Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 23, Issue 3, Pages 371-380Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.WCB.0000047369.05600.03
Keywords
renin angiotensin system; angiotensin II receptor types; brain ischemia; cerebrovascular regulation; stroke; genetic hypertension
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Inhibition of angiotensin II AT(1) receptors protects against stroke, reducing the cerebral blood flow decrease in the periphery of the ischemic lesion. To clarify the mechanism, spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were pretreated with the AT(1) receptor antagonist candesartan (0.3 mg . kg(-1) . d(-1)) for 28 days, a treatment identical to that which protected SHR from brain ischemia, and the authors studied middle cerebral artery (MCA) and common carotid morphology, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and protein expression in cerebral microvessels, principal arteries of the Willis polygon, and common carotid artery. The MCA and common carotid artery of SHR exhibited inward eutrophic remodeling, with decreased lumen diameter and increased media thickness when compared with WKY rats. In addition, there was decreased eNOS and increased iNOS protein and mRNA in common carotid artery, circle of Willis, and brain microvessels of SHR when compared with WKY rats. Both remodeling and alterations in eNOS and iNOS expression in SHR were completely reversed by long-term AT(1) receptor inhibition. The hemodynamic, morphologic, and biochemical alterations in hypertension associated with increased vulnerability to brain ischemia are fully reversed by AT(1) receptor blockade, indicating that AT(1) receptor activation is crucial for the maintenance of the pathologic alterations in cerebrovascular circulation during hypertension, and that their blockade may be of therapeutic advantage.
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