Brian J E, Faraci F M, Moore S A
Department of Anesthesia, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Am J Physiol Heart Circ Physiol. 2001 May;280(5):H2023-9. doi: 10.1152/ajpheart.2001.280.5.H2023.
Bradykinin (BK) is released in the brain during injury and inflammation. Activation of endothelial BK receptors produces acute dilatation of cerebral arterioles that is mediated by reactive oxygen species (ROS). ROS can also modulate gene expression, including expression of the inducible isoform of cyclooxygenase (COX-2). We hypothesized that exposure of the brain to BK would produce acute dilatation, which would be followed by a delayed dilatation mediated by COX-2. To test this hypothesis in anesthetized rats, BK was placed twice in cranial windows for 7 min, after which the windows were flushed to remove residual BK. The two BK exposures were separated by 30 min. Each BK exposure produced acute dilatation of cerebral arterioles, after which diameter rapidly returned to baseline. Over the subsequent 4.5 h after the second BK exposure, arterioles dilated 48 +/- 8%. Treatment of the cranial window with NS-398, a selective COX-2 inhibitor, or dexamethasone, significantly attenuated the delayed dilatation. Aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, did not alter the delayed dilatation. Cotreatment of cranial windows with BK, superoxide dismutase, and catalase also prevented the delayed dilatation. In separate experiments, exposure of the cortical surface to BK upregulated leptomeningeal expression of COX-2 mRNA. Our results suggest that acute, time-limited exposure of the brain to BK produces delayed dilatation of cerebral arterioles dependent on expression and activity of COX-2.
缓激肽（BK）在脑损伤和炎症期间于脑内释放。内皮BK受体的激活会导致脑小动脉急性扩张，这一过程由活性氧（ROS）介导。ROS还可调节基因表达，包括诱导型环氧化酶（COX-2）的表达。我们推测，脑暴露于BK会导致急性扩张，随后会出现由COX-2介导的延迟扩张。为了在麻醉大鼠中验证这一假设，将BK分两次置于颅骨视窗内7分钟，之后冲洗视窗以去除残留的BK。两次BK暴露间隔30分钟。每次BK暴露均会导致脑小动脉急性扩张，之后直径迅速恢复至基线水平。在第二次BK暴露后的4.5小时内，小动脉扩张了48±8%。用选择性COX-2抑制剂NS-398或地塞米松处理颅骨视窗，可显著减轻延迟扩张。诱导型一氧化氮合酶的选择性抑制剂氨基胍并未改变延迟扩张。用BK、超氧化物歧化酶和过氧化氢酶共同处理颅骨视窗也可防止延迟扩张。在单独的实验中，将皮质表面暴露于BK会上调软脑膜COX-2 mRNA的表达。我们的结果表明，脑急性、限时暴露于BK会导致脑小动脉延迟扩张，这依赖于COX-2的表达和活性。
