The Pathophysiologic Role of the Brain Renin‐Angiotensin System in Stroke Protection: Clinical Implications

Abstract

The brain possesses the same renin‐angiotensin system (RAS) as the systemic circulation. Recent experimental studies have shown that the brain RAS plays an important role in stroke and neuronal protection through its effector peptide angiotensin (Ang) II. Ang II exerts its stroke‐protective effects through stimulation of Ang II type 2 (AT₂) receptors. Angiotensin receptor blockers (ARBs) exert a dual influence, which is important in their stroke protective effects. They selectively block the Ang II type 1 (AT₁) receptors, decreasing local vasoconstriction, and allow free Ang II to stimulate the unoccupied AT₂ receptor and increase local vasodilation, resulting in the alleviation of local brain ischemia and limiting the volume and extent of brain loss. In contrast, angiotensin‐converting enzyme (ACE) inhibitors, by decreasing the amount of Ang II production, may diminish the stroke‐protective effects of Ang II. This perhaps could be a reason for the inferior stroke‐protective effect of ACE inhibitors compared with ARBs, which has been demonstrated in several clinical trials. The evidence for this effect of ARBs compared with ACE inhibitors, however, is only indirect. Ongoing clinical trials with head‐to‐head comparisons of ARBs and ACE inhibitors will hopefully provide the needed information.

The renin‐angiotensin system (RAS) plays an important role in cardiovascular homeostasis through its effector peptide angiotensin (Ang) II, the final product of the RAS cascade. Ang II, a potent vasoactive hormone, exerts its hemodynamic and structural effects through stimulation of its specific Ang II type 1 (AT₁) and Ang II type 2 (AT₂) receptors. Ang II is formed mainly through the classical pathway by the conversion of Ang I to Ang II through the angiotensin‐converting enzyme (ACE). In addition, Ang II is formed through alternate pathways by the action of other enzymes, especially chymase, which bypass the ACE pathway. ¹ This latter pathway has recently been attracting attention because the generation of Ang II is independent of the ACE pathway, making the ACE inhibitors ineffective for this part of the action of Ang II. In contrast, angiotensin receptor blockers (ARBs), which selectively block the AT₁ receptors, are not dependent on the mechanism of Ang II generation. The components of the RAS, which exist in the systemic circulation, have also been identified in the brain. ² , ³ In the brain, the RAS serves as a local autocrine system to maintain cerebral homeostasis. Its significance as a neuroprotector, however, was not recognized until recently, when clinical and experimental evidence suggested a stroke‐protective effect of Ang II mediated through the AT₂ receptor. In this review, clinical and experimental evidence for the important role of the brain RAS and its clinical and therapeutic implications will be summarized.

THE ROLE OF ANG II IN STROKE PROTECTION

The first provocative hypothesis that Ang II might have some stroke‐protective effects was advanced by Brown and Brown ⁴ 20 years ago. Their hypothesis was generated from the results of the first Medical Research Council trial ⁵ in which patients with mild hypertension treated with the diuretic bendrofluazide had a 70% decrease in stroke incidence, compared with a 27% decrease in stroke incidence in individuals treated with the β‐blocker propranolol for a similar reduction of blood pressure (BP). The greater stroke reduction with the diuretic was attributed to the stimulation of the brain RAS, which leads to increased production of Ang II that causes constriction of the larger cerebral arteries, thus decreasing the pressure in the small lenticular arteries and preventing the rupture of Charcot‐Bouchard microaneurysms and the development of cerebral hemorrhage. Brown and Brown also speculated that the same mechanism could apply to atherothrombotic strokes due to the dual action of Ang II in constricting the larger arteries and dilating the smaller ones. This latter effect of Ang II was attributed to the local release of prostacyclin or other vasodilatory prostaglandins. ⁶ , ⁷ It is possible that this action of Ang II was mediated through stimulation of the AT₂ receptors. ⁸

FUNCTION OF AT₁ AND AT₂ RECEPTORS

AT₁ Receptors

Both AT₁ and AT₂ receptors belong to the super‐family of G proteins, but they differ with respect to their expression and signaling pathways. The AT₁ receptor is ubiquitous and is fully expressed in the adult organism. Its signaling pathways include the G protein‐related cascade of phospholipases C, D, and A2 ⁹ and mediates the main actions of Ang II, which involve BP control, vasoconstriction, vascular remodeling, salt and water balance, and drinking behavior. ⁹ , ¹⁰ In the brain, Ang II acting through the AT₁ receptor may cause ischemic injury via local vasoconstriction and disruption of the local cerebral blood flow. Other possible mechanisms of Ang II mediated via the AT₁ receptor include induction of inflammation and production of reactive oxygen species resulting in cell destruction and apoptosis. ⁹ Neuronal necrosis and apoptosis have been observed after an ischemic stroke and although some brain cells are lost immediately, other cells in the periphery of the lesion (penumbra) remain alive but severely compromised and can be revived with the reestablishment of local blood flow. ¹¹ , ¹² Revival of these cells results in a decrease in volume and extent of brain injury. Therefore, interruption of the action of Ang II through blockade of the AT₁ receptors may limit the extent of the brain infarct. ¹¹ , ¹²

AT₂ Receptors

In contrast to AT₁ receptors, which are ubiquitously expressed in the adult organism, the AT₂ receptors are mainly fetal. Their number is greatly decreased after birth; however, they can still be identified in the vascular endothelial cells, the myocardium, and the central and peripheral neurons, as well as other tissues. ⁹ In addition, these receptors are greatly up‐regulated in areas of tissue injury such as myocardial infarction and brain damage. Li and colleagues ³ demonstrated a 2.1‐fold up‐regulation of AT₂ receptors by Western blot analysis in the ischemic area of the brain after middle cerebral artery occlusion (MCO) in rats. In contrast, there was no significant change in the AT₁ receptors. The signaling pathways of the AT₂ receptors are not well defined but include the activation of phospholipase A2, which leads to modification of lipid messengers and the increased activity of RAS p21, a protein kinase involved in neuronal survival and neurite outgrowth. ⁹ Other investigators have reported that stimulation of the AT₂ receptors preserves cognitive function in the rat. ⁶ Thus, the AT₂ receptor appears to play an important role in the stroke‐ and neuronal‐protective effects of Ang II, as depicted in the Figure.

STROKE‐PROTECTIVE EFFECTS OF ACE INHIBITORS AND ARBs

Experimental Evidence

Many animal studies in gerbils and rats have demonstrated that ARBs decrease the volume and the extent of infarcted brain tissue produced by MCO. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ The protective effects of Ang II on the ischemic brain of gerbils appeared to be mediated through stimulation of the AT₂ receptors. ¹⁴ Brain‐ischemic gerbils pretreated with either the selective AT₁‐receptor blocker losartan or the selective AT₂‐receptor agonist PD‐123319 but not the ACE inhibitor enalapril had decreased mortality. These experiments reinforced the hypothesis that Ang II exerts its cerebroprotective effects via stimulation of the AT₂ receptor; this effect appears to be enhanced by the selective blockade of the AT₁ receptors. Findings that support the above hypothesis have been reported ¹⁵ in normotensive Wistar rats and gerbils. ¹⁶ Intracerebral administration of low‐dose irbesartan, an ARB that blocked the cerebral but not the systemic AT₁ receptors for 5 days before the induction of local brain ischemia by MCO for 90 minutes, improved the neurologic outcome. In other studies in spontaneous hypertensive stroke‐prone rats, administration of the ARB losartan in low or high doses, had a cerebroprotective effect that was independent of its BP‐lowering effect. ¹⁷ , ¹⁸

Clinical Evidence

The experimental studies discussed above provide evidence of the cerebroprotective effects of ARBs compared with ACE inhibitors.

ACE Inhibitors. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), ¹⁹ treatment with perindopril resulted in only a 5% (not significant) reduction of recurrent stroke for 5/3 mm Hg reduction in BP compared with a 43% reduction with the combination of perindopril and the diuretic indapamide for a 12/5 mm Hg BP reduction. The additional 7‐mm Hg reduction of systolic BP (SBP) with combination therapy could have accounted for a 28% stroke reduction, not 43%, since it has been estimated that a 1.0‐mm Hg decrease in SBP accounts for approximately a 3% to 4% reduction in strokes. Similar results were reported in black patients in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ²⁰ The 40% higher incidence of strokes in individuals treated with lisinopril‐based therapy compared with a diuretic‐based treatment regimen cannot, however, be completely explained by the 4‐mm Hg higher SBP in the ACE inhibitor group. The Captopril Prevention Project (CAPP) ²¹ reported a 25% increase in stroke incidence in patients treated with a captopril‐based regimen by intent‐to‐treat analysis, compared with a 43% lower incidence of stroke in people treated with a β‐blocker/diuretic regimen. The authors speculate, however, that part of the higher incidence of stroke in the captopril group could be due to poorer control of BP in this group. The 3‐mm Hg difference in SBP may not account for the 25% higher incidence of strokes. In patients who achieved lower BP, however, the reduction appeared to be similar in both treated groups.

Similar results were reported by the second Australian National Blood Pressure Study (ANBP) ²² 22 of elderly hypertensive patients treated with ACE inhibitors or diuretics. In the original report, the results were equivocal, but in a subsequent analysis, ²³ stroke incidence was higher in the ACE inhibitor‐treated group, compared with the diuretic‐treated groups (2.3 vs 1.2 per 1000 patient‐years, or 47.8%). A large meta‐analysis of 28 outcomes trials including 179,122 hypertensive patients reported that the stroke‐protective effects of ACE inhibitors were fewer than with calcium channel blockers (CCBs), but benefit was greater in prevention of coronary heart disease with an ACE inhibitor compared with a CCB. ²⁴ Two other studies showed divergent results. The DIABetes Hypertension microalbuminura or proteinuria CARdiovascular events and Ramipril (DIABHYCAR) study ²⁵ did not show any difference in stroke incidence between ramipril and placebo in treated diabetic patients, although the SBP and diastolic BP were 2.4 and 1.1 mm Hg lower in the ramipril‐treated group, respectively. In contrast, the Heart Outcomes Prevention Evaluation (HOPE) study ²⁶ reported a 32% stroke reduction in the ramipril‐treated patients compared with placebo plus other medications, other than the ACE inhibitor, for a comparable reduction in BP. These studies are summarized in the Table. Thus, the data on stroke prevention in patients treated with ACE inhibitor‐based treatment are somewhat controversial.

Table.

Stroke Incidence from Clinical Trials of Angiotensin‐Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

Study	Subject Pathology	No. of Patients	Follow‐Up, y	Treatment	Change in Incidence of Stroke
PROGRESS 19	Poststroke	6105	4.0	Perindopril vs placebo	5.0% decrease
ALLHAT 20	Hypertensive	24,309	4.9	Lisinopril vs chlorthalidone	40% increase in blacks 15% increase (overall)
CAPP 21	Hypertensive	10,985	6.1	Captopril vs diuretics, β‐blockers	25% increase
ANBP 23	Elderly hypertensive	6083	4.1	Enalapril vs hydrochlorothiazide	48% increase
DIABHYCAR 25	Diabetic with microalbuminuria	4912	4.0	Ramipril vs placebo	No change
HOPE 26	Mostly normotensive with coronary artery disease and peripheral vascular disease	9297	5.0	Ramipril vs placebo	32% decrease
LIFE 27	Hypertensive with left ventricular hypertrophy	9193	4.5	Losartan vs atenolol	25% decrease
LIFE‐ISH 28	Elderly hypertensive	1326	4.7	Losartan vs atenolol	40% decrease
SCOPE 29	Elderly hypertensive	4964	3.7	Candesartan vs conventional drugs	28% decreasea
SCOPE‐ISH 30	Elderly hypertensive	1518	5.0	Candesartan vs conventional drugs	42% decrease
ACCESS‐PILOT 31	Poststroke	339	1.0	Candesartan vs placebo	52% decrease
MOSES 32	Poststroke hypertension	1405	2.5	Eprosartan vs nitrendipine	25% decrease
VALUE 33	High‐risk hypertensive	15,245	4.8	Valsartan vs amlodipine	25% decreaseb
aCandesartan reduced nonfatal stroke by 27.8% (P=.04) and all stroke by 23.6% (P=.056). bValsartan decreased stroke by the end of the study, but the overall stroke incidence was 15% higher in the valsartan group. See text for study name expansions.

Angiotensin Receptor Blockers. Several large clinical outcomes trials have reported that treating high‐risk hypertensive patients with ARBs results in a significant reduction of stroke. In the Losartan Intervention For Endpoint reduction (LIFE) study, ²⁷ hypertensive patients with left ventricular hypertrophy treated with a losartan‐based regimen had a 25% reduction in stroke incidence compared with those treated with an atenolol‐based treatment regimen with an almost similar decrease in BP (1‐mm Hg difference). In a substudy of the LIFE study in elderly patients with isolated systolic hypertension (LIFE‐ISH) and left ventricular hypertrophy, the incidence of stroke was 40% lower in the losartan‐treated compared with the atenolol‐treated patients. ²⁸ Additional findings were later reported by the investigators of the Study on Cognition and Prognosis in the Elderly (SCOPE) ²⁹ of elderly hypertensive patients. In this study, patients treated with an ARB, candesartan‐based regimen had a 27.8% reduction in nonfatal strokes and a 23.6% reduction in total strokes, compared with conventionally treated patients with a similar decrease in BP. It should be noted, however, that the control group was treated with placebo for the first 3 months of the study before being changed to active treatment; there was an initial BP difference of −3.2/1.6 mm Hg in the ARB‐treated group, which may have accounted for some of the difference. In a substudy of SCOPE of patients with isolated systolic hypertension, the stroke incidence was 42% lower in the candesartan‐treated group compared with the patients treated with placebo or active drugs. ³⁰ Results in the prevention of stroke recurrence with candesartan treatment were also reported from the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) pilot study. ³¹ In this study, treatment with candesartan cilexetil for hypertensive patients with a past stroke for 12 months resulted in a 52% reduction in recurrent strokes and cerebrovascular events compared with placebo plus antihypertensive agents other than the ARB, although there was no significant difference in BP between the 2 groups.

In a similar, longer‐term study of the Morbidity and Mortality after Stroke Eprosartan Study (MOSES), ³² hypertensive patients treated with either an eprosartan‐based or nitrendipine‐based regimen had a 25% reduction of recurrent strokes in favor of eprosartan for a similar decrease in BP. The results of the Valsartan Antihypertensive Long‐Term Use Evaluation (VALUE) study ³³ were not as expected. In this study, high‐risk hypertensive patients were treated with an ARB valsartan‐based or a CCB amlodipine‐based regimen. Due to the slower, early control of BP in the ARB treatment group, the early incidence of stroke was higher in this group. As the study progressed, however, and the BP differences between the 2 groups were narrowed, the incidence of stroke was lower in the valsartan treatment group but did not reverse the overall incidence of strokes, which was 15% higher in the valsartan treatment group by the end of the study. This study clearly demonstrated the importance of early BP control regarding the prevention of cardiovascular and cerebrovascular complications of hypertension.

In addition to these published studies, there are 2 ongoing studies that, when completed, may provide useful information. The Ongoing Telmisartan Alone and in comparison with Ramipril Global Endpoint Trial (ONTARGET) ³⁴ compares telmisartan 80 mg/d vs ramipril 10 mg/d vs their combination regarding myocardial infarction and stroke incidence in 25,600 high‐risk patients. The results of this study are expected to be published in 2007. The Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) ³⁵ is investigating the effects of 4 treatment regimens on recurrent strokes in 18,500 patients with a previous stroke. The drugs used in this study are extended‐release dipyridamole, 400 mg/d; aspirin, 50 mg/d; clopidogrel, 75 mg/d; and telmisartan, 80 mg/d. These drugs are used in combination in 4 treatment regimens. The duration of this study is 5 years, and the results are expected in 2008.

DISCUSSION

Stroke is a major cause of morbidity and mortality, and its incidence increases linearly with increasing age and BP. There are 700,000 incident strokes annually, of which 200,000 are recurrent strokes. ³⁶ Stroke, besides being a cause of long‐term disability, is also a significant burden on society and health care expenditures, which amounted to $56.8 billion in direct and indirect costs in the United States for 2005. ¹ Since stroke is linearly related to both SBP and diastolic BP, control of BP is critical in controlling stroke incidence. Whether the choice of drug selection for the treatment of hypertension might play a role in addition to good BP control is currently being investigated. In this review, evidence is presented that the brain possesses its own RAS and that Ang II plays an important role in stroke protection. In addition, evidence is presented that Ang II exerts its stroke‐protective effects through stimulation of the AT₂ receptors and that ARBs, by selectively blocking the AT₁ receptors and allowing the free Ang II to stimulate the unoccupied AT₂ receptors, produce a dual effect of decreasing local vasoconstriction and enhancing local vasodilation (Figure). The evidence suggesting that ARBs are superior to ACE inhibitors is only indirect; there are no studies, at present, that have compared ARBs with ACE inhibitors. It is anticipated that 2 ongoing trials, ONTARGET and PRoFESS, will provide needed information regarding ARBs and ACE inhibitors in stroke prevention. For now, the critical control of BP to target levels of <140/90 mm Hg for uncomplicated hypertensive patients and to <130/80 mm Hg for patients with diabetes or renal disease is critical. Medications that stimulate the RAS such as diuretics and CCBs may be useful in the treatment of hypertensive patients to prevent strokes. The stroke reduction reported in 4 large clinical trials of older hypertensive patients treated with a diuretic‐ or a CCB‐based regimen has been impressive. Patients treated with the diuretics indapamide ³⁶ or chlorthalidone ³⁷ or the CCBs nitrendipine ³⁸ or amlodipine ³⁹ had a stroke reduction of 29%, 36%, 42%, and 33%, respectively, compared with a control group. BP, however, was lower by 5/2, 2/4, 10.1/4.5, and 2.7/1.9 mm Hg, respectively, in the diuretic‐ or CCB‐treated groups. This may account for the difference in outcome. Drugs that suppress the RAS, such as ACE inhibitors and β‐blockers, however, may not be as effective in stroke reduction as are ARBs for example and may not be agents of choice. ⁴⁰

Figure.

Mechanism of stroke‐protective action of angiotensin II (Ang II) and its blockade by angiotensin receptor blockers (ARBs). Abbreviations: AT₁, Ang II type 1 receptor; AT₂, Ang II type 2 receptor; ‐, blockade of AT₁ action; +, enhancement of AT₂ action; ↓ decreased; ↑, increased.