Cooperative effect of angiotensin AT1 and endothelin ETA receptor antagonism limits the brain damage after ischemic stroke in rat

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 AT1 receptor inhibitor candesartan and the endothelin ETA 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 AT1 and endothelin ETA 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 AT1 and endothelin ETA 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 AT1 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 AT1 and endothelin ETA receptors reduces the brain damage and improves the neurological outcome after ischemic stroke in rat.