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

Size: px
Start display at page:

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

Transcription

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: ; hmilioni@uoi.gr. 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. Therefore, ongoing trials will further define the exact role of RAAS inhibitors and are urgently needed in secondary prevention, acute stroke, and prevention of cognitive decline. It is becoming evident that normal cardiovascular homeostasis is a result of a balance between the activities of the vasoconstrictive, hypertrophic, proliferative, fibrotic, and the vasoprotective axes of the RAAS. It is thus reasonable to suggest that the vasoprotective axis offers a novel target for the devolvement of improved therapy for stroke prevention. CNS REFERENCES 1. Guidelines for management of ischaemic stroke and transient ischaemic attack Cerebrovasc Dis. 2008;25(5): Dzau VJ, Re R. Tissue angiotensin system in cardiovascular medicine. A paradigm shift? Circulation. 1994;89(1): Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/ prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002;109(11): Zhou J, Pavel J, Macova M, et al. AT1 receptor blockade regulates the local angiotensin II system in cerebral microvessels from spontaneously hypertensive rats. Stroke. 2006;37(5): Veerasingham SJ, Raizada MK. Brain renin-angiotensin system dysfunction in hypertension: recent advances and perspectives. Br J Pharmacol. 2003;139(2): Gyurko R, Wielbo D, Phillips MI. Antisense inhibition of AT1 receptor mrna and angiotensinogen mrna in the brain of spontaneously hypertensive rats reduces hypertension of neurogenic origin. Regul Pept. 1993;49(2): Culman J, Blume A, Gohlke P, Unger T. The renin-angiotensin system in the brain: possible therapeutic implications for AT(1)-receptor blockers. J Hum Hypertens. 2002;16(Suppl 3): Ito H, Takemori K, Suzuki T. Role of angiotensin II type 1 receptor in the leucocytes and endothelial cells of brain microvessels in the pathogenesis of hypertensive cerebral injury. J Hypertens. 2001;19(3 Pt 2): Inaba S, Iwai M, Furuno M, et al. Continuous activation of renin-angiotensin system impairs cognitive function in renin/angiotensinogen transgenic mice. Hypertension. 2009;53(2): Faraci FM, Lamping KG, Modrick ML, et al. Cerebral vascular effects of angiotensin II: new insights from genetic models. J Cereb Blood Flow Metab. 2006;26(4): Shan Z, Cuadra AE, Sumners C, Raizada MK. Characterization of a functional (pro)renin receptor in rat brain neurons. Exp Physiol. 2008;93(5): Contrepas A, Walker J, Koulakoff A, et al. A role of the (pro)renin receptor in neuronal cell differentiation. Am J Physiol Regul Integr Comp Physiol. 2009;297(2):R Ramser J, Abidi FE, Burckle CA, et al. A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. Hum Mol Genet. 2005;14(8): Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC. ACE polymorphisms. Circ Res. 2006;98(9): Dichgans M. Genetics of ischaemic stroke. Lancet Neurol. 2007;6(2): Hajjar I, Sorond F, Hsu YH, Galica A, Cupples LA, Lipsitz LA. Renin angiotensin system gene polymorphisms and cerebral blood flow regulation: the MOBILIZE Boston study. Stroke. 2010;41(4): Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004;61(11): Brenner D, Labreuche J, Poirier O, Cambien F, Amarenco P. Renin-angiotensin-aldosterone system in brain infarction and vascular death. Ann Neurol. 2005;58(1): Rubattu S, Di Angelantonio E, Stanzione R, et al. Gene polymorphisms of the reninangiotensin-aldosterone system and the risk of ischemic stroke: a role of the A1166C/ AT1 gene variant. J Hypertens. 2004;22(11): Tuncer N, Tuglular S, Kilic G, Sazci A, Us O, Kara I. Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke. J Clin Neurosci. 2006;13(2): Munshi A, Sultana S, Kaul S, Reddy BP, Alladi S, Jyothy A. Angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischemic stroke in a South Indian population. J Neurol Sci. 2008;272(1-2): Pera J, Slowik A, Dziedzic T, Wloch D, Szczudlik A. ACE I/D polymorphism in different etiologies of ischemic stroke. Acta Neurol Scand. 2006;114(5): Mollsten A, Stegmayr B, Wiklund PG. Genetic polymorphisms in the renin-angiotensin system confer increased risk of stroke independently of blood pressure: a nested casecontrol study. J Hypertens. 2008;26(7): Tascilar N, Dursun A, Ankarali H, Mungan G, Ekem S, Baris S. Angiotensin-converting enzyme insertion/deletion polymorphism has no effect on the risk of atherosclerotic stroke or hypertension. J Neurol Sci. 2009;285(1-2): Sethi AA, Tybjaerg-Hansen A, Gronholdt ML, Steffensen R, Schnohr P, Nordestgaard BG. Angiotensinogen mutations and risk for ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease. Six case-control studies from the Copenhagen City Heart Study. Ann Intern Med. 2001;134(10): Schmidt H, Fazekas F, Kostner GM, van Duijn CM, Schmidt R. Angiotensinogen gene promoter haplotype and microangiopathy-related cerebral damage: results of the Austrian Stroke Prevention Study. Stroke. 2001;32(2): Schmidt H, Aulchenko YS, Schweighofer N, et al. Angiotensinogen promoter B-haplotype associated with cerebral small vessel disease enhances basal transcriptional activity. Stroke. 2004;35(11): Saavedra JM, Nishimura Y. Angiotensin and cerebral blood flow. Cell Mol Neurobiol. 1999;19(5): Gohlke P, Von Kugelgen S, Jurgensen T, et al. Effects of orally applied candesartan cilexetil on central responses to angiotensin II in conscious rats. J Hypertens. 2002;20(5): Nishimura Y, Ito T, Hoe K, Saavedra JM. Chronic peripheral administration of the angiotensin II AT(1) receptor antagonist candesartan blocks brain AT(1) receptors. Brain Res. 2000;871(1): 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): Groth W, Blume A, Gohlke P, Unger T, Culman J. Chronic pretreatment with candesartan improves recovery from focal cerebral ischaemia in rats. J Hypertens. 2003;21(11): Wei G, Dawson VL, Zweier JL. Role of neuronal and endothelial nitric oxide synthase in nitric oxide generation in the brain following cerebral ischemia. Biochem Biophys Acta. 1999;1455(1): Yamakawa H, Jezova M, Ando H, Saavedra JM. Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J Cereb Blood Flow Metab. 2003;23(3): Ando H, Zhou J, Macova M, Imboden H, Saavedra JM. Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats. Stroke. 2004;35(7): Ito T, Yamakawa H, Bregonzio C, Terron JA, Falcon-Neri A, Saavedra JM. 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): Ntaios G, Savopoulos C, Hatzitolios A. Telmisartan and carotid intima-media thickness regression: a class effect of angiotensin-receptor blockers? Hypertens Res. 2008;31(12): , author reply Zhou J, Ando H, Macova M, Dou J, Saavedra JM. Angiotensin II AT1 receptor blockade abolishes brain microvascular inflammation and heat shock protein responses in hypertensive rats. J Cereb Blood Flow Metab. 2005;25(7): Ito H, Takemori K, Kawai J, Suzuki T. AT1 receptor antagonist prevents brain edema without lowering blood pressure. Acta Neurochir Suppl. 2000;76( CNS Spectr 15:11 628

11 40. Tamarat R, Silvestre JS, Durie M, Levy BI. Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. Lab Invest. 2002;82(6): Silvestre JS, Levy BI. [The renin-angiotensin system and post-ischemic angiogenesis]. Bull Acad Natl Med. 2004;188(4): ; discussion Forder JP, Munzenmaier DH, Greene AS. Angiogenic protection from focal ischemia with angiotensin II type 1 receptor blockade in the rat. Am J Physiol Heart Circ Physiol. 2005;288(4):H Munzenmaier DH, Greene AS. Chronic angiotensin II AT1 receptor blockade increases cerebral cortical microvessel density. Am J Physiol Heart Circ Physiol. 2006;290(2): H Brdon J, Kaiser S, Hagemann F, Zhao Y, Culman J, Gohlke P. Comparison between early and delayed systemic treatment with candesartan of rats after ischaemic stroke. J Hypertens. 2007;25(1): Engelhorn T, Goerike S, Doerfler 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 Cereb Blood Flow Metab. 2004;24(4): Fagan SC, Kozak A, Hill WD, et al. Hypertension after experimental cerebral ischemia: candesartan provides neurovascular protection. J Hypertens. 2006;24(3): 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(3): Werner C, Hoffman WE, Kochs E, Rabito SF, Miletich DJ. Captopril improves neurologic outcome from incomplete cerebral ischemia in rats. Stroke. 1991;22(7): Sadoshima S, Fujii K, Ooboshi H, Ibayashi S, Fujishima M. Angiotensin converting enzyme inhibitors attenuate ischemic brain metabolism in hypertensive rats. Stroke. 1993;24(10): ; discussion Lu Q, Zhu YZ, Wong PT. Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats. Neuroreport. 2005;16(17): Hamai M, Iwai M, Ide A, et al. Comparison of inhibitory action of candesartan and enalapril on brain ischemia through inhibition of oxidative stress. Neuropharmacology. 2006;51(4): Sugawara T, Chan PH. Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal. 2003;5(5): Krikov M, Thone-Reineke C, Muller S, Villringer A, Unger T. Candesartan but not ramipril pretreatment improves outcome after stroke and stimulates neurotrophin BNDF/TrkB system in rats. J Hypertens. 2008;26(3): Takemori K, Ito H, Suzuki T. Effects of the AT1 receptor antagonist on adhesion molecule expression in leukocytes and brain microvessels of stroke-prone spontaneously hypertensive rats. Am J Hypertens. 2000;13(11): Li J, Culman J, Hortnagl H, et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. Faseb J. 2005;19(6): Hauser W, Johren O, Saavedra JM. Characterization and distribution of angiotensin II receptor subtypes in the mouse brain. Eur J Pharmacol. 1998;348(1): 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):R 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): Gallinat S, Yu M, Dorst A, Unger T, Herdegen T. Sciatic nerve transection evokes lasting up-regulation of angiotensin AT2 and AT1 receptor mrna in adult rat dorsal root ganglia and sciatic nerves. Brain Res Mol Brain Res. 1998;57(1): Lucius R, Gallinat S, Rosenstiel P, Herdegen T, Sievers J, Unger T. The angiotensin II type 2 (AT2) receptor promotes axonal regeneration in the optic nerve of adult rats. J Exp Med. 1998;188(4): Mogi M, Li JM, Iwanami J, et al. Angiotensin II type-2 receptor stimulation prevents neural damage by transcriptional activation of methyl methanesulfonate sensitive 2. Hypertension. 2006;48(1): Vervoort VS, Beachem MA, Edwards PS, et al. AGTR2 mutations in X-linked mental retardation. Science. 2002;296(5577): Vervoort VS, Guzauskas G, Archie J, Schwartz CE, Stevenson RE, Srivastava AK. AGTR2 in brain development and function. Am J Med Genet A. 2006;140(5): 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): Wu L, Iwai M, Nakagami H, et al. Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury. Circulation. 2001;104(22): Cosentino F, Savoia C, De Paolis P, et al. Angiotensin II type 2 receptors contribute to vascular responses in spontaneously hypertensive rats treated with angiotensin II type 1 receptor antagonists. Am J Hypertens. 2005;18(4 Pt 1): Chabrashvili T, Kitiyakara C, Blau J, et al. Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression. Am J Physiol Regul Integr Comp Physiol. 2003;285(1):R McCarthy CA, Vinh A, Callaway JK, Widdop RE. Angiotensin AT2 receptor stimulation causes neuroprotection in a conscious rat model of stroke. Stroke. 2009;40(4): Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2000;356(9246): Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(2): Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359(9311): Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3): 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 randomised trial. Lancet. 2004;363(9426): Lithell H, Hansson 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(5): Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287): Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359(12): Schrader J, Luders S, Kulschewski A, et al. The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke. 2003;34(7): Schrader J, Luders S, Kulschewski A, et al. Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. 2005;36(6): NAVIGATOR Study Group, Holman RR, Haffner SM, McMurray JJ, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362(16): Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15): Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362(9395): Turnbull F, Neal B, Pfeffer M, et al. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25(5): Reboldi G, Angeli F, Cavallini C, et al. Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis. J Hypertens. 2008;26(7): Boutitie F, Oprisiu R, Achard JM, et al. Does a change in angiotensin II formation caused by antihypertensive drugs affect the risk of stroke? A meta-analysis of trials according to treatment with potentially different effects on angiotensin II. J Hypertens. 2007;25(8): Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338(b Ntaios G, Bath P, Michel P. Blood pressure treatment in acute ischemic stroke: a review of studies and recommendations. Curr Opin Neurol. 2010;23(1): Adams HP Jr., del Zoppo G, Alberts 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: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38(5): Shinohara Y, Yamaguchi T. Outline of the Japanese Guidelines for the Management of Stroke 2004 and subsequent revision. Int J Stroke. 2008;3(1): Hill K. Australian Clinical Guidelines for Acute Stroke Management Int J Stroke. 2008;3(2): Network Meta-Analysis: Risk of stroke Elliott W. American Society of Hypertension 2009 Scientific Meeting; May 6, 2009; San Francisco, CA. CNS Spectr 15:11 629

Preventing the cardiovascular complications of hypertension

Preventing the cardiovascular complications of hypertension European Heart Journal Supplements (2004) 6 (Supplement H), H37 H42 Preventing the cardiovascular complications of hypertension Peter Trenkwalder* Department of Internal Medicine, Starnberg Hospital, Ludwig

More information

Cardiovascular Protection and the RAS

Cardiovascular Protection and the RAS Cardiovascular Protection and the RAS Katalin Kauser, MD, PhD, DSc Senior Associate Director, Boehringer Ingelheim Pharmaceutical Inc. Micardis Product Pipeline Scientific Support Ridgefield, CT, USA Cardiovascular

More information

Data Alert #2... Bi o l o g y Work i n g Gro u p. Subject: HOPE: New validation for the importance of tissue ACE inhibition

Data Alert #2... Bi o l o g y Work i n g Gro u p. Subject: HOPE: New validation for the importance of tissue ACE inhibition Vascular Bi o l o g y Work i n g Gro u p c/o Medical Education Consultants, In c. 25 Sy l van Road South, We s t p o rt, CT 06880 Chairman: Carl J. Pepine, MD Professor and Chief Division of Cardiovascular

More information

The Beneficial Role of Angiotensin- Converting Enzyme Inhibitor in Acute Myocardial Infarction

The Beneficial Role of Angiotensin- Converting Enzyme Inhibitor in Acute Myocardial Infarction The Beneficial Role of Angiotensin- Converting Enzyme Inhibitor in Acute Myocardial Infarction Cardiovascular Center, Korea University Guro Hospital 2007. 4. 20 Seung-Woon Rha, MD, PhD Introduction 1.

More information

Journal of the American College of Cardiology Vol. 44, No. 6, by the American College of Cardiology Foundation ISSN /04/$30.

Journal of the American College of Cardiology Vol. 44, No. 6, by the American College of Cardiology Foundation ISSN /04/$30. Journal of the American College of Cardiology Vol. 44, No. 6, 2004 2004 by the American College of Cardiology Foundation ISSN 0735-1097/04/$30.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2004.06.034

More information

Clinical Updates in the Treatment of Hypertension JNC 7 vs. JNC 8. Lauren Thomas, PharmD PGY1 Pharmacy Practice Resident South Pointe Hospital

Clinical Updates in the Treatment of Hypertension JNC 7 vs. JNC 8. Lauren Thomas, PharmD PGY1 Pharmacy Practice Resident South Pointe Hospital Clinical Updates in the Treatment of Hypertension JNC 7 vs. JNC 8 Lauren Thomas, PharmD PGY1 Pharmacy Practice Resident South Pointe Hospital Objectives Review the Eighth Joint National Committee (JNC

More information

Cerebral involvement in hypertensive cardiovascular disease

Cerebral involvement in hypertensive cardiovascular disease European Heart Journal Supplements (2003) 5 (Supplement F), F19 F25 Cerebral involvement in hypertensive cardiovascular disease Hypertension Unit, Hospital Clinic (IDIBAPS), University of Barcelona, Barcelona,

More information

LXIV: DRUGS: 4. RAS BLOCKADE

LXIV: DRUGS: 4. RAS BLOCKADE LXIV: DRUGS: 4. RAS BLOCKADE ACE Inhibitors Components of RAS Actions of Angiotensin i II Indications for ACEIs Contraindications RAS blockade in hypertension RAS blockade in CAD RAS blockade in HF Limitations

More information

Should beta blockers remain first-line drugs for hypertension?

Should beta blockers remain first-line drugs for hypertension? 1 de 6 03/11/2008 13:23 Should beta blockers remain first-line drugs for hypertension? Maros Elsik, Cardiologist, Department of Epidemiology and Preventive Medicine, Monash University and The Alfred Hospital,

More information

RAS Blockade Across the CV Continuum

RAS Blockade Across the CV Continuum A Summary of Recent International Meetings RAS Blockade Across the CV Continuum Copyright New Evidence Presented at the 2009 Congress of the European Society of Cardiology (August 29-September 2, Barcelona)

More information

Metabolic Consequences of Anti Hypertensives: Is It Clinically Important?

Metabolic Consequences of Anti Hypertensives: Is It Clinically Important? Metabolic Consequences of Anti Hypertensives: Is It Clinically Important?,FACA,FICA,MASH,FVBWG,MISCP CONSULTANT OF CARDIOLOGY DIRECTOR OF PORT-FOUAD HOSPITAL CCU Consideration of antihypertensive agents

More information

The CARI Guidelines Caring for Australasians with Renal Impairment. Blood Pressure Control role of specific antihypertensives

The CARI Guidelines Caring for Australasians with Renal Impairment. Blood Pressure Control role of specific antihypertensives Blood Pressure Control role of specific antihypertensives Date written: May 2005 Final submission: October 2005 Author: Adrian Gillian GUIDELINES a. Regimens that include angiotensin-converting enzyme

More information

Effects of the angiotensin II type-1 receptor antagonist telmisartan on endothelial activation induced by advanced glycation endproducts

Effects of the angiotensin II type-1 receptor antagonist telmisartan on endothelial activation induced by advanced glycation endproducts Effects of the angiotensin II type-1 receptor antagonist telmisartan on endothelial activation induced by advanced glycation endproducts Serena Del Turco, Teresa Navarra, Giuseppina Basta, Raffaele De

More information

Management of Hypertension

Management of Hypertension Clinical Practice Guidelines Management of Hypertension Definition and classification of blood pressure levels (mmhg) Category Systolic Diastolic Normal

More information

Hypertension Update Clinical Controversies Regarding Age and Race

Hypertension Update Clinical Controversies Regarding Age and Race Hypertension Update Clinical Controversies Regarding Age and Race Allison Helmer, PharmD, BCACP Assistant Clinical Professor Auburn University Harrison School of Pharmacy July 22, 2017 DISCLOSURE/CONFLICT

More information

By Prof. Khaled El-Rabat

By Prof. Khaled El-Rabat What is The Optimum? By Prof. Khaled El-Rabat Professor of Cardiology - Benha Faculty of Medicine HT. Introduction Despite major worldwide efforts over recent decades directed at diagnosing and treating

More information

The problem of uncontrolled hypertension

The problem of uncontrolled hypertension (2002) 16, S3 S8 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh The problem of uncontrolled hypertension Department of Public Health and Clinical Medicine, Norrlands

More information

Disclosure of Relationships

Disclosure of Relationships Disclosure of Relationships Over the past 12 months Dr Ruilope has served as Consultant and Speakers Bureau member of Astra-Zeneca, Bayer, Daiichi-Sankyo, Menarini, Novartis, Otsuka, Pfizer, Relypsa, Servier

More information

Hypertension Update 2009

Hypertension Update 2009 Hypertension Update 2009 New Drugs, New Goals, New Approaches, New Lessons from Clinical Trials Timothy C Fagan, MD, FACP Professor Emeritus University of Arizona New Drugs Direct Renin Inhibitors Endothelin

More information

In the Literature 1001 BP of 1.1 mm Hg). The trial was stopped early based on prespecified stopping rules because of a significant difference in cardi

In the Literature 1001 BP of 1.1 mm Hg). The trial was stopped early based on prespecified stopping rules because of a significant difference in cardi Is Choice of Antihypertensive Agent Important in Improving Cardiovascular Outcomes in High-Risk Hypertensive Patients? Commentary on Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators.

More information

Ferrari R, Fox K, Bertrand M, Mourad J.J, Akkerhuis KM, Van Vark L, Boersma E.

Ferrari R, Fox K, Bertrand M, Mourad J.J, Akkerhuis KM, Van Vark L, Boersma E. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular mortality in hypertension: a meta-analysis of randomized controlled trials Ferrari R, Fox K, Bertrand

More information

Slide notes: References:

Slide notes: References: 1 2 3 Cut-off values for the definition of hypertension are systolic blood pressure (SBP) 135 and/or diastolic blood pressure (DBP) 85 mmhg for home blood pressure monitoring (HBPM) and daytime ambulatory

More information

Proceedings of the 34th World Small Animal Veterinary Congress WSAVA 2009

Proceedings of the 34th World Small Animal Veterinary Congress WSAVA 2009 www.ivis.org Proceedings of the 34th World Small Animal Veterinary Congress WSAVA 2009 São Paulo, Brazil - 2009 Next WSAVA Congress : Reprinted in IVIS with the permission of the Congress Organizers PROTEINURIA

More information

Antihypertensive Agents Part-2. Assistant Prof. Dr. Najlaa Saadi PhD Pharmacology Faculty of Pharmacy University of Philadelphia

Antihypertensive Agents Part-2. Assistant Prof. Dr. Najlaa Saadi PhD Pharmacology Faculty of Pharmacy University of Philadelphia Antihypertensive Agents Part-2 Assistant Prof. Dr. Najlaa Saadi PhD Pharmacology Faculty of Pharmacy University of Philadelphia Agents that block production or action of angiotensin Angiotensin-converting

More information

The retinal renin-angiotensin system: implications for therapy in diabetic retinopathy

The retinal renin-angiotensin system: implications for therapy in diabetic retinopathy (2002) 16, S42 S46 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh : implications for therapy in diabetic retinopathy AK Sjølie 1 and N Chaturvedi 2 1 Department

More information

State of the art treatment of hypertension: established and new drugs. Prof. M. Burnier Service of Nephrology and Hypertension Lausanne, Switzerland

State of the art treatment of hypertension: established and new drugs. Prof. M. Burnier Service of Nephrology and Hypertension Lausanne, Switzerland State of the art treatment of hypertension: established and new drugs Prof. M. Burnier Service of Nephrology and Hypertension Lausanne, Switzerland First line therapies in hypertension ACE inhibitors AT

More information

Lowering blood pressure in 2003

Lowering blood pressure in 2003 UPDATE CLINICAL UPDATE Lowering blood pressure in 2003 John P Chalmers and Leonard F Arnolda Institute for International Health, University of Sydney, Sydney, NSW. John P Chalmers, MD, FRACP, Professor

More information

VALUE OF ACEI IN THE MANAGEMENT OF HYPERTENSION

VALUE OF ACEI IN THE MANAGEMENT OF HYPERTENSION VALUE OF ACEI IN THE MANAGEMENT OF HYPERTENSION Dr Catherine BESEME Paris 6 th December 2005 6 th International Congress of Bangladesh Society of Medicine Hypertension is a risk factor at the source, with

More information

renoprotection therapy goals 208, 209

renoprotection therapy goals 208, 209 Subject Index Aldosterone, plasminogen activator inhibitor-1 induction 163, 164, 168 Aminopeptidases angiotensin II processing 64 66, 214 diabetic expression 214, 215 Angiotensin I intrarenal compartmentalization

More information

The Road to Renin System Optimization: Renin Inhibitor

The Road to Renin System Optimization: Renin Inhibitor The Road to Renin System Optimization: Renin Inhibitor A New Perspective on the Renin-Angiotensin System (RAS) Yong-Jin Kim, MD Seoul National University Hospital Human and Economic Costs of Hypertension

More information

Reducing proteinuria

Reducing proteinuria Date written: May 2005 Final submission: October 2005 Author: Adrian Gillin Reducing proteinuria GUIDELINES a. The beneficial effect of treatment regimens that include angiotensinconverting enzyme inhibitors

More information

Role of Clopidogrel in Acute Coronary Syndromes. Hossam Kandil,, MD. Professor of Cardiology Cairo University

Role of Clopidogrel in Acute Coronary Syndromes. Hossam Kandil,, MD. Professor of Cardiology Cairo University Role of Clopidogrel in Acute Coronary Syndromes Hossam Kandil,, MD Professor of Cardiology Cairo University ACS Treatment Strategies Reperfusion/Revascularization Therapy Thrombolysis PCI (with/ without

More information

Outcomes and Perspectives of Single-Pill Combination Therapy for the modern management of hypertension

Outcomes and Perspectives of Single-Pill Combination Therapy for the modern management of hypertension Outcomes and Perspectives of Single-Pill Combination Therapy for the modern management of hypertension Prof. Massimo Volpe, MD, FAHA, FESC, Chair of Cardiology, Department of Clinical and Molecular Medicine

More information

Hypertension and diabetic nephropathy

Hypertension and diabetic nephropathy Hypertension and diabetic nephropathy Elisabeth R. Mathiesen Professor, Chief Physician, Dr sci Dep. Of Endocrinology Rigshospitalet, University of Copenhagen Denmark Hypertension Brain Eye Heart Kidney

More information

Angiotensin II binds to either the angiotensin II type 1

Angiotensin II binds to either the angiotensin II type 1 Angiotensin AT 2 Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke Claudia A. McCarthy, BBNS(Hons); Antony Vinh, PhD; Jennifer K. Callaway, PhD; Robert E. Widdop, PhD Background

More information

Optimal blockade of the Renin- Angiotensin-Aldosterone. in chronic heart failure

Optimal blockade of the Renin- Angiotensin-Aldosterone. in chronic heart failure Optimal blockade of the Renin- Angiotensin-Aldosterone Aldosterone- (RAA)-System in chronic heart failure Jan Östergren Department of Medicine Karolinska University Hospital Stockholm, Sweden Key Issues

More information

ACE inhibitors vs ARBs Myths and Facts

ACE inhibitors vs ARBs Myths and Facts ACE inhibitors vs ARBs Myths and Facts Prof. Dr. med. Frank Ruschitzka, FRCP (Edinburgh) Director Heart Failure/Transplantation Clinic University Clinic Zurich Switzerland Conflict of interest: Bayer,

More information

Angiotensin II (Ang II) is a potent vasoactive substance in

Angiotensin II (Ang II) is a potent vasoactive substance in Stroke Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation Masaru Iwai, MD, PhD*; Hong-Wei Liu, MD*; Rui Chen, MD; Ayumi Ide, BS; Shoko Okamoto, BS; Ryuji Hata,

More information

The hypertensive effects of the renin-angiotensin

The hypertensive effects of the renin-angiotensin Comparison of Telmisartan vs. Valsartan in the Treatment of Mild to Moderate Hypertension Using Ambulatory Blood Pressure Monitoring George Bakris, MD A prospective, randomized, open-label, blinded end-point

More information

7/18/2018. Cerebral Vasospasm: Current and Emerging Therapies. Disclosures. Objectives

7/18/2018. Cerebral Vasospasm: Current and Emerging Therapies. Disclosures. Objectives Cerebral : Current and Emerging Therapies Chad W. Washington MS, MD, MPHS Assistant Professor Department of Neurosurgery Disclosures None Objectives Brief Overview How we got here Review of Trials Meta-analysis

More information

Cedars Sinai Diabetes. Michael A. Weber

Cedars Sinai Diabetes. Michael A. Weber Cedars Sinai Diabetes Michael A. Weber Speaker Disclosures I disclose that I am a Consultant for: Ablative Solutions, Boston Scientific, Boehringer Ingelheim, Eli Lilly, Forest, Medtronics, Novartis, ReCor

More information

Entresto Development of sacubitril/valsartan (LCZ696) for the treatment of heart failure with reduced ejection fraction

Entresto Development of sacubitril/valsartan (LCZ696) for the treatment of heart failure with reduced ejection fraction Cardio-Metabolic Franchise Entresto Development of sacubitril/valsartan (LCZ696) for the treatment of heart failure with reduced ejection fraction Randy L Webb, PhD Rutgers Workshop October 21, 2016 Heart

More information

Treating Hypertension in Individuals with Diabetes

Treating Hypertension in Individuals with Diabetes Treating Hypertension in Individuals with Diabetes Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any

More information

In the name of GOD. Animal models of cardiovascular diseases: myocardial infarction & hypertension

In the name of GOD. Animal models of cardiovascular diseases: myocardial infarction & hypertension In the name of GOD Animal models of cardiovascular diseases: myocardial infarction & hypertension 44 Presentation outline: Cardiovascular diseases Acute myocardial infarction Animal models for myocardial

More information

Pathology of Hypertension

Pathology of Hypertension 2016-03-07 Pathology of Hypertension Honghe Zhang honghezhang@zju.edu.cn Tel:88208199 Department of Pathology ❶ Genetic predisposition ❷ Dietary factors ❸ Environmental factors ❹ Others Definition and

More information

Cardiovascular and cerebrovascular outcomes in elderly hypertensive patients treated with either ARB or ACEI

Cardiovascular and cerebrovascular outcomes in elderly hypertensive patients treated with either ARB or ACEI Journal of Geriatric Cardiology (2012) 9: 252 257 2012 JGC All rights reserved; www.jgc301.com Research Articles Open Access Cardiovascular and cerebrovascular outcomes in elderly hypertensive patients

More information

Angiotensin Receptor Blockers: Novel Role in High-Risk Patients

Angiotensin Receptor Blockers: Novel Role in High-Risk Patients Angiotensin Receptor Blockers: Novel Role in High-Risk Patients UsmanJaved, MD a, Prakash C. Deedwania, MD, FACC, FACP, FCCP, FAHA a,b, * KEYWORDS Angiotensin receptor blockers RAAS blockade Cardioprotection

More information

Introductory Clinical Pharmacology Chapter 41 Antihypertensive Drugs

Introductory Clinical Pharmacology Chapter 41 Antihypertensive Drugs Introductory Clinical Pharmacology Chapter 41 Antihypertensive Drugs Blood Pressure Normal = sys

More information

Risk Factors for Ischemic Stroke: Electrocardiographic Findings

Risk Factors for Ischemic Stroke: Electrocardiographic Findings Original Articles 232 Risk Factors for Ischemic Stroke: Electrocardiographic Findings Elley H.H. Chiu 1,2, Teng-Yeow Tan 1,3, Ku-Chou Chang 1,3, and Chia-Wei Liou 1,3 Abstract- Background: Standard 12-lead

More information

Combination therapy Giuseppe M.C. Rosano, MD, PhD, MSc, FESC, FHFA St George s Hospitals NHS Trust University of London

Combination therapy Giuseppe M.C. Rosano, MD, PhD, MSc, FESC, FHFA St George s Hospitals NHS Trust University of London Combination therapy Giuseppe M.C. Rosano, MD, PhD, MSc, FESC, FHFA St George s Hospitals NHS Trust University of London KCS Congress: Impact through collaboration CONTACT: Tel. +254 735 833 803 Email:

More information

PROGRESS: Prevention of Recurrent Stroke

PROGRESS: Prevention of Recurrent Stroke STATE OF THE ART REVIEW SERIES REVIEW PAPER PROGRESS: Prevention of Recurrent Stroke Hisatomi Arima, MD, PhD; John Chalmers, MD, PhD From The George Institute for Global Health, University of Sydney and

More information

Scientific conclusions and detailed explanation of the scientific grounds for the differences from the PRAC recommendation

Scientific conclusions and detailed explanation of the scientific grounds for the differences from the PRAC recommendation Annex I Scientific conclusions, grounds for variation to the terms of the marketing authorisations and detailed explanation of the scientific grounds for the differences from the PRAC recommendation 1

More information

JNC 8 -Controversies. Sagren Naidoo Nephrologist CMJAH

JNC 8 -Controversies. Sagren Naidoo Nephrologist CMJAH JNC 8 -Controversies Sagren Naidoo Nephrologist CMJAH Joint National Committee (JNC) Panel appointed by the National Heart, Lung, and Blood Institute (NHLBI) First guidelines (JNC-1) published in 1977

More information

ACE inhibitors: still the gold standard?

ACE inhibitors: still the gold standard? ACE inhibitors: still the gold standard? Session: Twenty-five years after CONSENSUS What have we learnt about the RAAS in heart failure? Lars Køber, MD, D.Sci Department of Cardiology Rigshospitalet University

More information

BLOOD PRESSURE-LOWERING TREATMENT

BLOOD PRESSURE-LOWERING TREATMENT BLOOD PRESSURE-LOWERING TRIALS NUMBER OF PARTICIPANTS NUMBER OF PERCENTAGE OF MEAN AGE MEAN - (YEARS) TRIALS WITH ANALYSIS BY GENDER N, (%) 69,473 28,008 40.3% 70.2 3.2 3/5 (60%) APPENDIX 2 1 BLOOD PRESSURE-LOWERING

More information

ANGIOTENSIN II RECEPTOR BLOCKERS: MORE THAN THE ALTERNATIVE PRESENTATION BY: PATRICK HO, USC PHARM D. CANDIDATE OF 2017 MENTOR: DR.

ANGIOTENSIN II RECEPTOR BLOCKERS: MORE THAN THE ALTERNATIVE PRESENTATION BY: PATRICK HO, USC PHARM D. CANDIDATE OF 2017 MENTOR: DR. ANGIOTENSIN II RECEPTOR BLOCKERS: MORE THAN THE ALTERNATIVE PRESENTATION BY: PATRICK HO, USC PHARM D. CANDIDATE OF 2017 MENTOR: DR. CRAIG STERN, PHARMD, MBA, RPH, FASCP, FASHP, FICA, FLMI, FAMCP RENIN-ANGIOTENSIN

More information

Antihypertensive Trial Design ALLHAT

Antihypertensive Trial Design ALLHAT 1 U.S. Department of Health and Human Services Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic National Institutes

More information

Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease

Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease European Heart Journal (2003) 24, 475 484 Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease PROGRESS Collaborative Group 1*

More information

Systolic Hypertension in the Elderly: Addressing an Unmet Need

Systolic Hypertension in the Elderly: Addressing an Unmet Need REVIEW Systolic Hypertension in the Elderly: Addressing an Unmet Need Daniel A. Duprez, MD, PhD Cardiovascular Division, Medical School, University of Minnesota, Minn. ABSTRACT Systolic hypertension is

More information

How clinically important are the results of the large trials in hypertension?

How clinically important are the results of the large trials in hypertension? How clinically important are the results of the large trials in hypertension? Stéphane LAURENT, MD, PhD, FESC Pharmacology Department and PARCC / INSERM U970 Hôpital Européen Georges Pompidou, Université

More information

Hypertension Update Warwick Jaffe Interventional Cardiologist Ascot Hospital

Hypertension Update Warwick Jaffe Interventional Cardiologist Ascot Hospital Hypertension Update 2008 Warwick Jaffe Interventional Cardiologist Ascot Hospital Definition of Hypertension Continuous variable At some point the risk becomes high enough to justify treatment Treatment

More information

Difficult to Treat Hypertension

Difficult to Treat Hypertension Difficult to Treat Hypertension According to Goldilocks JNC 8 Blood Pressure Goals (2014) BP Goal 60 years old and greater*- systolic < 150 and diastolic < 90. (Grade A)** BP Goal 18-59 years old* diastolic

More information

Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) Trial of Cardiovascular Events in High-Risk Hypertensive Patients

Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) Trial of Cardiovascular Events in High-Risk Hypertensive Patients 1/5 This site became the new ClinicalTrials.gov on June 19th. Learn more. We will be updating this site in phases. This allows us to move faster and to deliver better services. Show less IMPORTANT: Listing

More information

T. Suithichaiyakul Cardiomed Chula

T. Suithichaiyakul Cardiomed Chula T. Suithichaiyakul Cardiomed Chula The cardiovascular (CV) continuum: role of risk factors Endothelial Dysfunction Atherosclerosis and left ventricular hypertrophy Myocardial infarction & stroke Endothelial

More information

Blood Pressure Management in Acute Stroke. Bradley Molyneaux, M.D., Ph.D. Departments of Neurology & Critical Care Medicine University of Pittsburgh

Blood Pressure Management in Acute Stroke. Bradley Molyneaux, M.D., Ph.D. Departments of Neurology & Critical Care Medicine University of Pittsburgh Blood Pressure Management in Acute Stroke Bradley Molyneaux, M.D., Ph.D. Departments of Neurology & Critical Care Medicine University of Pittsburgh 80 yo M w/ R MCA syndrome NIHSS 14 A balancing act Cerebral

More information

9/17/2015. Reference: Ruschitzka F. J Hypertens 2011;29(Suppl 1):S9-14.

9/17/2015. Reference: Ruschitzka F. J Hypertens 2011;29(Suppl 1):S9-14. 0 1 2 Reference: Ruschitzka F. J Hypertens 2011;29(Suppl 1):S9-14. 3 Slide notes: Large trials such as ALLHAT, LIFE and ASCOT show that the majority of patients with hypertension will require multiple

More information

Should All Patients Be Treated with Ace-inh /ARB after STEMI with Preserved LV Function?

Should All Patients Be Treated with Ace-inh /ARB after STEMI with Preserved LV Function? Should All Patients Be Treated with Ace-inh /ARB after STEMI with Preserved LV Function? Avi Shimony, MD, FESC Cardiology Division Soroka University Medical Center Ben-Gurion University, Beer-Sheva Disclosure

More information

Lab Period: Name: Physiology Chapter 14 Blood Flow and Blood Pressure, Plus Fun Review Study Guide

Lab Period: Name: Physiology Chapter 14 Blood Flow and Blood Pressure, Plus Fun Review Study Guide Lab Period: Name: Physiology Chapter 14 Blood Flow and Blood Pressure, Plus Fun Review Study Guide Main Idea: The function of the circulatory system is to maintain adequate blood flow to all tissues. Clinical

More information

Therapeutic Targets and Interventions

Therapeutic Targets and Interventions Therapeutic Targets and Interventions Ali Valika, MD, FACC Advanced Heart Failure and Pulmonary Hypertension Advocate Medical Group Midwest Heart Foundation Disclosures: 1. Novartis: Speaker Honorarium

More information

Since the initial description of angiotensin II mediated

Since the initial description of angiotensin II mediated CLINICAL CARDIOLOGY: PHYSICIAN UPDATE Manipulation of the Renin-Angiotensin System Michael M. Givertz, MD Since the initial description of angiotensin II mediated hypertension 40 years ago, basic and clinical

More information

Perioperative use of angiotensin blockade

Perioperative use of angiotensin blockade Perioperative use of angiotensin blockade Dr Fiona Chow on behalf of A/Prof Ian Fraser Epworth HealthCare 1 surgical_operation_with_surgeons_and_nurses_royalty_free_clipart_picture_100616-172691-620048.jpg

More information

HYPERTENSION IN EMERGENCY MEDICINE Michael Jay Bresler, M.D., FACEP

HYPERTENSION IN EMERGENCY MEDICINE Michael Jay Bresler, M.D., FACEP HYPERTENSION IN EMERGENCY MEDICINE Michael Jay Bresler, M.D., FACEP What is normal blood pressure? Prehypertension 130-139/80-90 Compared with normal BP Double the risk for developing hypertension. Lifestyle

More information

Blood Pressure Targets: Where are We Now?

Blood Pressure Targets: Where are We Now? Blood Pressure Targets: Where are We Now? Diana Cao, PharmD, BCPS-AQ Cardiology Assistant Professor Department of Clinical & Administrative Sciences California Northstate University College of Pharmacy

More information

47 Hypertension in Elderly

47 Hypertension in Elderly 47 Hypertension in Elderly YOU DO NOT HEAL OLD AGE; YOU PROTECT IT; YOU PROMOTE IT; YOU EXTEND IT Sir James Sterling Ross Abstract: The prevalence of hypertension rises with age and the complications secondary

More information

Hypertension Management: A Moving Target

Hypertension Management: A Moving Target 9:45 :30am Hypertension Management: A Moving Target SPEAKER Karol Watson, MD, PhD, FACC Presenter Disclosure Information The following relationships exist related to this presentation: Karol E. Watson,

More information

Υπέρταση στις γυναίκες

Υπέρταση στις γυναίκες Υπέρταση στις γυναίκες Ελένη Τριανταφυλλίδη Διευθύντρια ΕΣΥ Καρδιολογίας Υπεύθυνη Αντιυπερτασικού Ιατρείου Β Πανεπιστημιακή Καρδιολογική Κλινική Νοσοκομείο ΑΤΤΙΚΟΝ Cardiovascular disease is the Europe

More information

Heart Failure: Combination Treatment Strategies

Heart Failure: Combination Treatment Strategies Heart Failure: Combination Treatment Strategies M. McDonald MD, FRCP State of the Heart Symposium May 28, 2011 None Disclosures Case 69 F, prior MIs (LV ejection fraction 25%), HTN No demonstrable ischemia

More information

ALLHAT. Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic

ALLHAT. Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic 1 U.S. Department of Health and Human Services National Institutes of Health Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker

More information

Blood pressure control. Rok Humar, PhD Department of Research

Blood pressure control. Rok Humar, PhD Department of Research Blood pressure control Rok Humar, PhD Department of Research Mean arterial blood pressure is determined by Blood volume Cardiac output Peripheral resistance Blood capacitance Resistance of the system to

More information

Abbreviations Cardiology I

Abbreviations Cardiology I Cardiology I and Clinical Controversies Joseph J. Saseen, Pharm.D., FCCP, BCPS (AQ Cardiology) Reviewed by Stuart T. Haines, Pharm.D., FCCP, BCPS; and Michelle M. Richardson, Pharm.D., FCCP, BCPS Learning

More information

HYPERTENSION GUIDELINES WHERE ARE WE IN 2014

HYPERTENSION GUIDELINES WHERE ARE WE IN 2014 HYPERTENSION GUIDELINES WHERE ARE WE IN 2014 Donald J. DiPette MD FACP Special Assistant to the Provost for Health Affairs Distinguished Health Sciences Professor University of South Carolina University

More information

1. Antihypertensive agents 2. Vasodilators & treatment of angina 3. Drugs used in heart failure 4. Drugs used in arrhythmias

1. Antihypertensive agents 2. Vasodilators & treatment of angina 3. Drugs used in heart failure 4. Drugs used in arrhythmias 1. Antihypertensive agents 2. Vasodilators & treatment of angina 3. Drugs used in heart failure 4. Drugs used in arrhythmias Only need to know drugs discussed in class At the end of this section you should

More information

The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 7 January 2009

The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 7 January 2009 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 7 January 2009 LERCAPRESS 10 mg/10 mg, film-coated tablets Pack of 30 (CIP code: 385 953-3) Pack of 90 (CIP code:

More information

The target blood pressure in patients with diabetes is <130 mm Hg

The target blood pressure in patients with diabetes is <130 mm Hg Controversies in hypertension, About Diabetes diabetes and and metabolic Cardiovascular syndrome Risk ESC annual congress August 29, 2011 The target blood pressure in patients with diabetes is

More information

ROLE OF INFLAMMATION IN HYPERTENSION. Dr Barasa FA Physician Cardiologist Eldoret

ROLE OF INFLAMMATION IN HYPERTENSION. Dr Barasa FA Physician Cardiologist Eldoret ROLE OF INFLAMMATION IN HYPERTENSION Dr Barasa FA Physician Cardiologist Eldoret Outline Inflammation in CVDs the evidence Basic Science in Cardiovascular inflammation: The Main players Inflammation as

More information

Therefore MAP=CO x TPR = HR x SV x TPR

Therefore MAP=CO x TPR = HR x SV x TPR Regulation of MAP Flow = pressure gradient resistance CO = MAP TPR Therefore MAP=CO x TPR = HR x SV x TPR TPR is the total peripheral resistance: this is the combined resistance of all blood vessels (remember

More information

Is there a need of new RAAS blockers in diabetic hypertension?

Is there a need of new RAAS blockers in diabetic hypertension? Is there a need of new RAAS blockers in diabetic hypertension? Dr. Dominik N. Müller First World Congress on Controversies in Obesity, Diabetes and Hypertension Berlin October 2006 Renin-Angiotensin System

More information

ALLHAT Role of Diuretics in the Prevention of Heart Failure - The Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial

ALLHAT Role of Diuretics in the Prevention of Heart Failure - The Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial 1 ALLHAT Role of Diuretics in the Prevention of Heart Failure - The Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial Davis BR, Piller LB, Cutler JA, et al. Circulation 2006.113:2201-2210.

More information

HYPERTENSION IN CKD. LEENA ONGAJYOOTH, M.D., Dr.med RENAL UNIT SIRIRAJ HOSPITAL

HYPERTENSION IN CKD. LEENA ONGAJYOOTH, M.D., Dr.med RENAL UNIT SIRIRAJ HOSPITAL HYPERTENSION IN CKD LEENA ONGAJYOOTH, M.D., Dr.med RENAL UNIT SIRIRAJ HOSPITAL Stages in Progression of Chronic Kidney Disease and Therapeutic Strategies Complications Normal Increased risk Damage GFR

More information

Circulation. Blood Pressure and Antihypertensive Medications. Venous Return. Arterial flow. Regulation of Cardiac Output.

Circulation. Blood Pressure and Antihypertensive Medications. Venous Return. Arterial flow. Regulation of Cardiac Output. Circulation Blood Pressure and Antihypertensive Medications Two systems Pulmonary (low pressure) Systemic (high pressure) Aorta 120 mmhg Large arteries 110 mmhg Arterioles 40 mmhg Arteriolar capillaries

More information

National Horizon Scanning Centre. Irbesartan (Aprovel) for prevention of cardiovascular complications in patients with persistent atrial fibrillation

National Horizon Scanning Centre. Irbesartan (Aprovel) for prevention of cardiovascular complications in patients with persistent atrial fibrillation Irbesartan (Aprovel) for prevention of cardiovascular complications in patients with persistent atrial fibrillation August 2008 This technology summary is based on information available at the time of

More information

The renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system Cardiology 59 Using ARBs in the elderly patient Effective management of hypertension can substantially reduce the risk of complications. The angiotensin receptor blockers are one of the latest anti-hypertensive

More information

CNS Effects of Aldosterone :

CNS Effects of Aldosterone : CNS Effects of Aldosterone : Critical Roles in salt-sensitive sensitive hypertension and CHF. Frans HH Leenen MD, PhD, FRCPC, FAHA 2 Renin Angiotensin Aldosterone System Circulatory RAAS Tissue RAAS: -

More information

heart failure John McMurray University of Glasgow.

heart failure John McMurray University of Glasgow. A to Z of RAAS blockade in heart failure John McMurray BHF Cardiovascular Research Centre University of Glasgow. RAAS inhibition in CHF ACE inhibition in patients with low LVEF CHF CONSENSUS Enalapril

More information

The CARI Guidelines Caring for Australasians with Renal Impairment. ACE Inhibitor and Angiotensin II Antagonist Combination Treatment GUIDELINES

The CARI Guidelines Caring for Australasians with Renal Impairment. ACE Inhibitor and Angiotensin II Antagonist Combination Treatment GUIDELINES ACE Inhibitor and Angiotensin II Antagonist Combination Treatment Date written: September 2004 Final submission: September 2005 Author: Kathy Nicholls GUIDELINES No recommendations possible based on Level

More information

Effects of Poststroke Losartan Versus Captopril Treatment on Myogenic and Endothelial Function in the Cerebrovasculature of SHRsp

Effects of Poststroke Losartan Versus Captopril Treatment on Myogenic and Endothelial Function in the Cerebrovasculature of SHRsp Effects of Poststroke Losartan Versus Captopril Treatment on Myogenic and Endothelial Function in the Cerebrovasculature of SHRsp John S. Smeda, PhD; John J. McGuire, PhD Background and Purpose We assessed

More information

Blood Pressure Goal in Elderly Hypertensive Patients with Diabetes Mellitus: A Subanalysis of the CASE-J Trial

Blood Pressure Goal in Elderly Hypertensive Patients with Diabetes Mellitus: A Subanalysis of the CASE-J Trial Blood Pressure Goal in Elderly Hypertensive Patients with Diabetes Mellitus: A Subanalysis of the CASE-J Trial Kenji Ueshima 1, Shinji Yasuno 1, Sachiko Tanaka 1, Akira Fujimoto 1, Toshio Ogihara 2, Takao

More information

Chapter 10 Worksheet Blood Pressure and Antithrombotic Agents

Chapter 10 Worksheet Blood Pressure and Antithrombotic Agents Complete the following. 1. A layer of cells lines each vessel in the vascular system. This layer is a passive barrier that keeps cells and proteins from going into tissues; it also contains substances

More information

Drugs acting on the reninangiotensin-aldosterone

Drugs acting on the reninangiotensin-aldosterone Drugs acting on the reninangiotensin-aldosterone system John McMurray Eugene Braunwald Scholar in Cardiovascular Diseases, Brigham and Women s Hospital, Boston & Visiting Professor, Harvard Medical School

More information

Can Anti-hypertension Therapy Reverse Vascular Aging and Dementia?

Can Anti-hypertension Therapy Reverse Vascular Aging and Dementia? 2012. 4. 20-21 춘계심장학회 _ 부산 Can Anti-hypertension Therapy Reverse Vascular Aging and Dementia? Jeong Bae Park, MD, PhD Cardiology, Cheil General Hospital, Kwandong University, Seoul, Korea The Pulse : revived

More information