RAS Inhibition Attenuates Cognitive Impairment by Reducing Blood-Brain Barrier Permeability in Hypertensive Subjects

Recent studies have suggested that blood-brain barrier (BBB) abnormalities are present from an early stage in patients exhibiting mild symptoms of cognitive impairment during the development of hypertension. There is also growing body of evidence suggesting the potential role of the renin-angiotensin system (RAS) in the pathogenesis of small-vessel disease and cognitive impairment. However, the specific contribution of the RAS to BBB disruption and cognitive impairment remains unclear. We found a significant leakage from brain microvessels in the hippocampus and impaired cognitive functions in angiotensin II (AngII)-infused hypertensive mice, which were associated with increased brain AngII levels. These changes were not observed in AngII-infused AT(1a) receptor (-/-) mice. We also observed that Dahl salt-sensitive hypertensive rats exhibited hypertension, leakage from brain microvessels in the hippocampus, and impaired cognitive function. In these animals, treatment with an AngII receptor blocker, olmesartan, did not alter blood pressure, but markedly ameliorated leakage from brain microvessels and restored the cognitive decline. These data support the hypothesis that RAS inhibition attenuates cognitive impairment by reducing BBB injury, which is independent of blood pressure changes.