko J. The combination of the AT1 and AT2 angiotensin receptors to its cognitive effects. Acta Neurobiol Exp. 1996;56:49–54.Google Scholar
  23. 23.
    Iwai M, Liu HW, Chen R, et al. Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor stimulation. Circulation. 2004;110:843–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Harding JW, Wright JW, Swanson GN, et al. AT4 receptors: specificity and distribution. Kidney Intern. 1994;46:1510–2.CrossRefGoogle Scholar
  25. 25.
    DeGasparo M, Catt KJ, Inagami T, et al. International union of pharmacology XXIII. The angiotensin II receptors. Pharmacol Rev. 2000;52:415–72.Google Scholar
  26. 26.
    Wright JW, Harding JW. The angiotensin AT4 receptor subtype as a target for the treatment of memory dysfunction associated with Alzheimer’s disease. J Renin Angiotensin Aldosterone Syst. 2008;9:226–37.PubMedCrossRefGoogle Scholar
  27. 27.
    Coleman JK, Krebs LT, Hamilton TA, et al. Autoradiographic identification of kidney angiotensin IV binding sites and angiotensin IV –induced renal cortical blood flow changes in rats. Peptides. 1998;19:269–77.PubMedCrossRefGoogle Scholar
  28. 28.
    Hamilton TA, Handa RK, Harding JW, Wright JW. A role for the angiotensin IV/AT4 system in mediating natriuresis in the rat. Peptides. 2001;22:935–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Kramar EA, Harding JW, Wright JW. Angiotensin II-and IV-induced changes in cerebral blood flow. Roles of AT1, AT2, and AT4 receptor subtypes. Regul Pept. 1997;68:131–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Stragier B, Debundel D, Sarre S, et al. Involvement of insulin-regulated aminopeptidase in the effects of the renin-angiotensin fragment angiotensin IV: a review. Heart Fail Rev. 2008;13:321–37.PubMedCrossRefGoogle Scholar
  31. 31.
    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;24:937–40.PubMedCrossRefGoogle Scholar
  32. 32.
    Dalmay F, Mazouz H, Allard J, et al. Non- AT (1)- receptor mediated protective effect of angiotensin against acute ischemic stroke in the gerbil. J Renin Angiotensin Aldosterone Syst. 2001;2:103–6.PubMedGoogle Scholar
  33. 33.
    Kozak W, Kozak A, Johnson MH, Elewa HF, Fagan SC. Vascular protection with candesartan after experimental acute stroke in hypertensive rats: a dose-response study. J Pharmacol Exp Ther. 2008;326:773–82.PubMedCrossRefGoogle Scholar
  34. 34.
    Dahlof B, Devereaux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in Losartan For Endpoint reduction (LIFE) in hypertension: a randomized trial against atenolol. Lancet. 2002;359:995–1003.PubMedCrossRefGoogle Scholar
  35. 35.
    Kjeldsen SE, Dahlof B, Devereaux RB, et al. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention For Endpoint reduction (LIFE) substudy. JAMA. 2002;288:1491–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Lithell H, Hanson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875–86.PubMedCrossRefGoogle Scholar
  37. 37.
    Papademetriou V, Farsang C, Elmfeld D, et al. Stroke prevention with the angiotensin II type 1 receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE). J Am Coll Cardiol. 2004;44:1175–80.PubMedGoogle Scholar
  38. 38.
    Schrader J, Luders S, Kulshewski A, et al. The ACCESS study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke. 2003;34:1699–703.PubMedCrossRefGoogle Scholar
  39. 39.
    Schrader J, Luders S, Kulshewski A, et al. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a randomized controlled study (MOSES). Stroke. 2005;36:1218–26.PubMedCrossRefGoogle Scholar
  40. 40.
    Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with a regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet. 2004;363:2022–31.PubMedCrossRefGoogle Scholar
  41. 41.
    Yusuf S, Koon KT, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. The ONTARGET Investigators. N Engl J Med. 2008;358:1547–59.PubMedCrossRefGoogle Scholar
  42. 42.
    Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial. The Telmisartan Randomised Assessment Study in ACE iN tolerant Subjects with Cardiovascular Disease (TRANSCEND) Investigators. Lancet. 2008;372:1174–83.PubMedCrossRefGoogle Scholar
  43. 43.
    Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. For the PRoFESS Study Group. N Engl J Med. 2008;359:1225–37.PubMedCrossRefGoogle Scholar
  44. 44.
    Sandset EC, Barth PM, Boysen G, et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomized, placebo-controlled, double-blind trial. Lancet. 2011;377:741–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Chrysant SG. Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence. J Hum Hypertens. 2005;19:923–31.PubMedCrossRefGoogle Scholar
  46. 46.
    Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics-2011 update. A report from the American Heart Association. Circulation. 2011;123:e18–e209.PubMedCrossRefGoogle Scholar
  47. 47.
    Turnbull F, Neal B, Algert C, et al. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005;165:1410–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Turnbull F, Neal B, Ninomiya T, et al. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomized trials. BMJ. 2008;336:1121–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Czernichow S, Zanchetti A, Turnbull F, et al. Blood Pressure Lowering Treatment trialists’ Collaboration. The effects of blood pressure reduction and different blood pressure-lowering regimens on major cardiovascular events according to baseline blood pressure: meta-analysis of randomized trials. J Hypertens. 2011;29:4–16.PubMedCrossRefGoogle Scholar
  50. 50.
    Turnbull F. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomized trials. Lancet. 2003;362:1527–35.PubMedCrossRefGoogle Scholar
  51. 51.
    Turnbull F, Neal B, Pfeffer M, et al. Blood Pressure Treatment Trialists’ Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25:951–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: a meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:1665–83.CrossRefGoogle Scholar
  53. 53.
    Chrysant SG. Stroke prevention with losartan in the context of other antihypertensive drugs. Drugs Today. 2004;40:791–801.PubMedCrossRefGoogle Scholar
  54. 54.
    Ovbiagele B, Diener HC, Yusuf S, Martin RH, Cotton D, et al. Level of systolic blood pressure within the normal range and risk of recurrent stroke. JAMA. 2011;306:2137–44.PubMedCrossRefGoogle Scholar
  55. 55.
    Adams HP, Del Zoppo G, Albers MJ, et al. Guidelines for the early management of adults with ischemic stroke. A Guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke. 2007;38:1655–711.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.University of Oklahoma College of MedicineOklahoma CityUSA

Personalised recommendations