Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats

Background and Purpose-Angiotensin II, through stimulation of AT(1) recepto rs, not only controls blood pressure but also modulates cerebrovascular flo w. We sought to determine whether selective AT(1) antagonists could be ther apeutically advantageous in brain ischemia during chronic hypertension. Methods-We pretreated spontaneously hypertensive rats (SHR) and normotensiv e Wistar-Kyoto controls with the AT(1) antagonist candesartan (CV-11974), 0 .5 mg/kg per day, for 3 to 14 days, via subcutaneously implanted osmotic mi nipumps. We analyzed cerebral blood flow by laser-Doppler flowmetry, cerebr al stroke in SHR after occlusion of the middle cerebral artery with reperfu sion, and brain AT(1) receptors by quantitative autoradiography. Results-Candesartan treatment normalized blood pressure and the shift towar d higher blood pressures at both the upper and lower limits of cerebrovascu lar autoregulation in SHR. Candesartan pretreatment of SHR for 14 days part ially prevented the decrease in blood flow in the marginal zone of ischemia and significantly reduced the volume of total and cortical infarcts after either 1 or 2 hours of middle cerebral artery occlusion with reperfusion, r elative to untreated SHR, respectively. This treatment also significantly r educed brain edema after 2 hours of middle cerebral artery occlusion with r eperfusion. In SHR, candesartan markedly decreased AT(1) binding in areas i nside (nucleus of the solitary tract) and outside (area postrema) the blood -brain barrier and in the middle cerebral artery. Conclusions-Pretreatment with an AT(1) antagonist protected hypertensive ra ts from brain ischemia by normalizing the cerebral blood flow response, pro bably through AT(1) receptor blockade in cerebral vessels and in brain area s controlling cerebrovascular flow during stroke.