Chronic pretreatment with candesartan improves recovery from focal cerebral ischaemia in rats

Objective In the present study, we investigated whether systemic pretreatment with the AT1 receptor antagonist, candesartan, reduces neuronal injury after cerebral ischaemia in rats. Design and methods Focal cerebral ischaemia in male, normotensive Wistar rats was induced by 90 min middle cerebral artery occlusion (MCAO) followed by reperfusion. Experiment 1: Candesartan was injected intravenously (i.v.) at doses of 0.1 or 0.3 mg/kg, 4 h prior to ischaemic injury. Experiment 2: Rats were treated with candesartan [0.1 mg/ kg, subcutaneously (s.c.) twice daily], on 5 consecutive days prior to ischaemia. The last injection was administered 12 h before MCAO. Mean arterial pressure (MAP) was measured before, during and after ischaemic injury. Twenty-four hours after ischaemia, neurological outcome, infarct volume and brain oedema were evaluated. Results Acute i.v. pretreatment with candesartan, 0.1 and 0.3 mg/kg, dose-dependently decreased MAP before, during and after ischaemic injury but did not improve recovery from brain ischaemia. Systemic long-term s.c. pretreatment with 0.1 mg/kg candesartan, reduced MAP during and after ischaemia to the same extent as did the i.v. dose of 0.1 mg administered 4 h before MCAO, but significantly improved neurological outcome and reduced infarction size and oedema of the ipsilateral hemisphere when compared with the vehicle-treated group. Conclusion Long-term blockade of AT1 receptors improves neurological outcome of focal cerebral ischaemia and protects brain tissue against ischaemic injury. (C) 2003 Lippincott Williams Wilkins.