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CARDIOVASCULAR

Vascular Protection with Candesartan after Experimental Acute Stroke in Hypertensive Rats: A Dose-Response Study

Institute of General and Molecular Biology, Nicolas Copernicus University, Torun, Poland (W.K.); Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia (A.K., H.F.E., S.C.F.); Departments of Neurology (S.C.F.) and Biostatistics (M.H.J.), Medical College of Georgia, Specialty Care Service Line, VA Medical Center, Augusta, Georgia (A.K., H.F.E., S.C.F.)

We have shown that candesartan decreases the acute stroke-induced elevation of mean arterial blood pressure (MAP) in Wistar rats and improves functional outcome. The aim of the present study was to determine whether the same benefit could be achieved in spontaneously hypertensive rats (SHR). Animals were subjected to middle cerebral artery occlusion (MCAO) or sham for 3 h followed by reperfusion. Either candesartan (0.1, 0.3, or 1.0 mg/kg) or saline was administered. MAP of the rats was monitored by means of telemetry, and neurological function was assessed. Infarct size, edema formation, and hemoglobin content in the ischemic hemisphere were evaluated 24 h after the stroke. MAP of SHR increased immediately upon MCAO from 135 (baseline) to 189 mm Hg, and it remained elevated until reperfusion. Candesartan decreased MAP in a dose-dependent manner, with a drop below baseline after a dose of 1.0 mg/kg. SHRs experienced greater blood pressure (BP)-lowering effects of candesartan after stroke compared with a sham condition (p < 0.0001). Neurological deficit after stroke was reduced in candesartan-treated animals, revealing a dose-dependent effect (p < 0.01). Infarct size, edema formation, and hemoglobin content were all reduced by candesartan at doses of 0.1 and 0.3 mg/kg (p < 0.05 for all). Candesartan (1 mg/kg) was not different from saline. Low doses of candesartan provide neurovascular protection after stroke in SHRs. Caution is warranted because acute stroke increases the sensitivity to BP lowering, which, in turn, increases the likelihood of overshooting.

Address correspondence to: Dr. Susan C. Fagan, University of Georgia College of Pharmacy, CJ-1020 Medical College of Georgia, 1120 15th Street, Augusta, GA 30912-2450. E-mail: sfagan{at}mail.mcg.edu