The Role of Angiotensin II Receptors in Stroke Protection
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- Chrysant, S.G. Curr Hypertens Rep (2012) 14: 202. doi:10.1007/s11906-012-0257-8
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The hypothesis that angiotensin II (Ang II) might have a stroke-protective role was first proposed by Brown and Brown about 25 years ago. Their hypothesis was generated from the results of the first Medical Research Council trial in patients with mild to moderate hypertension, which showed that patients treated with the diuretic bendrofluazide had a 70% decrease in strokes compared with those treated with the β-blocker propranolol for similar blood pressure reduction. This hypothesis, which remained dormant for many years, was recently resurrected by several experimental studies that showed that the brain possesses its own renin-angiotensin system (RAS) similar to the one existing in the systemic circulation. These studies also showed that the brain RAS plays an important role in stroke prevention and neuronal protection through its active peptide Ang II. In addition, these studies demonstrated that the beneficial effects of Ang II are mediated through stimulation of its subtype 2 receptors, and possibly through stimulation of the subtype 4 receptors by Ang IV, a metabolite of Ang II. Drugs that selectively block the Ang II subtype 1 receptors, such as the angiotensin receptor blockers, have shown superior protection against strokes and neuronal damage than drugs that decrease the generation of Ang II, such as the angiotensin-converting enzyme inhibitors and β-blockers. In this review, the role of the Ang II receptors and their mechanism of action regarding stroke prevention are discussed in view of the evidence from experimental and clinical studies.
KeywordsRenin-angiotensin system (RAS)AngiotensinReceptorsAT1AT2AT4Angiotensin receptor blockers (ARBs)StrokePreventionExperimental studiesClinical trialsBlood pressure
The provocative hypothesis that angiotensin II (Ang II) might have stroke-protective effects was first advanced by Brown and Brown  25 years ago. Their hypothesis was generated from the results of the first Medical Research Council trial, which showed that patients treated with the diuretic bendrofluazide had a 70% decrease in strokes compared with those treated with the β-blocker propranolol for similar blood pressure (BP) reduction . However, their suggestion was out of the norm at that time and was quickly forgotten. Now it is widely recognized that the renin-angiotensin system (RAS) plays an important role in cardiovascular homeostasis through its effector peptide Ang II—the final product of the RAS cascade. Ang II exerts its vascular hemodynamic, trophic, and other effects through stimulation of its specific type 1 (AT1), type 2 (AT2), and type 4 (AT4) receptors [3, 4]. Ang II is formed through an enzymatic processing from Ang I by the angiotensin-converting enzyme (ACE) in the plasma, the brain, as well as other tissues [5, 6]. Besides this classical pathway, Ang II is also formed by alternate pathways through the action of other enzymes, especially chymase, which bypass the ACE pathway, and its action is blocked by the angiotensin receptor blockers (ARBs), but not the ACE inhibitors . In the brain, the RAS has an autocrine function, maintaining cerebral homeostasis and blood flow regulation. However, its significance as a neuroprotector was later discovered, first by experimental and subsequently by clinical studies. These studies confirmed the original hypothesis of Brown and Brown , that Ang II has a stroke-protective effect, and in addition delineated its mechanism of action. It is now fairly well-accepted that Ang II exerts its stroke-protective effects mainly through stimulation of the AT2 receptors, and quite possibly through stimulation of the AT4 receptors. In this review, the most important experimental and clinical studies are presented supporting the neuroprotective and stroke-protective effects of Ang II, as well as the therapeutic options available for stroke protection.
The Pathophysiology of Stroke
Stroke is usually caused by a clot or thrombus in a cerebral artery, leading to ischemic stroke, or by the rupture of a cerebral artery, leading to hemorrhagic stroke. Ischemic stroke is more common (90%) and is the focus of this paper. However, both of these events cause severe deprivation of oxygen and glucose of the immediate brain tissue (core), leading to severe brain dysfunction and death within minutes [7, 8]. Besides this severely damaged area of the brain, there is another adjoining, larger area of the brain called the penumbra whose blood supply, although greatly compromised, it is still viable and can be saved with prompt intervention (within 6 h) either mechanically or pharmacologically [8, 9]. This area is of major importance because prompt intervention provides a good chance to revive it; otherwise, it will eventually die [8, 9].
The Role of Angiotensin II Receptors in the Pathogenesis of Stroke
The Ang II plays an important role in brain circulation, homeostasis and stroke prevention, both of which are mediated through its receptors AT1, AT2, and possibly AT4.
Functions of angiotensin II receptors
Improves cognitive function
Nitric oxide generation
Reactive oxygen species
Glucose uptake facilitation
Sodium, water retention
Sodium, water loss
Recent studies have focused on the significance of AT4 receptors in preserving brain function. These receptors are stimulated by smaller fragments of Ang II such as Ang 3-8 (Ang IV). Ang IV binds to its specific receptor subtype 4 (AT4). These receptors are expressed in many tissues, including the brain, kidney, heart, and blood vessels [24–26]. Research studies into the physiologic actions of Ang IV have shown that it is an effector peptide of RAS, implying a vasodilator effect mediated through the AT4 receptor [27–29]. It has been demonstrated that inside neurons, Ang II is rapidly converted (80%) into Ang IV, but the conditions under which Ang IV is released remain to be elucidated . Recent studies in Sprague–Dawley rats have shown that the protective effects of pretreatment with candesartan after an acute stroke were abolished or markedly diminished with the administration of AT2 and AT4 antagonists . These studies also showed that the combined blockade of AT2 and AT4 receptors not only decreased the stroke-protective effects of candesartan but additionally had a deleterious effect similar to the one seen with ACE inhibitors. Structurally, the AT4 receptors are different from the AT1 and AT2 receptors and are attached to insulin-regulated aminopeptidase (IRAP), for which Ang IV has high binding affinity. Because IRAP is co-localized with the glucose transporter GLUT4, Ang IV might interact with the uptake of glucose . The known functions of AT4 receptors are listed in Table 1.
Stroke-Protective Effects of Angiotensin Receptor Blockers
The stroke-protective effects of ARBs are mediated through their dual action of blocking the AT1 receptors through which Ang II is exerting its vasoconstrictive, trophic, and cardiovascular remodeling effects, and at the same time of allowing Ang II to stimulate the unoccupied AT2 and AT4 receptors, leading to local cerebral vasodilatation and an increase in CBF. The stroke-protective actions of Ang II have been amply demonstrated by experimental and clinical studies.
Many animal studies in gerbils and rats have shown that ARBs decrease the volume and the extent of infracted brain tissue after induction of acute cerebral ischemia by carotid ligation [4, 31, 32] or MCAO [15, 33]. The mortality of gerbils after induction of acute brain ischemia by ligation of the right carotid artery was significantly decreased with pretreatment with the selective AT1 receptor blocker losartan or the selective AT2 receptor agonist PD 123319, but not with the ACE inhibitor enalapril . These experiments reinforce the hypothesis that Ang II exerts its cerebroprotective effects via stimulation of the AT2 receptors, and this action is further enhanced with selective blockade of the AT1 receptors. Findings supporting the above hypothesis have been also reported by other investigators [13, 32]. Normotensive male Wistar rats were pretreated for 5 days with intracerebral administration of a low dose of the ARB irbesartan, which blocked the cerebral, but not the systemic AT1 receptors. This pretreatment with irbesartan resulted in significant neuroprotection in rats after MCAO compared with rats treated with a vehicle . In other studies in salt-loaded spontaneously hypertensive rats (SHRs), or in SHRs after MCAO, treatment with the ARB losartan  or candesartan  resulted in cerebroprotection that was independent of the dose of the administered drug. In addition, other investigators have demonstrated that in addition to the dose, the timing of drug administration is important . In this study, normotensive Wistar rats were treated with candesartan, 0.3 or 3.0 mg/kg body weight, 3 and 24 h after acute ischemia due to MCAO. The results showed significant neurological improvement in the rats treated within 3 h compared with those treated 24 h after MCAO .
Stroke-protective effects of angiotensin receptor blockers from clinical trials
Change in stroke
Hypertensive with LVH
Losartan vs atenolol
Older adults with ISH
Losartan vs atenolol
Older adult hypertensive
Candesartan vs conventional treatment
Older adults with ISH
Candesartan vs conventional treatment
ACCESS PILOT 
Candesartan vs placebo
Eprosartan vs nitrendipine
Valsartan vs amlodipine
Ramipril vs telmisartan vs both
High-risk hypertensive, intolerant to ACEIs
Telmisartan vs placebo
Telmisartan vs placebo
Candesartan vs placebo
The Losartan Intervention For Endpoint reduction (LIFE) study  treated 9,193 hypertensive patients with left ventricular hypertrophy (LVH) with a losartan-based or an atenolol-based regimen for 4.5 years. The patients treated with losartan, 50 to 100 mg/d, had a 25% decrease in stroke incidence compared with those treated with atenolol, 50 to 100 mg/d, for similar reduction in BP. In a substudy of LIFE of 1,326 older adult patients with isolated systolic hypertension (ISH) and LVH  treated with the losartan-based and atenolol-based regimens for 4.7 years, the patients treated with the losartan-based regimen had a reduction in stroke incidence of 40% compared with those treated with the atenolol-based regimen. A decrease in stroke incidence was also demonstrated in the Study of Cognition and Prognosis in the Elderly (SCOPE). In this study, 4,964 older adult hypertensive patients treated with candesartan, 8 to 16 mg/d, for 3.7 years had a 27.8% decrease in nonfatal and 23.6% decrease in all strokes compared with those treated with conventional treatment . It should be stressed that the control group was treated with placebo for 3 months before starting conventional treatment, and the BP was 3.2/1.6 mm Hg lower in the candesartan-treated group, which could have accounted for part of the lower incidence of strokes in this group. In a SCOPE substudy of 1,518 patients with ISH treated with the same regimens for the same length of time, the stroke incidence was 42% lower in favor of the candesartan-treated group . In a pilot study of the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) in 339 patients with a previous stroke, there was a 52% decrease in stroke recurrence after 1 year of treatment with candesartan, 4 mg/d, the first day and 8 to 16 mg/d after day 2 compared with the control group, which was treated with placebo plus other drugs (except ARBs), with a similar reduction in BP . In a similar, longer-term study of the Morbidity and Mortality after Stroke Eprosartan Study (MOSES), 1,405 hypertensive patients with a previous stroke who were treated with eprosartan, 600 mg/d, had a 25% lower incidence of stroke compared with those treated with nitrendipine, 10 mg/d, for 2.5 years . The results of the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) study  were not as expected. In this study, 15,248 high-risk hypertensive patients were treated with valsartan, 80 to 160 mg/d, or amlodipine, 5 to 10 mg/d, for 4.8 years. Due to an early and significant decrease in BP from amlodipine, there was an early and significant reduction in strokes in this group. However, later on, as the difference in BP reduction was narrowed, the incidence of stroke was decreased by 25% in the valsartan-treated group. However, due to the earlier greater decrease in strokes, the overall stroke incidence was 15% lower in favor of amlodipine. The inferior decrease in BP by valsartan has been blamed on the lower maximum dose of valsartan (160 mg/d) used in this study instead of the 320-mg/d dose, which is considered equivalent to amlodipine, 10 mg/d. Also, the results of several recent clinical trials were equivocal with respect to stroke incidence.
The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) randomly assigned 25,620 high-risk older adult patients to treatment with telmisartan, 80 mg/d; ramipril, 10 mg/d; or their combination . After a mean follow-up of 4.7 years, there was no difference between the three treatment groups with respect to the primary composite end point of cardiovascular death, stroke, or hospitalization for heart failure. Similar results were reported from another trial, the Telmisartan Randomized Assessment Study in ACE intolerant subjects with cardiovascular Disease (TRANSCEND). In this study, 5,926 high-risk patients intolerant to ACE inhibitors were randomly assigned to telmisartan, 80 mg/d, or placebo and were observed for 4.7 years . The primary end points were identical to those of the ONTARGET study. There was no difference in the primary end points in this study as well, although BP was 4.2/2.2 mm Hg lower in the telmisartan-treated group. Another study similar to TRANSCEND was the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study . In this study, 20,332 patients with a recent ischemic stroke were randomly assigned to telmisartan, 80 mg/d, or placebo and were observed for 2.5 years. In this study as well, there was no difference between the two groups with respect to the primary end point of stroke recurrence. The nonsignificant difference in stroke incidence in these trials has been attributed to borderline elevated baseline BP and the concomitant treatment of patients with other cardiovascular drugs that could have prevented the incidence of new strokes.
Another very recent trial, the Scandinavian Candesartan Acute Stroke Trial (SCAST), also showed equivocal results . This study randomly assigned 2,029 patients with a recent acute stroke to treatment with candesartan or placebo for 7 days if their admissions BP was 140 mm Hg or greater. The dose of candesartan was increased from 4 mg/d on day 1 to 16 mg/d on days 3 to 7. The primary end points of myocardial infarction or stroke were assessed at 7 days and 6 months post-treatment. There was no indication that careful BP lowering with candesartan was beneficial to patients with acute ischemic stroke and raised systolic BP, and it was possibly harmful. However, it has been demonstrated that reduction of systolic BP below 140 mm Hg immediately after an acute ischemic stroke is not necessary and could have detrimental results, as discussed later.
Stroke is a major cause of morbidity and mortality, and its incidence increases linearly with increasing age and BP . It has been estimated that each year, 795,000 people experience a new or recurrent stroke, with 610,000 having new and 185,000 recurrent strokes . Of these strokes, 87% are ischemic and 13% are hemorrhagic . In addition to being a cause of long-term disability, strokes are also a significant burden on society and health care expenditures, accounting for 40.9 billion dollars in direct and indirect costs in the United States for 2007 . Because strokes are linearly related to BP level, control of BP is critical in preventing strokes. Whether the drug selection for the treatment of hypertension could play an additional role in stroke prevention is still debatable. Several large meta-analyses have shown a direct association between the level of BP and stroke incidence in hypertensive patients with or without diabetes and in those older or younger than 65 years of age, and there was no significant difference between the various drug regimens used and stroke incidence [47–49]. Similar findings were reported by meta-analyses comparing drugs that block the RAS, such as ACE inhibitors and ARBs [50, 51].
In this review, clinical and experimental evidence was presented indicating that the brain possesses its own RAS and that brain Ang II plays an important role in stroke protection, mediating its effects through stimulation of AT2 and possibly the AT4 receptors. Therefore, the ARBs, based on their dual mechanism of action, by blocking the local AT1 receptors and simultaneously allowing the Ang II to stimulate the unoccupied AT2 and possibly the AT4 receptors, result in an increase of local blood flow, which prevents the death of the compromised cells of the penumbra area of the brain and thus limits the extension of brain damage (Fig. 1). Whether this stroke-protective effect of ARBs is independent of the BP-lowering effect is questionable at this time, as has been thus far demonstrated by several large meta-analyses of prospective, randomized trials. In contrast to these meta-analyses, several experimental and clinical trials discussed previously have clearly demonstrated that the ARBs exert a superior stroke-protective effect compared with the drugs that suppress the production of Ang II, such as the ACE inhibitors and β-blockers . In addition, a recent large meta-analysis of 464,000 hypertensive patients treated with different drug regimens showed that those treated with β-blockers had a 18% higher stroke incidence than patients treated with other drug regimens, with no significant difference in BP reduction . However, in several recent clinical trials, a superior stroke-protective effect of ARBs compared with ACE inhibitors , or even placebo, was not clearly demonstrated [42–44]. It should be stated here perhaps, in defense of the ARBs, that in the ONTARGET , TRANSCEND , and PRoFESS  trials, the baseline BP was borderline elevated, and these patients were receiving other drugs in addition to the experimental ones that could have affected the outcome. Also, in a post-hoc analysis of the PRoFESS trial, it was found that the incidence of stroke was higher in patients with the very low systolic BP (<120 mm Hg), low to normal systolic BP (120–130 mm Hg), and very high systolic BP (≥150 mm Hg) groups . It is possible that a J-curve effect on systolic BP could account for the lack of stroke decrease in the telmisartan-treated compared with placebo-treated patients. In the case of the SCAST study , there are several problems in which candesartan was not better than placebo, or even worse in improving the survival rate of patients with acute stroke. In this study, patients with an acute ischemic stroke were treated immediately with candesartan if their admission systolic BP was 140 mm Hg or higher. However, it has been shown that lowering the systolic BP below 140 mm Hg immediately after an acute ischemic stroke has detrimental effects with respect to stroke extension and patient survival . In the SCAST study, there is speculation that the SBP was reduced below 140 mm Hg immediately after the stroke in several patients treated with candesartan, and that this could have accounted for the no benefit or even harm with candesartan. There is a possibility of a J-curve effect in this study as well with respect to systolic BP. Treatment of acute ischemic stroke is a very delicate process because in many patients, the hospital admission systolic BP is higher than 160 mm Hg and will return to normal levels after a few hours without any intervention . Therefore, immediate BP lowering is not necessary in the majority of such patients. Regardless of the debate as to whether ARBs are superior or not to other antihypertensive drugs in preventing strokes, we believe that ARBs should be preferred over other agents if there is no contraindication for their use because they are effective in lowering BP and are almost free of side effects.
In conclusion, good control of BP is critical in stroke protection. With respect to drug selection, ARBs should be preferred alone or in combination with other drugs that stimulate Ang II production, such as diuretics and calcium channel blockers . However, the focus should always be good BP control over the long term, regardless of drug selection.
No potential conflicts of interest relevant to this article were reported.