Pharmaceutical Modulation of the Renin Angiotensin Aldosterone System for Stroke Prevention: A Review of Experimental and Clinical Evidence

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1 doi: /S Review Article Pharmaceutical Modulation of the Renin Angiotensin Aldosterone System for Stroke Prevention: A Review of Experimental and Clinical Evidence Elisavet Moutzouri, MD, George Daios, MD, PhD, Moses Elisaf, MD, PhD, and Haralampos J. Milionis, MD, PhD ABSTRACT The renin angiotensin aldosterone system (RAAS) has been implicated in the pathogenesis of cerebrovascular diseases. During the past decades, AU: INCLUDE A NUMBER? RAAS has gained attention as an important therapeutic target in cardiovascular medicine. Modulation of the RAAS for primary and secondary stroke prevention seems an appealing strategy. Several experimental studies have showed that pre-treatment with RAAS inhibitors prior to the initiation of ischemia exerts favorable effects on infarct volume, brain edema, and cerebral blood flow in the marginal zone. Furthermore, the activation of angiotensin receptor type 2 has been associated with neuroprotective effects. Accumulating evidence based on recent FOCUS POINTS Current experimental evidence suggests an important role of the renin angiotensin aldosterone system (RAAS) in the pathogenesis of cerebrovascular diseases; its modulation of the RAAS appears to be a potential target for primary and secondary stroke prevention. Experimental studies have showed that blockade of RAAS exerts neuroprotective effects in ischemic stroke animal models. Recent clinical trials indicate that RAAS inhibitors have a potential role in stroke prevention. Future research on the putative pleiotropic effect of RAAS inhibitors (independently of blood pressure lowering) on stroke risk would be welcome. presents experimental data on the neuroprotective actions of RAAS inhibitors and available evidence regarding their effects on stroke risk, and discuss future directions for research. clinical trials indicate that blockade of RAAS has a potential role in stroke prevention. This review summarizes the pathophysiological aspects of brain RAAS and its constituents, INTRODUCTION Current experimental evidence suggests that the renin-angiotensin-aldosterone system Dr. Moutzouri is [TITLE], Dr. Elisaf is professor of medicine, and Dr. Milionis is assistant professor of internal medicine in the Department of Internal Medicine at the University of Ioannina School of Medicine in Greece. Dr. Daios is lecturer of internal medicine at the University of Thessaly School of Medicine in Greece. Faculty Disclosures: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest. Submitted for publication: May 18, 2010; Accepted for publication: August 9, 2010; First published online: November 1, Please direct all correspondence to: Haralampos J. Milionis, MD, PhD, Assistant Professor of Internal Medicine, Department of Internal Medicine, School of Medicine University of Ioannina, Ioannina, Greece; Tel: , Fax: ; CNS Spectr 15:11 619

2 (RAAS) has an important role in the pathophysiology of cerebrovascular diseases. Modulation of the RAAS for primary and secondary stroke prevention seems an appealing strategy. However, there is limited clinical evidence, while current European Stroke Organization (ESO) recommendations do not include RAAS modulation for secondary stroke prevention. 1 The current review summarizes the physiology of brain RAAS and its constituents, and presents animal-model experimental data on the neuroprotective actions of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs). Finally, we present the main clinical trials which investigated the effect of RAAS inhibitors on stroke risk and discuss future directions for research. BRAIN RENIN ANGIOTENSIN ALDOSTERONE SYSTEM Like all other tissue RAAS, brain RAAS is regulated independent from the peripheral RAAS 2,3 ; animal model studies revealed that all RAAS components (angiotensinogen, angiotensin type 1 [AT1R] and 2 receptors [AT2R] and ACE) are synthesized by the endothelium of the cerebral microvasculature and upregulated in spontaneously hypertensive rats (SHRs) (Figure). 4 Besides the well-known actions of angiotensin-ii in the brain (regulation of vasopressin release, sympathetic activation and blood pressure regulation), inappropriate brain RAAS activity has been implicated in the pathogenesis of arterial hypertension, via FIGURE. Circulating and brain renin angiotensin aldosterone system (RAAS) 4 yet not completely identified mechanisms. 5,6 In addition, evidence is accumulating that brain RAAS may be critically involved in the regulation of pathophysiological processes during or after cerebral ischemia via AT1R and AT2R. 7,8 Enhanced endothelial AT1R expression in cerebral micro- and macro-vasculature (middle cerebral artery) in both SHR and spontaneously hypertensive stroke-prone rats (SHRSPs), suggests a pivotal role of RAAS in cerebral ischemia. 8 In transgenic mice expressing both human renin and angiotensinogen genes it has been shown that continuous activation of the brain RAAS leads to cognitive impairment through AT1R activation along with increased oxidative stress and decreased cerebral surface blood flow. 9 Both peripheral and tissue RAAS has been implicated in the modulation of cerebral blood flow (CBF). Angiotensin-II was shown to induce vasoconstriction in cerebral arteries via AT1R and Rho kinase activation pathways. 10 Recently, a novel component of tissue RAAS has been recognized, the (pro)renin receptor. 3 Renin and prorenin bind to this receptor and induce the activation of mitogen-activated protein kinase (MAPK) ERK1 and ERK2 isoforms. 3 This phosphorylation induces the expression of several genes that contribute to target organ damage, like plasminogen activator inhibitor 1 (PAI-1), transforming growth factor β (TGF-β), collagen, and fibrinogen. 3 Experimental studies in rats showed that (pro)renin receptor is widely distributed in the brain (hypothalamus, brainstem, subfornical organ, the supraaortic nucleus, the rostral ventrolateral medulla, the paraventricular nuclei, and the nucleus tractus solitarius) and that this receptor is functional, though the exact actions remain to be elucidated. 11,12 It was also shown that the renin-(pro)renin receptor interaction is of physiological consequence, since it inhibits action potential frequency in neurons. 11 (Pro)renin receptor s activation is not inhibited neither from AT1R antagonists or AT2R antagonists. 12 In addition, (pro)renin receptor mrna was upregulated in SHR compared to wistar Kyoto (WK) rats. 4 (Pro)renin receptor has been suggested to induce neuronal differentiation. 12 Interestingly, human mutation in the (pro)renin receptor gene have been linked with mental retardation, further pointing toward this assumption. 12,13 Moutzouri E, Daios G, Elisaf M, Milionis HJ. CNS Spectr. Vol 15, No GENETIC VARIATION IN THE RAAS AND RISK OF STROKE Among the various sequence variations in CNS Spectr 15:11 620

3 RAAS, the insertion/deletion (I/D) polymorphism in ACE has been studied most widely. 14 ACE has an essential role in the production of angiotensin II and the degradation of bradykinin, thereby affecting vascular tone, endothelial function, and smooth-muscle-cell proliferation. Individuals homozygous for the D allele have an approximately two-fold higher level of circulating enzyme in comparison to individuals homozygous for the I allele. 14 Thus, the I/D polymorphism has become a strong candidate for cardiovascular risk. 14,15 Recently, an analysis of 335 community-dwelling eldersin the MOBILIZE Boston study (Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly of Boston), suggested that the angiotensinogen gene may be involved in vasoreactivity independent of blood pressure. 16 In a meta-analysis of 2,990 predominantly white patients and 11,305 controls, the DD genotype was shown to confer a small but significant risk of ischemic stroke (OR 1.21; 95%, CI ). 17 Since then, the effect of D allele on ischemic stroke has been explored in several studies has been shown to be small and inconsistent Of note, none of the studies was powered to detect a 20% risk increase. 15 Again, the effect of the I/D polymorphism on ischemic stroke subtypes has been investigated in several small studies, but with variable results. 14,15,24 There is evidence that the A1166C polymorphism of the angiotensin II type-1-receptor gene is associated with ischemic stroke. 15 A1166C has been associated with several vascular phenotypes and it seems possible that this polymorphism acts by affecting blood pressure. In one study the association with ischemic stroke was found to be more prominent particularly in hypertensives. 18 The angiotensinogen (AGT) gene has also been evaluated in several studies with conflicting results with statistically significant associations represent chance findings rather than real phenomena. 25 Of interest, it has been reported that the B haplotype of the AGT promoter in the absence of the wild-type A haplotype might represent a genetic susceptibility factor for cerebral small-vessel disease. 26 Further investigation showed that certain mutations in the B-haplotype enhance AGT promoter activity in astrocyte thus suggesting an increased cerebral RAS activity in patients with cerebral small-vessel disease. 27 NEUROPROTECTIVE EFFECTS OF ARBS IN ISCHEMIC STROKE ANIMAL MODELS Treatment With ARBs Before the Onset of Ischemia While the antihypertensive effects of ARBs have mainly been attributed to inhibition of AT1R at the periphery, evidence has accumulated that inhibition of central AT1R may also contribute to the effects of these compounds. Several studies demonstrated that ARBs have neuroprotective effects either as chronic pretreatment or in the setting of acute ischemia (Table 1). In chronic hypertension, peripheral and brain RAAS overdrive induces hypertrophy and hyperplasia of the cerebral vasculature, leading to increased resistance and limited capacity to dilate. 28 This represents a countervailing way to protect the brain microcirculation from high perfusion rates. On the other hand, this impairs the ability of cerebral blood vessels to dilate at low blood pressures. Thus, CBF autoregulation in hypertension is disturbed. 28 During brain ischemia, in addition to the abovementioned hypertensive changes in blood vessels, CBF autoregulation is altered as well. 28 In most experimental studies the ARB used was candesartan, since it has been shown to inhibit central angiotensin II receptors more effectively compared to other ARBs. 29,30 In both SHR and normotensive rats subjected to middle cerebral artery occlusion (MCAO), chronic pretreatment with candesartan has been associated with significant reductions in infarct volume, brain edema, as well as improved neurological outcome. 31,32 On the contrary, in one study acute pretreatment was not associated with improved outcome, even though blood pressure reduction was of the same extent. 32 A large number of experimental studies showed that in hypertension ARBs and ACEIs do not influence baseline CBF but shift the autoregulation curve toward lower blood pressures, thus normalizing altered CBF autoregulation curve. 28 An early study showed that pretreatment with candesartan normalized the CBF response, in terms of preventing CBF reduction in the marginal zone of ischemia. 31 This phenomenon is mediated by the effect of candesartan on NO synthetases (NOS). Three NOS isoforms are identified, the neuronal (nnos), the endothelial (enos) and the inducible calcium-independent (inos) isoform. It has been postulated that nnos pro- CNS Spectr 15:11 621

4 motes ischemic damage. Specifically, enos has been shown to be neuroprotective while inos and nnos cytotoxic in experimental models of ischemia. It has been proven, that during early stages of ischemia, enos expression is upregulated and peaks after 10 minutes, while in later stages there nnos synthesis is increased. 33 It was shown that in SHR there was decreased enos and increased inos protein and mrna in common carotid artery, in principal arteries in the circle of Willis and brain microvessels. Longterm pretreatment with candesartan completely reverses all the above mentioned alterations and restores enos/nnos ratio. 34 Moreover, following candesartan treatment, pathological vascular hypertrophy of cerebral microvasculature, MCA and carotid artery is reversed, and therefore brain is less vulnerable to brain ischemia and stroke in chronic hypertension. 35 Subsequent studies in normotensive rats TABLE 1. Experimental Studies With ARBs Before the Initiation of Ischemia Study Animal Intervention Therapy Results Ito et al 39 SHRSP None AT1R antagonist TCV- 116 for 2 weeks (a nonhypotensive dose) Groth et al 32 Male normotensive rats 90 min MCAO with reperfusion Ito et al 36 SHR Permanent MCAO Candesartan IV 0.1 or 0.3 mg/kg 4 hours prior to MCAO Candesartan 0.2 mg/kg SC 5 days prior to MCAO Candesartan 0.1 or 0.3/ kg/day Nicardipine 0.1 mg/kg/ day Captopril 3 mg/kg/day SC for 3 or 28 days Zhou et SHR None Candesartan 0.3 mg/kg/ al 38 day SC for 4 weeks Forder et al 42 Nishimura et al 31 Adult male Sprague- Daley rats SHR and WK control rats Cauterization of cortical surface vessels 1 or 2 hous MCAO with reperfusion Losartan 50 mg/day PO for 2 weeks prior to ischemia Candesartan 0.5 mg/kg/ day for 3 or 14 days Reduction in ICAM-1 and fibrinogen expression in endothelial cells of cerebral microvessels Increase in GLUT-1 expression Both treatments reduced CBF in the zone of ischemia below 20% of baseline with the same BP reduction. Candesartan for 5 days prior to MCAO improved neurological outcome, reduced total volume of ischemic injury by 47% (versus vehicle treated group) and reduced edema in the ipsilateral hemisphere by 33% (versus vehicle treated group). Treatment with candesartan for 28 days reduced infarct area by 31%, increased MCA external diameter by 16%, reduced MCA media thickness by 23%. Captopril reduced infarct area by 25%. Nicardipine had no effect. Candesartan reduced macrophage infiltration, TNFα, IL1-β mrna and Nf-kB in cerebral microvessels and the transcription of HSP 60, 70, 90 and heat shock factor 1. Pretreated rats had significantly reduced average infarct size (0.40%±0.16 versus 2.91%±0.54 for pretreated and untreated rats, respectively), significantly increased vessel density and increased average vessel size. Candesartan pretreatment shifted both the upper and lower limit of cerebrovascular autoregulation toward lower blood pressures. Pretreatment for 14 days prevented the decrease of CBF in the marginal zone of ischemia, reduced the volume of total and cortical infarcts (58% and 64% compared with controls, at 1 hour reperfusion) and reduced brain edema after 2 hours of MCAO. ARBs=angiotensin receptor blockers; SHRSP=spontaneously hypertensive rats, stroke prone; AT1R=angiotensin II type 1 receptor; ICAM-1=intercellular adhesion molecule 1; GLUT-1=glucose transporter 1; MCAO=middle cerebral artery occlusion; CBF=cerebral blood flow; BP=blood pressure; SHR=spontaneously hypertensive rats; MCA=middle cerebral artery; TNF-α=tumor necrosis factor α; IL1-β=interleukin 1 β; HSP=heat shock protein; WK=wistar Kyoto. Moutzouri E, Daios G, Elisaf M, Milionis HJ. CNS Spectr. Vol 15, No CNS Spectr 15:11 622

5 compared the effects of candesartan, captopril, and nicardipine as acute (3 days) or chronic (28 days) pretreatment prior to MCAO. Infarct area reduction, brain edema, CBF alterations in the peripheral area of ischemia and MCA external diameter and media thickness were assessed. Chronic pretreatment with candesartan and captopril was associated with marked reduction of the infarct area compared to nifedipine. Chronic candesartan pretreatment also reduced brain edema, increased MCA diameter, decreased MCA media thickness and produced smaller CBF decreases in the peripheral area. 36 This beneficial effect of candesartan on MCA media thickness is similar to the effect of telmisartan on carotid intima-media thickness, although concern was raised whether this stands for a class affect of ARBs. 37 Interestingly, both captopril and nifedipine decreased CBF in the periphery, suggesting that candesartan-induced neuroprotection may involve other pathways too. Several studies showed that the normalization of CBF autoregulation curve and the hemodynamic effects of RAAS blockers are not the only pathophysiologic mechanisms which mediate their putative neuroprotection. 8 Anti-inflammatory, antiapoptotic, and antioxidant properties have also been demonstrated. In particular, AT1 receptor has been shown to be upregulated in macrophages in SHRSP compared to controls. 8 Following candesartan treatment in SHR, intercellular adhesion molecule 1 (ICAM-1) expression and perivascular macrophage infiltration is decreased in cerebral microvessels and carotid artery of SHR. 35 In SHR, 4 weeks treatment with candesartan decreases the macrophage infiltration, the expression of tumour necrosis factor a (TNFa), Il-beta, Nf-KB and heat shock protein (HSP) genes in cerebral microvessels (HSP 60, 70, 90, and heat shock factor-1); the latter were shown to be upregulated in SHR versus normotensive controls. 38 In SHRSP treated for 2 weeks with an ARB, brain edema was prevented in a BP-independent manner, and fibrinogen and ICAM-1 expression in cerebral microvessels were reduced. 39 Angiotensin II has been implicated in the angiogenic process, mainly through AT1R activation pathway. 40,41 Administration of losartan for 2 weeks before initiation of ischemia in rats was associated with decreased infarct size and increased angiogenesis (increased collateralization) as revealed by morphological examination. 42 Hence, it seems that this may represent another therapeutic effect of ARBs during ischemia. 42,43 Treatment with ARBs After the Onset of Ischemia Data concerning the neurologic effects of blocking the RAAS after the onset of brain ischemia are limited and inconclusive. In one experimental study, candesartan subcutaneous infusions at a low- and a high-dose were administered in a normotensive mice-model, initiated 3 or 24 hours after onset of MCAO and continued for 7 days. Mean systolic and diastolic blood pressure were markedly and rapidly reduced with the high dose and moderately reduced with the low-dose during the follow up period of 4 hours. Only the lowand early-dose succeeded to reduce infarct size and brain edema. Neurological outcomes were better only with the early-onset treatment, with a slightly better outcome in the low-dose treatment group. The high-dose candesartan induced greater blood pressure reductions, which may account for the lack of beneficial effects. As a result of acute treatment, candesartan failed to induce a shift of the cerebrovascular autoregulation curve towards lower blood pressures and consequently, to maintain an adequate cerebral perfusion during marked blood pressure reductions. 44 A shift in the autoregulation curve could only be observed after pretreatment with candesartan lasting 7 and 14 days (Table 2). 31 However, other groups have demonstrated that candesartan administration within 24 hours and for 7 days after MCAO, improved neurological outcome and reduced infarct volume. 45 In normotensive rats subjected to MCAO, candesartan treatment after reperfusion was associated with neurovascular protection. Under these experimental conditions mean arterial pressure (MAP) during MCAO is markedly increased. In the candesartan group MAP returned in pre-stroke values. The candesartan treated animals showed reduced infarct volumes and edema as well as improved neurological scores. 46 The same experimental conditions for stroke induction were used in SHR treated with candesartan at reperfusion. Candesartan reduced mean arterial pressure in a dose dependent manner with a drop below baseline with the high-dose candesartan. Infarct size and edema formation were reduced only with candesartan at lower doses, suggesting that neuroprotection is also dose-dependent. 47 CNS Spectr 15:11 623

6 ARBS VERSUS ACEIS IN ISCHEMIC STROKE ANIMAL MODELS Compared with ARBs, there is less experimental evidence on ACEIs for neuroprotection in experimental stroke. 48,49 The neuroprotective effect of candesartan was compared with that of ramipril at doses that provided equal antihypertensive effects. 50 SHR were treated with both for 4 weeks and subjected to MCAO without reperfusion. Infarct volume and neurologic deficits were assessed. At low doses (with BP reductions: mmhg) there was no effect on infarct volume or neurologic deficit with neither treatment. At higher doses (with BP reduction: mmhg to normotensive levels) both drugs significantly reduced infarct size compared to normotensive rats. At medium doses (with BP reduction: 40 mmhg) only candesartan significantly reduced infarct size and improved neurologic function. 50 Systemic pretreatment with candesartan or enalapril for 10 days (two doses: a non-hypotensive and a hypotensive) was examined in rats after MCAO without reperfusion. Ischemic area, neurologic deficit, cerebral blood flow, superoxide production, AT1R and AT2R expression were determined. 51 Enalapril did not affect either infarct volume or neurologic deficit, whereas candesartan at both doses improved both. Candesartan improved the CBF reduction in the periphery region, whereas enalapril did not. Candesartan reduced superoxide production, which is known to increase in stroke, 52 at both the cerebral cortex and arterial wall, and decreased NADPH oxidase activity while enalapril produced no effect. The reduction of ischemic area by candesartan was dose dependent and mediated via inhibition of oxidative stress. 51 In another study, normotensive rats were pretreated for 5 days with equipotent doses of candesartan and ramipril. MCAO with reperfusion was induced and infarct size and neurological outcome were assessed. The non-hypotensive dose of candesartan reduced infarct volume and attenuated brain edema, whereas both hypotensive and non- TABLE 2. Experimental Studies With ARBs Before the Initiation of Ischemia Study Animals Intervention Treatment Results Fagan Male WK rats 3-hour et al 46 MCAO with reperfusion Brdon et al 44 Engelhorn et al 45 Normotensive rats 90-minute MCAO with reperfusion 1-hour MCAO with reperfusion Kozak SHR 3-hour et al 47 MCAO with reperfusion Candesartan 1 mg/kg IV at reperfusion Candesartan 0.3 or 3 mg/ kg/day 3 or 24 hours after reperfusion and continued for 7 days Candesartan 0.5 mg/kg IV 2 hours prior to MCAO 24 hours after MCAO 2 hours before and every 24 hours after MCAO Candesartan 0.1, 0.3, and 1 mg/kg at reperfusion Candesartan treatment reduced BP, infarct size (59% versus 38%; P=.01, for treated rats and controls respectively), reduced brain edema (17.97 versus 11.33%; P<.001, for treated rats and controls, respectively), reduced hemoglobin content and improved neurological outcome. Candesartan administration at 3 hours improved neurological outcome, candesartan 0.3 mg/kg at 3 hours reduced infarct area by 57%, and brain edema. Candesartan 3 mg/kg and candesartan at 24 hours had no effect on infarct volume or brain edema. All treatments reduced infarct size. Only candesartan after MCAO improved neurological score Candesartan reduced MAP in a dose dependent manner. Candesartan 1 mg/kg reduced MAP below baseline. Candesartan 0.1 and 0.3 mg/kg improved neurological score. WK=wistar Kyoto; MCAO=middle cerebral artery occlusion; BP=blood pressure; SHR=spontaneously hypertensive rats. Moutzouri E, Daios G, Elisaf M, Milionis HJ. CNS Spectr. Vol 15, No CNS Spectr 15:11 624

7 hypotensive doses of candesartan did not result in such an effect. The neurological outcome was also better with candesartan treatment. 53 In another experimental study, SHRSP were treated for 4 weeks with either an ARB (TCV-116) or an ACEI (captopril). 54 Expression of ICAM-1, GLUT-1 in endothelial cells of brain microvessels were determined. The AT1 R antagonist and captopril both ameliorated the expression of ICAM-1 and the expression of adhesion molecules on leucocytes, with the ARB being more effective. 54 AT2 RECEPTOR STIMULATION IN THE BRAIN Experimental data suggests that angiotensin II may have a cerebroprotective effect, mediated not only via AT1R but also via AT2R. It has been postulated that relative stimulation of AT2R signalling from increased levels of angiotensin II following ARB treatment could have a therapeutic advantage and may in part account for the above mentioned protective effects of ARBs in preventing neurological damage after stroke. AT2R actions in the brain remain unclear. AT2R is expressed not only in vessels wall, but also neuronally expressed in the thalamus, hypothalamus and specific brainstem nuclei, 55,56 as well as in motor and learning-associated areas. 57 In addition, AT2R are re-expressed in certain pathological conditions, such as neuronal injury and vascular injury. 58,59 AT2R stimulation promotes axonal regeneration in the optic nerve 60 and cell differentiation and regeneration in neuronal tissues. 61 AT2R has also been implicated in brain developmental processes; the AT2R gene in X chromosome have been linked with mental retardation in humans. 62,63 In mice subjected to MCAO without reperfusion, AT2R mrna level at 24 hours after MCAO was significantly increased in the ischemic area compared to non ischemic area, whereas AT1R expression was not significantly increased indicating that AT2R may have a pivotal role after brain ischemia. 61 Apart from their documented vasodilator activity, AT2R seems to have also neuroprotective effects. In AT2R deficient mice (-/-) subjected to MCAO, ischemic area, neurologic deficit and cerebral blood flow reduction in the periphery of the ischemic area was larger compared to controls. 64 AT2 R (-/-) mice also showed increased levels of NAPDH oxidase and superoxide production. In addition, pretreatment with valsartan at a non-hypotensive dose for 5 days prevented the neurological damage in control mice but not completely in AT2R (-/-) mice. Thus, AT2R may possess neuroprotective effects and is implicated in oxidative stress following ischemic injury and modulation of CBF. This study, as well as others, suggests that AT2R stimulation by unbound angiotensin II caused by AT1R blockade is involved in ARBs protective actions. 50,51,64-66 Treatment with an ARB has also been shown to upregulate AT2R expression in ischemic areas as well as in cerebral circulation in SHR. 4,50,51 Further evidence for the neuroprotective potential of AT2R are provided by the observation that administration of an AT2R antagonist (PD123319) almost completely attenuated the neuroprotective effects observed with candesartan pretreatment for 4 weeks in SHR subjected to MCAO. 50 AT2R (-/-) mice demonstrate greater impairment of cognitive function after focal ischemia. In vitro and in vivo studies showed that AT2R provide neural protection and preservation of cognitive function through methyl methanesulfonate sensitive 2, an enzyme suggested to play pivotal role in DNA repairing. 61 Stimulation of AT2R has also been shown to decrease the expression of NADPH oxidase subunit 67 and hence reduces oxidative stress, which is known to be enhanced in brain ischemia. 52,64 Recently the direct stimulation of central AT2R has been evaluated in stroke rat-models. 68 SHR were treated for 5 days with centrally administered AT2R agonist and then subjected to focal cerebral ischemia with reperfusion. Infarct volume and neurologic deficit were evaluated after 72 hours. The results clearly indicated a neuroprotective effect of the AT2R agonist, since the treated animals had reduced infarct volumes, reduction in oxidative stress and improved neurologic deficit. These effects were dose- related, BP independent and inhibited by co-treatment with an AT2R antagonist. CLINICAL TRIALS ON THE ROLE OF RAAS INHIBITORS IN PRIMARY AND SECONDARY STROKE PREVENTION Accumulating evidence based on recent clinical trials indicate that blockade of RAAS has a potential role in stroke prevention. Current data regarding the ideal antihypertensive drug regimen for primary stroke prevention are inconclusive and more carefully designed large clinical trials are needed for safe conclusions to be extracted. In CNS Spectr 15:11 625

8 addition, prevention of cognitive decline or even improvement of slightly diminished brain function could be a treatment goal for antihypertensive treatment in the future. Some clinical data suggest advantages for ACE inhibitors, ARBs, and calcium channel antagonists. On the basis of available data, national authorities report that for primary stroke prevention all major classes of antihypertensive drugs are effective. 69,70 In the Losartan Intervention For Endpoint trial (LIFE), 9,193 hypertensive patients were randomized to once daily atenolol or losartan with a mean follow-up of 4.8 years. No significant differences in BP measurements were reported between the 2 groups. 71 Losartan reduced fatal and non-fatal stroke incidence by 25% compared to atenolol in patients with essential hypertension and left ventricular hypertrophy. 71 However, it could not be determined whether this reduction reflected only the positive effects of losartan or whether negative vascular effects of atenolol contributed. The Heart Outcomes Prevention Evaluation (HOPE) trial had already shown that ramipril protects high risk patients against stroke in a blood pressure independent manner. 72 In the Valsartan Antihypertensive Long term Use Evaluation (VALUE) trial that compared amlodipine or valsartan treatment regimens in hypertensives patients at high cardiovascular risk, stroke incidence was not different between the amlodipine and valsartan group. 73 However, there were only small differences in both systolic and diastolic blood pressure between treatment arms, whereas amlodipine achieved blood pressure control within a shorter time interval compared to valsartan. The Study on Cognition and Prognosis in the elderly (SCOPE) demonstrated a significant risk reduction in non-fatal stroke rate (27.8%) in elderly patients treated with candesartan compared to controls. 74 Blood pressure reduction was of slightly greater magnitude in the candesartan group, but it is not clear whether only this difference accounts for the observed stroke reduction. 74 Regarding secondary stroke prevention, large randomized trials have failed to demonstrate a favorable effect of RAAS blocking agents compared with other antihypertensive drug regimens. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) enrolled patients with a history of stroke or transient ischemic attack within the previous 5 years. 75 Patients were randomized to perindopril, perindopril/indapamide, or placebo. Blood pressure reductions were equal at the end of the study. PROGRESS showed that the combination of perindopril/indapamide resulted in significant stroke risk reduction compared. In contrast, perindopril did not significantly reduce stroke recurrence compared to placebo. The effect of perindopril/indapamide in the PROGRESS was similar regardless if patients were hypertensive at baseline. 75 In the Telmisartan to Prevent Recurrent Stroke and Cardiovascular Events (PRoFESS) study, ischemic stroke patients were randomized at a median interval of 15 days after the event to receive telmisartan or placebo. 76 After a mean follow up of 2.5 years, telmisartan did not significantly reduce stroke recurrence compared to placebo. 76 However, a post-hoc analysis of PRoFESS showed that after the first 6 months, patients in the telmisartan treated group had a lower rate of recurrent stroke compared to placebo, 76 which suggests that if follow-up was longer, statistically significant results might have been demonstrated. The Evaluation of Acute Candesartan Cilexitil Therapy in Stroke Survivors (ACCESS) study, a phase II trial, tested the safety and efficacy of candesartan started at day 1 after stroke with a target blood pressure reduction of 10% to 15% within 24 hours. 77 During the placebo controlled phase of 7 days, there were no significant differences in blood pressure among groups. At day 7, control patients switched to candesartan (if previously hypertensives) or remained without antihypertensive treatment (if previously normotensives). Blood pressure control was similar during the follow up period of 12 months. ACCESS was prematurely interrupted due to a favorable effect in total vascular events and the cumulative 12 month mortality in favor of candesartan. Hence, ACCESS concluded that treatment with an ARB in the acute post-stroke period is safe and has a favourable BP independent effect. 77 The Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) study demonstrated that in hypertensive stroke patients eprosartan based treatment produced a significant lower total cerebrovascular events as compared with nitrendipine-based regimen. 78 The mean follow up was of 2.5 years and the mean interval from prior stroke was 24 months. Blood pressure normalization was achieved early in both groups, with insignificant differences among them. 78 Recently, the Nateglinide and Valsartan in Impaired Glucose CNS Spectr 15:11 626

9 Tolerance Outcomes Research trial (NAVIGATOR) assessed the effect of valsartan on cardiovascular risk in patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors. After a follow up of 6.5 years, valsartan did not reduce the rate of fatal and nonfatal stroke compared to placebo. 79 In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), telmisartan, ramipril, and their combination were equivalent in the reduction of fatal and nonfatal stroke in patients with coronary, peripheral, or cerebrovascular disease or diabetes with endorgan damage. 80 The Blood Pressure Lowering Treatment Trialists collaboration suggested that a treatment regimen based on a calcium channel blocker may be more effective in reducing stroke compared with β-blockers and diuretics or ACEIs, while β- blockers and diuretics tended to be more effective than ACEIs. 81 In another meta-analysis, the magnitude of blood pressure reduction was a major predictor of the size of the reductions in major cardiovascular events; it was also concluded that there is no blood pressure independent effect on stroke risk reduction with neither ACEIs nor ARBs. 82 Recently, it was shown that ARBs result in a small but statistically significant stroke risk reduction compared to ACEIs, which seems to be a class-effect. However, authors could not determine whether this effect was mediated by a possibly greater blood pressure reduction achieved with ARBs. 83 It was also shown that drugs which raise angiotensin II levels (thiazide diuretics, ARBs, calcium channel antagonists) may confer significant protection against stroke compared to drugs which decrease angiotensin II levels (ACEIs, β-blockers, and long acting non-dihydropyridine calcium antagonists), independently of their blood pressure lowering effects. 84 Similarly, a large recently published meta-analysis suggested that in the prevention of major cardiovascular events there are no blood pressure-independent effects between different antihypertensive regimens, and that the most important factor is the degree of blood pressure reduction. 85 BLOOD PRESSURE MANAGEMENT IN ACUTE ISCHEMIC STROKE There is wide controversy regarding the proper blood pressure management in the acute ischemic stroke. 86 The results of observational and intervention studies on blood pressure during acute stroke have been inconsistent, which also reflects to the level of evidence of current guidelines. ESO recommends cautious antihypertensive treatment at blood pressure levels >220/120 mmhg, or >185/100 mmhg in patients receiving thombolysis (class IV). 1 Similar recommendations are provided by the American Heart Association/ American Stroke Association (AHA/ASA), 87 the Japanese Stroke Society, 88 and the National Stroke Foundation in Australia. 89 Regarding the choice of the antihypertensive regimen, there is no direct recommendation and it is suggested that the treating physician should decide on a case-by-case basis. 87 FURTHER DIRECTIONS OF RESEARCH Given the presence of a local RAAS in the brain which may have a pivotal role in the pathophysiology of arterial hypertension and brain ischemia, studies that would offer further insight on a putative pleiotropic (blood pressure independent) effect of RAAS inhibitors on stroke risk would be welcome. Such an effect of ARBs was identified in experimental studies; however, the ideal length of treatment and the extent to which central AT1R are (or should be) inhibited remain questionable. Regarding AT2R, their stimulation may represent a potential target for stroke prevention and management, but further research is needed to clarify the signal transduction pathways and the underlying molecular mechanisms. Finally, further clarification of the pathophysiology of brain ischemia will provide tools to protect the ischemic cerebral tissue. In this aspect, special emphasis should be given to the exact time-dependent modulations in oxidative stress and NO modulation during acute ischemia, as well as the expression, localization, and interactions of angiotensin receptors. CONCLUSION During the past decades RAAS has rapidly gained attention as an important therapeutic target in cardiovascular medicine. Recent advances in basic research provide evidence that RAAS is far more complicated than once believed. The advent of tissue RAAS and the recently discovered (pro)renin receptor as well as the interaction of RAAS with other systems are of particular interest and current research aims to elucidate their exact functions and clinical relevance. Treatment of hypertension is of paramount importance for the prevention of stroke. In an CNS Spectr 15:11 627

10 analysis estimating the reduction in stroke risk with the hypertensive medications, which included nearly 270,000 hypertensive patients in 60 clinical trials, all medications were significantly better than placebo (OR 1.56, 95% CI: ) for reducing the risk of stroke. Diuretics and calcium-channel blockers were slightly more protective than ARBs (OR 1.10, 95% CI: ) but were significantly better than ACEIs (OR 1.17, 95% CI: ) and β-blockers (OR 1.22, 95% CI: ). 90 Hypertension is considered not only the most important risk factor for stroke, but 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 ACEIs, ARBs, and calcium channel antagonists. However, currently the existing data are not sufficient for clinical recommendations. 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