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(Stroke. 2002;33:2297.)
© 2002 American Heart Association, Inc.

Original Contributions

Protection Against Ischemia and Improvement of Cerebral Blood Flow in Genetically Hypertensive Rats by Chronic Pretreatment With an Angiotensin II AT₁ Antagonist

Takeshi Ito, MD; Haruki Yamakawa, MD; Claudia Bregonzio, PhD; José A. Terrón, PhD; Alicia Falcón-Neri, BSc Juan M. Saavedra, MD

From the Section on Pharmacology, Intramural Research Program, National Institute of Mental Health, Bethesda, Md.

Correspondence to Juan M. Saavedra, MD, Section on Pharmacology, Intramural Research Program, National Institute of Mental Health, 10 Center Dr, Bldg 10, Room 2D-57, Bethesda, MD 20892. E-mail Saavedrj{at}irp.nimh.nih.gov

Background and Purpose— Pretreatment with angiotensin II AT₁ 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-¹⁴C]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 <0.50 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 AT₁ 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.

Key Words: cerebral blood flow • hypertension • peptides • receptors • stroke

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