Stroke prevention: is it possible?If so, which antihypertensiveagent should be used?Shokei KimDepartment of Pharmacology, Osaka City University Graduate School of

Medicine, Osaka, Japan

Address for correspondence: Dr Shokei Kim, Associate Professor, Department of Pharmacology,Osaka City University Graduate School of Medicine, Osaka, Japan

Key words: Angiotensin receptor blockers – Candesartan – Cerebral blood flow – Hypertension – Stroke– Vascular autoregulation

442 Paper 2382

Background

Blood pressure control is very important for strokeprevention: this finding is supported by a large amountof clinical evidence1–3. However, it has not yet beendetermined which antihypertensive agents are mosteffective to prevent stroke.

As stroke is characterised by vascular remodelling anddysfunction and by effects on the cerebral circulation,selecting an agent that has a direct vascular protectiveeffect beyond blood pressure control may be desirable.

Angiotensin receptor blockers (ARBs) are known tohave cardiac and renal protective effects and animportant mechanism for this protection is theprevention of vascular remodelling. In a rat ballooninjury model, which is known to induce a dramaticformation of the neointima, the ARB candesartansignificantly prevents neointimal formation4.Furthermore, ARBs inhibit vascular remodelling in anumber of different experimental vascular diseasemodels, including spontaneously hypertensive rats(SHR), balloon injury in stroke-prone spontaneouslyhypertensive rats (SHRSP) and type 2 diabetic rats5.

Cerebral vascularautoregulation

One important question to come out of the research to

date with angiotensin II is whether the pleiotropic

effect(s) of this agent on the heart and kidney also

applies to the brain. The ARBs have dramatic and

differential effects on cerebral vascular autoregulation

curves in normotensive patients6–8 (Figure 1).

Hypertension is known to shift the autoregulation curve

to the right6. Interestingly, the ARB candesartan shifts

the autoregulation curve to the left7,8, showing that

candesartan normalises cerebral vascular autoregulation.

In contrast, losartan is reported to shift the

autoregulation curve toward the right9. Of these two

ARBs, only candesartan normalises cerebral blood flow

autoregulation. Currently, the mechanism for these

differential effects of candesartan and losartan on

autoregulation is unknown.

The importance of blood pressure control in strokeprevention is supported by a large body of clinicalevidence. However, it is not known whichantihypertensive agents are most effective inpreventing stroke. As stroke is characterised byvascular remodelling and dysfunction and byeffects on the cerebral circulation, selecting an

agent that has a direct vascular protective effectbeyond blood pressure control may be desirable.Results with the angiotensin receptor blockers(ARBs) in clinical trials (LIFE and SCOPE) supportthe findings in animal models that ARBs may be apromising therapeutic option for prevention ofstroke and possibly, cognitive decline.

S U M M A R Y

CURRENT MEDICAL RESEARCH AND OPINION®

VOL. 19, NO. 5, 2003, 442–444

© 2003 LIBRAPHARM LIMITED

0300-7995

doi:10.1185/030079903125001965

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© 2003 LIBRAPHARM LTD – Curr Med Res Opin 2003; 19(5) Stroke Prevention: Which Antihypertensive Agent? Kim 443

Candesartan and cerebralblood flow

In addition to the improvement of cerebral vascularautoregulation by candesartan, a recent report10 showedthat candesartan treatment protected against ischaemiaand improved cerebral blood flow in spontaneouslyhypertensive rats subjected to middle cerebral arteryocclusion. The apparent beneficial effect of candesartanon blood circulation in the brain may play an importantrole in treating or preventing stroke, given thepathophysiology of the disease.

Effects of candesartan inSHRSP rats

Recent work from this laboratory comparing the effectsof the calcium channel blockers (CCB) amlodipine withthe ARB candesartan in salt-loaded SHRSP showscandesartan (1 mg/kg) and amlodipine (1 mg/kg)produced only a small reduction in blood pressure in theSHRSP rats. However, the effect on survival was verydifferent between amlodipine and candesartan (Figure2). In the placebo group, all of the rats died in the earlyphase of the study. In the amlodipine group, all of therats died within 150 days, whereas throughout the drugtreatment period all of the rats survived in thecandesartan group. There were no deaths in thecandesartan group until the drug was withdrawn and theanti-stroke effect of candesartan appeared to continueeven after candesartan was withdrawn, as shown by theextended survival period.

LIFE and SCOPE results

Results seen to date with the ARBs in the LIFE andSCOPE studies support the findings in animal modelsthat ARBs may be a promising therapeutic option for theprevention of stroke and, possibly, cognitive decline.The LIFE study11 compared the ARB losartan with theβ-blocker atenolol. This study was performed in a groupof hypertensive patients (55–80 years) with evidence ofleft ventricular hypertrophy. One of the endpoints ofthe LIFE study was the effect of active treatment onfatal and non-fatal strokes. The results showed that 232patients receiving losartan and 309 receiving atenololhad fatal or non-fatal stroke (relative risk 0.75; 95% CI,0.63–0.89; p =0.001). Thus, losartan was significantlymore effective than atenolol in reducing strokes inpatients with hypertension, diabetes and left-ventricularhypertrophy. Furthermore, losartan seems to havebenefits beyond blood pressure control. Similarly, in theSCOPE study12 there was a significant 28% reduction( p = 0.041) of non-fatal stroke, which was a pre-specified secondary endpoint. In addition, there was asignificant reduction ( p = 0.04) in cognitive decline inpatients with a baseline MMSE score of 24–28 whentreated with candesartan (post hoc analysis).

Conclusion

Stroke is characterised by vascular remodelling anddysfunction and by effects on the cerebral circulation.Therefore, selecting an agent that has a direct vascularprotective effect beyond blood pressure control may bedesirable. Several studies have shown that ARBs inhibitvascular remodelling in a number of differentexperimental vascular disease models, includingspontaneously hypertensive rats (SHR), balloon injury

Figure 1. Differential effects of angiotensin receptor blockers(ARBs) on cerebrovascular autoregulation6–9

BP (mmHg)60 160

Cerebral blood flow

Normotension

Hypertension(Strandgaard, 19736)

Losartan to right(Stromberg, 199310)

Candesartan to left(Vraamark, 19958)

Figure 2. Effects of candesartan and amlodipine on survivalin salt-loaded, stroke-prone spontaneously hypertensive rats

(SHRSP)

0 50 100 150 200 250

Su

rviv

al r

ate

(%)

Period days

Vehicle Amlodipine 1 mg/kg

Drug treatment

0

20

40

60

80

100

Candesartan 1 mg/kg

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444 Stroke Prevention: Which Antihypertensive Agent? © 2003 LIBRAPHARM LTD – Curr Med Res Opin 2003; 19(5)

in stroke-prone spontaneously hypertensive rats(SHRSP) and type 2 diabetic rats5. These experimentalfindings with ARBs, particularly candesartan, and therecent results from the LIFE11and SCOPE12 trials,provide further evidence that ARBs may be a promisingtherapeutic option for the prevention of stroke and,possibly, cognitive decline.

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4. Kim S, Kawamura M, Wanibuchi H, et al. Angiotensin II type 1receptor blockade inhibits the expression of immediate-earlygenes and fibronectin in rat injured artery. Circulation1995;92(1):88-95

5. Kim S, Iwao H. Molecular and cellular mechanisms ofangiotensin II-mediated cardiovascular and renal diseases.Pharmacol Rev 2000;52(1):11-34

6. Strandgaard S, Olesen J, Skinhoj E, Lassen NA. Autoregulation ofbrain circulation in severe arterial hypertension. BMJ1973;1(5852):507-10

7. Vraamark T, Waldemar G, Strandgaard S, Paulson OB.Angiotensin II receptor antagonist CV-11974 and cerebral bloodflow autoregulation. J Hypertens 1995;13(7):755-61

8. Nishimura Y, Ito T, Saavedra JM. Angiotensin II AT(1) blockadenormalizes cerebrovascular autoregulation and reduces cerebralischemia in spontaneously hypertensive rats. Stroke2000;31(10):2478-86

9. Stromberg C, Naveri L, Saavedra JM. Nonpeptide angiotensinAT1 and AT2 receptor ligands modulate the upper limit of cere-bral blood flow autoregulation in rats. J Cereb Blood Flow Metab1993;13(2):298-303

10. Ito T, Yamakawa H, Bregonzio C, Terron JA, Falcon-Neri A,Saavedra JM. Protection against ischaemia and improvement ofcerebral blood flow in genetically hypertensive rats by chronicpretreatment with an angiotensin II AT1 antagonist. Stroke2002;33(9):2297-303

11. Kjeldsen SE et al. Cardiovascular morbidity and mortality in theLosartan Intervention For Endpoint reduction in hypertensionstudy (LIFE): a randomised trial against atenolol. Lancet2002;359:995-1003

12. Lithell H, Hansson L, Skoog I, et al., for the SCOPE StudyGroup. The Study on Cognition and Prognosis in the Elderly(SCOPE): principal results of a randomized double-blind inter-vention trial. J Hypertens 2003;21:875-86

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2382, Accepted for publication: 13 May 2003Published Online: 02 July 2003

doi:10.1185/030079903125001965

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