Inhibition of the Renin-Angiotensin System and the Prevention of Stroke Authors
First Online: 20 August 2012 DOI:
Cite this article as: Schrader, J., Kulschewski, A. & Dendorfer, A. Am J Cardiovasc Drugs (2007) 7: 25. doi:10.2165/00129784-200707010-00003 Abstract
BP is the most important determinant of the risk of stroke. A small reduction in BP results in a substantial reduction of both ischemic and hemorrhagic stroke. Any of the commonly used antihypertensive drugs lower the incidence of stroke, with larger reductions in BP resulting in larger reductions in risk. Experimental evidence has linked the renin-angiotensin system (RAS) to the development and progression of cerebrovascular disease. Inhibition of the RAS has beneficial cerebrovascular effects and may reduce the risk of stroke in a manner possibly independent from the alterations of BP. Some clinical trials even suggest that ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) exert cerebroprotective effects beyond BP lowering, but the evidence is controversial. Studies on specific protective actions of antihypertensive drugs are generally hampered by the fact that any treatment-related difference in BP may play a dominant role in the prevention of stroke. There are also indications that the protective potency of ARBs might be superior to that of ACE inhibitors, due to their differential activation of angiotensin II type 2 receptors, but the clinical relevance of this mechanism is unclear.
Some studies in primary prevention of stroke, acute stroke, and secondary prevention show advantages for ARBs beyond controlling BP alone. In primary prevention, the LIFE randomized trial showed a significant difference in stroke rate in favor of losartan compared with atenolol despite similar reductions in BP. In acute stroke, the role of hypertension and its treatment remains controversial. ACCESS, however, suggested that an ARB is safe in hypertensive acute stroke patients and may offer advantages independent from BP control. In secondary stroke prevention, there are very few antihypertensive trials. These trials show that BP lowering is at least as successful as in primary prevention, but the absolute stroke risk is much higher. An ACE inhibitor was effective compared with placebo in the PROGRESS trial. The MOSES study showed that eprosartan prevented vascular events more effectively than nitrendipine, despite similar BP-lowering effects.
Hypertension is not only the most important risk factor for stroke, but is also closely correlated with cognitive decline and dementia. Therefore, prevention of cognitive decline or even improvement of slightly diminished brain function should be an important goal for antihypertensive treatment in the future. Some clinical data suggest advantages for ACE inhibitors, ARBs, and calcium channel antagonists. Currently, however, the existing data are not sufficient for clinical recommendations.
Therefore, ongoing trials will further define the exact role of inhibitors of the RAS and are urgently needed in secondary prevention, in acute stroke, and in the prevention of cognitive decline.
World Health Organization. The world health report 2002: reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization, 2002.
Murray SJ, Lopez AD. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge (MA): Harvard School of Public Health on behalf of the World Health Organization and the World Bank, 1996.
Sarti C, Rastenyte D, Capaitis Z, et al. International trends in mortality from stroke, 1968 to 1994. Stroke 2000; 32: 1588–601.
Chalmers J, Chapman N. Challenges for the prevention of primary and secondary stroke: the importance of lowering blood pressure and total cardiovascular risk. Blood Press 2001; 10: 344–51.
Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–13.
Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated hypertension in the elderly: meta-analysis of outcome trials. Lancet 2000; 355: 865–72.
MacMahon S, Rodgers A. Blood pressure, antihypertensive treatment and stroke risk. J Hypertens 1994; 12 Suppl. 10: S5–14.
Chobanian AV, Bakris GL, Black HR et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003; 289: 2560–72.
Kazama K, Wang G, Frys K, et al. Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 2003; 285: H1890–9.
Baumbach GL, Sigmund CD, Faraci FM. Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen. Hypertension 2001; 41: 50–5.
Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 2002; 89 Suppl. 2A: 3A–10A.
Rajagopalan S, Meng XP, Ramasamy S, et al. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of cascular matrix metalloproteinases in vitro: implications for atherosclerotic plaque stability. J Clin Invest 1996; 98: 2572–9.
Rajagopalan S, Kurz S, Munzel T, et al. Angiotensin II-mediated hypertension in the rat increases vascular Superoxide production via membrane NADH/ NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest 1996; 97: 1916–23.
Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: from genes to treatment. Arch Intern Med 2003; 163: 1155–64.
Stoll M, Unger T. Angiotensin and its AT receptor: new insights into an old system. Regul Pept 2001; 99: 175–82.
Wilms H, Rosenstiel P, Unger T, et al. Neuroprotection with angiotensin receptor antagonists: a review of the evidence and potential mechanisms. Am J Cardiovasc Drugs 2005; 5(4): 245–53.
Saavedra JM, Nishimura Y. Angiotensin and cerebral blood flow. Cell Mol Neurobiol 1999; 19: 553–73.
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.
Labinjoh C, Newby DE, Pellegrini MP, et al. Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition. J Am Coll Cardiol 2000; 38: 1402–8.
Gohlke P, Kuwer I, Schnell A, et al. Blockade of bradykinin B2 receptors prevents the increase in capillary density induced by chronic angiotensin-converting enzyme inhibitor treatment in stroke-prone spontaneously hypertensive rats. Hypertension 1997; 29 (1 Pt 2): 478–82.
Magy L, Vincent F, Faure S, et al. The renin-angiotensin systems: evolving pharmacological perspectives for cerebroprotection. Curr Pharm Des 2005; 11(25): 3275–91.
Inada Y, Wada T, Ojima M, et al. Protective effects of candesartan cilexetil (TCV-116) against stroke, kidney dysfunction and cardiac hypertrophy in strokeprone spontaneously hypertensive rats. Clin Exp Hypertens 1997; 19: 1079–99.
Stier Jr CT, Chander P, Gutstein WH, et al. Therapeutic benefit of captopril in saltloaded stroke-prone spontaneously hypertensive rats is independent of hypotensive effect. Am J Hypertens 1991; 4: 680–7.
Stier Jr CT, Adler LA, Levine S, et al. Stroke prevention by Iosartan in strokeprone spontaneously hypertensive rats. J Hypertens Suppl 1993; 11: S37–42.
von Lutterotti N, Camargo MJ, Campbell Jr WG, et al. Angiotensin II receptor antagonist delays renal damage and stroke in salt-loaded Dahl salt-sensitive rats. J Hypertens 1992; 10: 949–57.
Muller F, Lartaud I, Bray L, et al. Chronic treatment with the angiotensin I converting enzyme inhibitor, perindopril, restores the lower limit of autoregulation of cerebral blood flow in the awake renovascular hypertensive rat. J Hypertens 1990; 8: 1037–42.
Sadoshima S, Fuji F, Ooboshi H, et al. Angiotensin converting enzyme inhibitors attenuate ischemic brain metabolism in hypertensive rats. Stroke 1993; 24: 1561–7.
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.
Nishimura Y, Ito T, Saavedra JM. Angiotensin II AT1 blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 2000; 31: 2478–86.
Ando H, Zhou J, Macova M, et al. Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats. Stroke 2004; 35(17): 1726–31.
Ito T, Yamakawa H, Bregonzio C, et al. Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin II AT1 antagonist. Stroke 2002; 33(9): 2297–303.
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.
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.
Dendorfer A, Dominiak P, Schunkert H. ACE inhibitors and angiotensin II receptor antagonists. In: von Eckardstein A, editor. Handbook of experimental pharmacology. Vol. 170. Berlin: Springer Verlag, 2005: 402–436.
Lonn E, Yusuf S, Dzavik V, et al., SECURE Investigators. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation 2001; 103(7): 919–925.
Schieffer B, Wirger A, Meybrunn M, et al. Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation 1994; 89(5): 2273–82.
Boos CJ, Lip GY. Targeting the renin-angiotensin-aldosterone system in atrial fibrillation: from pathophysiology to clinical trials. J Hum Hypertens 2005; 19(11): 855–9.
Fernandez LA, Spencer DD, Kaczmar Jr T. Angiotensin II decreases mortality rate in gerbils with unilateral carotid ligation. Stroke 1986; 17(1): 82–5.
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.
Haberl RL. Role of angiotensin receptor subtypes in the response of rabbit brain arterioles to angiotensin. Stroke 1994; 25(7): 1476–9.
Haberl RL, Decker PJ, Einhaupl KM. Angiotensin degradation products mediate endothelium-dependent dilation of rabbit brain arterioles. Circ Res 1991; 68(6): 1621–7.
Walther T, Olah L, Harms C, et al. Ischemic injury in experimental stroke depends on angiotensin II. FASEB J 2002; 16(2): 169–76.
Iwai M, Liu HW, Chen R, et al. Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor stimulation. Circulation 2004; 110(7): 843–8.
Sugawara T, Kinouchi H, Oda M, et al. Candesartan reduces Superoxide production after global cerebral ischemia. Neuroreport 2005; 16: 325–8.
Phillips MI, Sumners C. Angiotensin II in central nervous system physiology. Regul Pept 1998; 78(1–3): 1–11.
Saavedra JM. Brain and pituitary angiotensin. Endocr Rev 1992; 13(2): 329–80.
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: 2391–9.
Nishimura Y, Ito T, Hoe K, et al. Chronic peripheral administration of the angiotensin II AT (1) receptor antagonist candesartan blocks brain AT (1) receptors. Brain Res 2000; 871(1): 29–38.
Tsutsumi K, Saavedra JM. Characterization and development of angiotensin II receptor subtypes (AT1 and AT2) in rat brain. Am J Physiol 1991; 261 (1 Pt 2): R209–16.
Li J, Culman J, Hortnagl H, et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB J 2005; 19(6): 617–9.
Culman J, Blume A, Gohlke P, et al. The renin-angiotensin system in the brain: possible therapeutic implications for AT (1)-receptor blockers. J Hum Hypertens 2002; 16 Suppl. 3: S64–70.
Reinecke K, Lucius RA, 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.
Lou M, Blume A, Zhao Y, et al. Sustained blockade of brain AT1 receptors before and after focal cerebral ischemia alleviates neurologic deficits and reduces neuronal injury, apoptosis, and inflammatory responses in the rat. J Cereb Blood Flow Metab 2004; 24(5): 536–47.
Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens 2003; 21: 1055–76.
Dahlof B, Devereux RB, Kjeldsen SE, et al., for the LIFE Study Group. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359: 995–1003.
Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet 2004; 363: 2022–31.
Sever PS. Anglo-Scandinavian cardiac outcomes trial-blood pressure lowering arm (ASCOT-BPLA). American College of Cardiology 2005 Scientific Sessions; 2005 Mar 6–9; Orlando.
Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischemic attack. Lancet 2001; 358: 1033–41.
Schrader J, Lüders S, Kulschewski A, et al., for the MOSES Study Group. Morbidity and mortality after stroke: eprosartan compared with nitrendipine for secondary prevention (MOSES). Stroke 2005; 36: 1218–26.
Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356: 359–65.
Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST). A randomized controlled trial. JAMA. 2003; 290: 2805–16.
Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366–72.
HOPE (Heart Outcomes Prevention Evaluation) Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–53.
Bosch J, Yusuf S, Pogue J, et al., on behalf of the HOPE Investigators. Use of ramipril in preventing stroke: double blind randomized trial. BMJ 2002; 324: 1–5.
Schrader J, Lüders S. Preventing stroke: high risk patients should receive perindopril irrespective of blood pressure. BMJ 2002; 324: 687–8.
Staessen JA, Wang J, Lutgarde T. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001; 358: 1305–15.
Svensson P, de Faire U, Sleight P, et al. Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE sub-study. Hypertension 2001; 38: E28–32.
Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared with atenolol: the losartan intervention for end point reduction in hypertension (LIFE) study. J Am Coll Cardiol 2005; 45: 712–9.
Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: the losartan intervention for end point reduction in hypertension (LIFE) study. J Am Coll Cardiol 2005; 45: 705–11.
Kizer JR, Dahlöf B, Kjeldsen SE, et al. Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the losartan intervention for endpoint reduction in hypertension study. Hypertension 2005; 45: 46–52.
Morfis L, Schwartz R, Poulos R, et al. Blood pressure changes in acute cerebral infarction and hemorrhage. Stroke 1997; 28: 1401–5.
Leonardi-Bee J, Bath P, Phillips S, et al., IST Collaborative Group. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002; 33(5): 1315–20.
Wahlgren NG, McMahon DG, DeKeyser J, et al. Intravenous Nimodipine West European Stroke Trial (IN-WEST) of nimodipine in the treatment of acute ischemic stroke. Cerebrovasc Dis 1994; 4: 204–10.
International Society of Hypertension Writing Group. International Society of Hypertension (ISH): statement on the management of blood pressure in acute stroke: J Hypertens 2003; 21: 665–72.
Adams Jr HP, Adams RJ, Brott TG, et al. for the Stroke Council of the American Stroke Association. Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke 2003; 23: 1056–83.
Willmot M, Leonardi-Bee J, Bath PM. High blood pressure in acute stroke and subsequent outcome: a systematic review. Hypertension 2004; 43: 18–24.
Vemmos KN, Tsivgoulis G, Spengos K, et al. Association between 24-h blood pressure monitoring variables and brain oedema in patients with hyperacute stroke. J Hypertens 2003; 21: 2167–73.
Castillo J, Leira R, Carcia MM, et al. Blood pressure decrease during the acute phase of ischemic stroke is associated with brain injury and poor stroke outcome. Stroke 2004; 35: 520–7.
Robinson T, Waddington A, Ward-Close S, et al. The predictive role of 24-hour compared with casual blood pressure levels on outcome following acute stroke. Cerebrovasc Dis 1997; 7: 264–72.
Dyker AG, Grosset DG, Lees KR. Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke. Stroke 1997; 28: 580–3.
Schrader J, Lüders S, Kulschewski A, et al. Evaluation of acute candesartan cilexetil therapy in stroke survivors. Stroke 2003; 34: 1699–703.
Chalmers J. Blood pressure in acute stroke: in search of evidence. J Hypertens 2005; 23: 277–8.
Rodgers A, MacMahon S, Gamble G, et al. Blood pressure and risk of stroke in patients with cerebrovascular disease: the United Kingdom transient ischaemic attack collaborative group [letter]. BMJ 1996; 313: 147.
Gueyffier F, Boissel J-P, Boutitie F, et al., for the INDANA (Individual Data Analysis of Antihypertensive intervention trial) Project Collaborators. Effect of antihypertensive treatment in patients having already suffered from stroke: gathering the evidence. Stroke 1997; 28: 2557–62.
PATS Collaborating Group. Post-stroke antihypertensive treatment study: a preliminary result. Chin Med J 1995; 108: 710–7.
Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 2003; 34: 2741–9.
Elias MF, Wolf PA, d’Agostino RB, et al. Untreated blood pressure levels is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol 1993; 138: 353–64.
Kilander L, Nyman H, Boberg M, et al. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension 1998; 31: 780–6.
Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of blood pressure and dementia. Lancet 1996; 347: 1141–5.
Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging 2000; 21: 49–55.
Tzourio C, Dufouil C, Ducimetiere P, et al. Cognitive decline in individuals with high blood pressure: a longitudinal study in the elderly. EVA Study Group. Neurology 1999; 53: 1948–52.
Elias PK, Elias MF, Robbins MA, et al. Blood pressure-related cognitive decline: does age make a difference? Hypertension 2004; 44(5): 612–3.
Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003; 348: 1215–22.
Yamamoto Y, Akiguchi I, Oiwa K, et al. Twenty-four-hour blood pressure and MRI as predictive factors for different outcomes in patients with lacunar infarct. Stroke 2002; 33: 297–305.
Bernick C, Kuller L, Dulberg Jr C, et al. Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology 2001; 57: 1222–9.
Uehara T, Tabuchi M, Mori E. Risk factors for silent cerebral infarcts in subcortical white matter and basal ganglia. Stroke 1999; 30: 378–82.
Kobayashi S, Okada K, Koide H, et al. Subcortical silent brain infarction as a risk factor for clinical stroke. Stroke 1997; 28: 1932–9.
Hougaku M, Matsumoto K, Kitagawa K, et al. Silent cerebral infarction as a form of hypertensive target organ damage in the brain. Hypertension 1992; 20: 816–20.
Sugiyama T, Lee JD, Shimizu H, et al. Influence of treated blood pressure on progression of silent cerebral infarction. J Hypertens 1999; 17: 679–84.
SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991; 265: 3255–64.
Prince MJ, Bird AS, Blizard RA. Is the cognitive function of older patients affected by antihypertensive treatment? Result from 54 months of the Medical Research Council’s trial of hypertension in older adults. BMJ 1996; 312: 801–5.
Forette F, Seux ML, Staessen JA, et al., for the Syst-Eur Investigators. Prevention of dementia in randomised double-blind placebo-controlled systolic hypertension in Europe (Syst-Eur) trial. Lancet 1998; 352: 1347–351.
Tzourio C, Anderson C, Chapman N, et al., PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003; 163: 1069–75.
Skoog J. Scope: CVD and dementia end points by cognitive function at baseline. Paris: International Society of Hypertension, 2004.
Tedesco MA, Ratti G, Mennella S, et al. Comparison of losartan and hydrochlorothiazide on cognitive function and quality of life in hypertensive patients. Am J Hypertens 1999; 12: 1130–4.
Ohrui T, Tomita N, Sato-Nakagawa T, et al. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology 2004; 63(7): 1324–5.
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