Stenman Emelie, Jamali Roya, Henriksson Marie, Maddahi Aida, Edvinsson Lars
Institution of Clinical Sciences Lund, Department of Experimental Vascular Research, Lund University, BMC A13, 22184 Lund, Sweden.
Eur J Pharmacol. 2007 Sep 10;570(1-3):142-8. doi: 10.1016/j.ejphar.2007.05.049. Epub 2007 Jun 9.
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.
脑缺血导致脑动脉中平滑肌细胞内皮素和血管紧张素受体的表达增强。我们推测这种现象可能有害，并且联合使用非降压剂量的血管紧张素AT(1)受体抑制剂坎地沙坦和内皮素ET(A)受体拮抗剂ZD1611进行急性治疗可减少实验性缺血性卒中的梗死面积。采用腔内丝线技术对雄性Wistar大鼠诱导大脑中动脉短暂闭塞2小时，随后再灌注。动物在闭塞后立即接受全身性坎地沙坦（0.05毫克/千克/天）、ZD1611（0.15毫克/千克/天）、两者联合用药或赋形剂。48小时后处死大鼠，将脑切片并用1% 2,3,5-三苯基氯化四氮唑（TTC）染色，测定缺血损伤体积。采集大脑中动脉用于血管紧张素AT(1)和内皮素ET(A)受体表达的免疫细胞化学研究。与赋形剂对照组相比，单独使用坎地沙坦或ZD1611并没有显著减少脑损伤或改善神经学评分。然而，联合抑制血管紧张素AT(1)和内皮素ET(A)受体可减少脑损伤并改善神经学评分（两者P<0.05）。该治疗未改变静息平均动脉血压。此外，缺血大脑中动脉平滑肌细胞中血管紧张素AT(1)受体上调，联合治疗可使其恢复正常。总之，本研究表明联合抑制血管紧张素AT(1)和内皮素ET(A)受体可减少大鼠缺血性卒中后的脑损伤并改善神经学预后。
