Mechanisms of the Anti-Ischemic Effect of Angiotensin II AT1 Receptor Antagonists in the Brain

Abstract

SUMMARY1. Circulating and locally formed Angiotensin II regulates the cerebral circulation through stimulation of AT 1 receptors located in cerebrovascular endothelial cells and in brain centers controlling cerebrovascular flow.2. The cerebrovascular autoregulation is designed to maintain a constant blood flow to the brain, by vasodilatation when blood pressure decreases and vasoconstriction when blood pressure increases.3. During hypertension, there is a shift in the cerebrovascular autoregulation to the right, in the direction of higher blood pressures, as a consequence of decreased cerebrovascular compliance resulting from vasoconstriction and pathological growth. In hypertension, when perfusion pressure decreases as a consequence of blockade of a cerebral artery, reduced cerebrovascular compliance results in more frequent and more severe strokes with a larger area of injured tissue.4. There is a cerebrovascular angiotensinergic overdrive in genetically hypertensive rats, manifested as an increased expression of cerebrovascular AT 1 receptors and increased activity of the brain Angiotensin II system. Excess AT 1 receptor stimulation is a main factor in the cerebrovascular pathological growth and decreased compliance, the alteration of the cerebrovascular eNOS/iNOS ratio, and in the inflammatory reaction characteristic of cerebral blood vessels in genetic hypertension. All these factors increase vulnerability to brain ischemia and stroke.5. Sustained blockade of AT 1 receptors with peripheral and centrally active AT 1 receptor antagonists (ARBs) reverses the cerebrovascular pathological growth and inflammation, increases cerebrovascular compliance, restores the eNOS/iNOS ratio and decreases cerebrovascular inflammation. These effects result in a reduction of the vulnerability to brain ischemia, revealed, when an experimental stroke is produced, in protection of the blood flow in the zone of penumbra and substantial reduction in neuronal injury.6. The protection against ischemia resulting is related to inhibition of the ReninAngiotensin System and not directly related to the decrease in blood pressure produced by these compounds. A similar decrease in blood pressure as a result of the administration of β-adrenergic receptor and calcium channel blockers does not protect from brain ischemia.7. In addition, sustained AT 1 receptor inhibition enhances AT 2 receptor expression, associated with increased eNOS activity and NO formation followed by enhanced vasodilatation. Direct AT 1 inhibition and indirect AT 2 receptor stimulation are associated factors normalizing cerebrovascular compliance, reducing cerebrovascular inflammation and decreasing the vulnerability to brain ischemia.

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

“…Among other drugs thought to confer stroke protection via the eNOS/cGMP pathway are the phytoalexine resveratrol, the neuro-and cardioprotectant found in red wine (Tsai et al, 2007), peroxisome proliferator-activated receptor-g agonists (Chu et al, 2006), and angiotensin II receptor 1 antagonists (Saavedra et al, 2006;Oyama et al, 2010). These approaches, however, need to be examined more closely before clinical evaluation is feasible; as with hormones, it remains to be elucidated whether eNOS phosphorylation is the only important mechanism or whether there are other important modes of action.…”

Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults

“…The hemodynamic mechanisms of AngII are primarily mediated through activation of the type 1 angiotensin receptor (AT 1 ; Saavedra 2005) localized to brain regions involved in autonomic function (Ando et al 2004). Increased brain RAS activity is associated with increased AT 1 expression in cerebral arteries and microvessels promoting endothelial dysfunction, vascular inflammation, and blood-brain barrier permeability (Nishimura 2001;Ando et al 2004;Saavedra et al 2006). This AT 1 -induced pathophysiological cascade is characteristic of aging phenotypes causing progressive changes in cerebral circulation and white matter microstructure (Nation et al 2010;Saavedra et al 2011).…”

Effects of telmisartan on the cerebral circulation of hypertensive patients with chronic-stage stroke

“…A study of hypertensive rats by Saavedra et al 20 found that blockade of AT1 receptors increases expression of AT2 receptors, leading to enhanced endothelial nitric oxide synthase activity and nitric oxide production in vascular endothelium. Meanwhile, Nagata et al 21 reported that olmesartan therapy in elderly patients with hypertension improved cerebral hypoperfusion by boosting nitric oxide concentration.…”