Protection Against Ischemia and Improvement of Cerebral Blood Flow in Genetically Hypertensive Rats by Chronic Pretreatment With an Angiotensin II AT ₁ Antagonist

Abstract

Background and Purpose-Pretreatment with angiotensin II AT 1 receptor antagonists protects against cerebral ischemia.We studied whether modulation of cerebral blood flow (CBF) and morphometric changes in brain arteries participated in this protective mechanism. Methods-We pretreated adult spontaneously hypertensive rats with equally antihypertensive doses of candesartan (0.1 or 0.3 mg/kg per day), nicardipine (0.1 mg/kg per day), or captopril (3.0 mg/kg per day) for 3 or 28 days via subcutaneous osmotic minipumps followed by permanent left middle cerebral artery (MCA) occlusion distal to the origin of the lenticulostriate arteries. We measured CBF by autoradiography with 4-iodo-[N-methyl-14 C]antipyrine 3 hours after operation and the areas of infarct and tissue swelling 24 hours after operation. Morphometric changes in the MCA were studied after antihypertensive treatment. Results-Twenty-eight days of candesartan pretreatment decreased the infarct area by 31%; reduced the CBF decrease at the peripheral area of ischemia and the cortical volume of severe ischemic lesion, where CBF was Ͻ0.50 mL/g per minute; increased the MCA external diameter by 16%; and reduced the media thickness of the MCA by 23%. Captopril pretreatment for 28 days decreased the infarct area by 25%. Pretreatment with candesartan for 3 days or nicardipine for 28 days was ineffective. Conclusions-Angiotensin II system inhibition protects against neuronal injury more effectively than calcium channel blockade. Protection after AT 1 receptor blockade is not directly correlated with blood pressure reduction but with normalization of MCA media thickness, leading to increased arterial compliance and reduced CBF decrease during ischemia at the periphery of the lesion.

Angiotensin II and aldosterone-induced neuronal damage in neurons through an astrocyte-dependent mechanism

“…We and others have shown that treatment with AT 1 receptor blockers can reduce the ischemic area in the brain and improve cognitive function in various animal models. 26,27 We have also reported that an MR blocker, eplerenone, attenuates stroke size in mice subjected to ischemic brain damage. 28 Moreover, recent evidence has suggested that AT 1 receptor blockers may reduce the incidence of neurodegenerative diseases.…”

Benefits of the angiotensin II receptor antagonist olmesartan in controlling hypertension and cerebral hemodynamics after stroke

“…1,2 In hypertensive patients, cerebral blood flow (CBF) is impaired, 3 not only by elevated blood pressure (BP) but also as a result of inflammation and oxidative stress in the vascular wall, induced by angiotensin II. 4,5 Angiotensin II receptor blockers (ARBs) and calcium channel blockers (CCBs) are widely used to treat hypertension. ARBs have been shown to reduce inflammation 6 and oxidative stress 7,8 by directly blocking the action of angiotensin II.…”

Angiotensin II AT1 Receptor Blockade Abolishes Brain Microvascular Inflammation and Heat Shock Protein Responses in Hypertensive Rats

“…Longterm blockade of Ang II AT 1 receptors in SHR reversed the pathological cerebrovascular remodeling, normalized the expression of endothelial and inducible nitric oxide synthase (eNOS and iNOS) and protected the animals against hypertensioninduced ischemic neuronal injury and stroke (Ito et al, 2002;Yamakawa et al, 2003).…”