Cerebral ischemia results in enhanced expression of smooth muscle cell endothelin and angiotensin receptors in cerebral arteries. We hypothesise that this phenomenon may be detrimental and that acute treatment with a combined non-hypotensive dose of the angiotensin AT 1 receptor inhibitor candesartan and the endothelin ET A receptor antagonist ZD1611 reduces the infarct in experimental ischemic stroke. Transient middle cerebral artery occlusion was induced in male Wistar rats by the intraluminal filament technique for 2 h followed by recirculation. The animals received systemic candesartan (0.05 mg/kg/day), ZD1611 (0.15 mg/kg/day), both combined or vehicle with start immediately after the occlusion. After 48 h the rats were sacrificed, the brains sliced and stained with 1% 2, 3, 5-triphenyltetrazolium chloride (TTC) and the volume of ischemic damage determined. The middle cerebral arteries were harvested for immunocytochemical studies of angiotensin AT 1 and endothelin ET A receptor expression. Candesartan or ZD1611 did alone not significantly decrease the brain damage or improve neurological scores as compared to vehicle controls. The combined inhibition of angiotensin AT 1 and endothelin ET A receptors however decreased the brain damage and improved the neurological scores (both P<0.05). The treatment did not change resting mean arterial blood pressure. In addition, there was an upregulation of angiotensin AT 1 receptors in the ischemic middle cerebral artery smooth muscle cells, which was normalised by the combined treatment. In conclusion, the present study shows that combined inhibition of angiotensin AT 1 and endothelin ET A receptors reduces the brain damage and improves the neurological outcome after ischemic stroke in rat.