Acute Treatment with Candesartan Reduces Early Injury After Permanent Middle Cerebral Artery Occlusion

Abstract

We have shown that reduction of blood pressure (BP) immediately after the onset of reperfusion reduced neurovascular damage and improved functional outcome after experimental cerebral ischemia and candesartan is particularly effective in improving long-term functional outcome. In this study, we sought to determine if early BP lowering with candesartan, in the presence of an occluded cerebral artery, will reduce injury and improve outcome after experimental stroke. Male Wistar rats underwent 24 h or 7 days of middle cerebral artery occlusion (MCAO). A single dose of 1 mg/kg candesartan was administered intravenously at 3 h after MCAO. Animals received neurobehavioral testing at 3 h, 24 h, and 7 days, and blood pressure was measured by telemetry. Animals had brain tissue collected for infarct size (24 h and 7 days), hemoglobin content, matrix metalloproteinase (MMP) activity, and vascular endothelial growth factor (VEGF) expression (24 h only). Candesartan significantly decreased blood pressure, infarct size (−20%; p = 0.021), hemoglobin excess (−50%; p = 0.0013), and edema (−35%; p = 0.0005) at 24 h after MCAO. This resulted in a reduced cerebral perfusion deficit (p = 0.034) in the ischemic hemisphere compared with saline and significantly improved Bederson scores and paw grasp. MMP-2, MMP-9, and VEGF were significantly increased by MCAO, but there were no differences between candesartan- and saline-treated animals. There were no significant differences in behavioral outcome at day 7. BP lowering with candesartan reduces early brain injury after experimental stroke even when the artery remains occluded. The early benefits were not sustained at 7 days, as seen in reperfused animals, however. The neuroprotection and neurorestorative properties of candesartan may occur by separate distinct mechanisms.