Sobey C G, Heistad D D, Faraci F M
Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Am J Physiol. 1998 Nov;275(5):H1606-12. doi: 10.1152/ajpheart.1998.275.5.H1606.
We tested the hypothesis that cerebral vasodilatation in response to arachidonate is dependent on activation of cyclooxygenase and cytochrome P-450 pathways and formation of endogenous reactive oxygen species and is mediated by activation of potassium channels. The diameter of cerebral arterioles was measured using cranial windows in anesthetized rats. Under control conditions [baseline diameter = 45 +/- 1 micrometer (mean +/- SE)], arachidonate (1-100 microM) and papaverine (10-50 microM) produced concentration-dependent vasodilatation. Cerebral vasodilator responses to arachidonate, but not papaverine, were abolished during topical application of indomethacin (10 microM, an inhibitor of cyclooxygenase) or catalase (100 U/ml, which inactivates hydrogen peroxide). In contrast, clotrimazole (10 microM) and 17-ODYA (20 microM), inhibitors of cytochrome P-450 activity, had no effect on dilator responses of cerebral arterioles to arachidonate. Superoxide dismutase (SOD, 100 U/ml) had no effect on vasodilator responses to papaverine or lower concentrations of arachidonate, whereas dilator responses to 100 microM arachidonate were inhibited modestly (by 22%) by SOD. Similarly, deferoxamine (1 mM) partly inhibited dilator responses to 10 and 100 microM arachidonate (by approximately 30% at each concentration). Tetraethylammonium ion (1 mM) or iberiotoxin (50 nM), inhibitors of calcium-activated potassium channels, markedly inhibited vasodilatation in response to arachidonate (by 70-90%) but not papaverine. These findings suggest that dilatation of cerebral arterioles in response to arachidonate is mediated largely by endogenously formed reactive oxygen species, which are generated from cyclooxygenase activity, and activation of calcium-activated potassium channels. Thus activation of potassium channels appears to be a major mechanism of cerebral vasodilatation in response to reactive oxygen species produced endogenously.
大脑动脉对花生四烯酸的血管舒张反应依赖于环氧化酶和细胞色素P-450途径的激活以及内源性活性氧的形成，并由钾通道的激活介导。在麻醉大鼠中使用颅骨视窗测量脑微动脉的直径。在对照条件下[基线直径 = 45 ± 1微米（平均值 ± 标准误）]，花生四烯酸（1 - 100微摩尔）和罂粟碱（10 - 50微摩尔）产生浓度依赖性血管舒张。在局部应用吲哚美辛（10微摩尔，一种环氧化酶抑制剂）或过氧化氢酶（100单位/毫升，可使过氧化氢失活）期间，大脑对花生四烯酸的血管舒张反应被消除，但对罂粟碱的反应未受影响。相比之下，细胞色素P-450活性抑制剂克霉唑（10微摩尔）和17 - ODA（20微摩尔）对脑微动脉对花生四烯酸的舒张反应没有影响。超氧化物歧化酶（SOD，100单位/毫升）对罂粟碱或较低浓度花生四烯酸的血管舒张反应没有影响，而对100微摩尔花生四烯酸的舒张反应被SOD适度抑制（22%）。同样，去铁胺（1毫摩尔）部分抑制了对10和100微摩尔花生四烯酸的舒张反应（在每个浓度下约为30%）。钙激活钾通道抑制剂四乙铵离子（1毫摩尔）或iberiotoxin（50纳摩尔）显著抑制了对花生四烯酸的血管舒张反应（70 - 90%），但对罂粟碱没有影响。这些发现表明，脑微动脉对花生四烯酸的舒张反应主要由内源性形成的活性氧介导，这些活性氧由环氧化酶活性产生，并激活钙激活钾通道。因此，钾通道的激活似乎是大脑对内源性产生的活性氧作出血管舒张反应的主要机制。
