If the answer is yes to the question above, what could be the pathophysiologic mechanism accounting for a greater cerebroprotective effect of diuretics compared with other antihypertensive drugs? A very bold hypothesis to explain this phenomenon was put forward by Brown and Brown19 after the publication of the MRC trial. These authors proposed that the activation of the renin angiotensin system and increased angiotensin II levels could have a protective effect against stroke. Angiotensin II, by predominantly constricting the larger cerebral blood vessels, would help protect the smaller reticular striate arteries where Charcot-Bouchard aneurysms usually are located, the rupture of which is a common cause of intracerebral hemorrhage in patients with hypertension. Fournier et al20 refined this hypothesis by suggesting that the protective effects against cerebrovascular disease were related to the angiotensin II non-AT1 receptors, which are only expressed in the ischemic zones of the brain. Non-AT1 receptors have been shown to become up-regulated after global ischemia in the brain and may serve as mediators of protective mechanisms by recruiting collateral circulation and decreasing neuronal apoptosis.21,22 Thus, blockade of the AT1 receptor (and sparing the non-AT1 receptor) by an angiotensin receptor blocker could be more protective against stroke than decreasing angiotensin II by ACE inhibition. In the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study, AT1 blockade with losartan potassium decreased the stroke risk 25% better than did atenolol-based therapy at similar blood pressure levels.23 Indeed, the superiority of AT1 blockade over ACE inhibition at equipotent blood pressure reduction was confirmed in 2 different experimental models.24,25 Conceivably, a greater stimulation of these non-AT1 rescue mechanisms by diuretics (which increase the activity of the renin angiotensin system), angiotensin receptor blockers, and calcium antagonists compared with β-blockers or ACE inhibitors would account for a greater protection against strokes in patients without cardiovascular disease. In contrast, in patients with cardiovascular disease, a high percentage of strokes probably originates directly from cardiac disease or destabilization of atherosclerotic plaque. In such a population, reduction of circulating angiotensin II levels by ACE inhibition would more likely be beneficial by reversing or preventing cardiovascular disease. The Fournier hypothesis would allow us to explain the distinctly smaller difference in ischemic strokes between diuretic and nondiuretic therapy in patients with a history of cardiovascular disease compared with those with no cardiovascular disease in the Klungel study12 and the cerebrovascular benefits of the ACE inhibitor used in the Heart Outcomes Prevention Evaluation (HOPE) study,26 in which more than 80% of the patients had cardiovascular disease. If this hypothesis holds true, diuretics, angiotensin receptor blockers, and calcium antagonists should prove to be more cerebroprotective than β-blockers or ACE inhibitors in hypertensive patients without preexisting heart disease.