Angiotensin modulation and cerebroprotection

Reviewer: K. W. Tim Park, MD
Beth Israel Deaconess Medical Center
Boston, MA

Hypertension is a significant risk factor for stroke, however, reduction of blood pressure by different classes of antihypertensives is not uniformly protective against cerebral injury.1 Whereas diuretics (especially thiazides), calcium channel blockers (CCBs), and angiotensin receptor blockers (ARBs) have been found to be efficacious,2-5 ƒ-blockers and angiotensin converting enzyme (ACE) inhibitors have not been shown to consistently reduce the risk and severity of stroke.6-9 Fournier et al.1 hypothesized that diuretics, CCBs, and ARBs increase angiotensin II (AG II) formation by stimulating renin secretion through sodium depletion, sympathetic activation, or blunting of the negative feedback. Stimulation of angiotensin type one (AT1) receptors may protect against strokes by causing vasoconstriciton of proximal cerebral arteries and preventing Charcot-Bouchard aneurysm from rupturing,10 while the cerebroprotective effect of AG II is by stimulation of type two (AT2) receptors. In a rat model of experimental brain ischemia, the AT1-specific ARB, irbesartan, in doses low enough not to affect the systemic blood pressure improved the neurologic outcome,11 but this effect was prevented by co-administration of an AT2 receptor blocker1. Similarly, in a gerbil model of acute stoke by carotid ligation, mortality was reduced either by administration of AG II (compared to an isohypertensive dose of metaraminol)12 or of an AT2 agonist.13 AT2 stimulation may facilitate the recruitment of collateral vessels and increase neuronal resistance to anoxia.1

Clinical studies of ACE inhibitors have produced mixed results on cerebral protection. In the perindopril protection against recurrent stroke study (PROGRESS),9 6,105 patients were randomized to perindopril or a placebo. The diuretic indapamide could be added at the discretion of the investigator. Whereas perindopril by itself did not produce a significant reduction in strokes, the combination of perindopril and indapamide produced a 43% relative risk reduction (RRR) (P < 0.001). Three other trials of ACE inhibitors did not find a significant RRR of strokes.14-16 On the other hand, in the Heart Outcomes Prevention Evaluation (HOPE) study,17 ramipril was associated with a 32% RRR in stroke (P < 0.01). It may be that whereas strokes in uncomplicated hypertension are often ischemic (lacunar) or hemorrhagic and related to small cerebral vessel disease,18 strokes associated with cardiac diseases (which the patients in the HOPE study frequently had) are most often embolic and related to plaque destabilization. Thus, depending on the study population, ACE inhibitors may reduce cardiac complicatons or have significant plaque stabilization effects, so as to secondarily reduce cerebrovascular complications (the HOPE study), but would not be expected to have a salutatory effect on cerebral vessels themselves (the PROGRESS study).

Theoretically, the ARBs provide double protection against strokes by inhibiting the AT1-receptor mediated proatherosclerotic effects and by causing a compensatory increase in AG II and enhancing AT2-mediated protection against cerebral ischemia. In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study,5 9,193 patients with hypertension and left ventricular hypertrophy were randomized to a regimen of losartan or atenolol to control blood pressure. The losartan group had a 25% RRR in stroke (P = 0.001) after a mean follow-up of four years and, in a subgroup,19 a 40% RRR in stroke (P = 0.02) after a follow-up of 4.7 years. Likewise, the acute candesartan cilexetil therapy in stroke survivors (ACCESS) study was designed to assess the safety of modest blood pressure reduction by candesartan cilexetil in the early treatment of stroke.20 The study was stopped prematurely, because of a marked imbalance in the endpoints of death or vascular events. After 339 patients, the odds ratio of death or a vascular event was 0.475 (i.e., 52.5% RRR) in favor of the candesartan group compared to the placebo group. The 12 month mortality was 2.9% vs 7.2% and the vascular event rate was 9.8% vs. 18.7% in favor of the candesartan group. These studies appear to provide a convincing support that ARBs provide cerebroprotection.

In summary, cerebroprotection may be afforded by measures to stimulate the AT2 receptors and block the AT1 receptors in the brain. ARBs provide both of these benefits and the cerebro-protection has been demonstrated in clinical studies. Although ACE inhibitors tend to result in indiscriminate reduction in both AT1 and AT2 stimulation in the brain, their systemic antiatherosclerotic effects may reduce cardiac complications and secondarily lead to reduction in strokes. This accounts for the conflicting results of the effect of ACEi on the incidence of strokes. Whether ARBs or ACE inhibitors may have cerebroprotective effects in relevant operative settings in man such as in carotid endarterectomy or with deep hypothermic circulatory arrest remains to be investigated.

References

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