The Role of Angiotensin II Receptors in Stroke Protection

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 beta-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 beta-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.