Liu Xiaoguang, Li Chunyuan, Falck John R, Roman Richard J, Harder David R, Koehler Raymond C
Dept. of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, 600 North Wolfe St./Blalock 1404, Baltimore, MD 21287-4961, USA.
Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H619-31. doi: 10.1152/ajpheart.01211.2007. Epub 2008 May 23.
Nitric oxide (NO) modulates vasodilation in cerebral cortex during sensory activation. NO is known to inhibit the synthesis of 20-HETE, which has been implicated in arteriolar constriction during astrocyte activation in brain slices. We tested the hypothesis that the attenuated cerebral blood flow (CBF) response to whisker stimulation seen after NO synthase (NOS) inhibition requires 20-HETE synthesis and that the ability of an epoxyeicosatrienoic acids (EETs) antagonist to reduce the CBF response is blunted after NOS inhibition but restored with simultaneous blockade of 20-HETE synthesis. In anesthetized rats, the increase in CBF during whisker stimulation was attenuated after the blockade of neuronal NOS with 7-nitroindazole. Subsequent administration of the 20-HETE synthesis inhibitor N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine (HET0016) restored the CBF response to control levels. After the administration of 7-nitroindazole, the inhibitory effect of an EETs antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) on the CBF response was lost, whereas the simultaneous administration of 7-nitroindazole and HET0016 restored the inhibitory effect of 14,15-EEZE. The administration of HET0016 alone had only a small effect on the evoked CBF response in rats. Furthermore, in neuronal NOS(+/+) and NOS(-/-) mice, HET0016 administration did not increase the CBF response to whisker stimulation. In neuronal NOS(+/+) mice, HET0016 also blocked the reduction in the response seen with acute NOS inhibition. These results indicate that 20-HETE synthesis normally does not substantially restrict functional hyperemia. Increased NO production during functional activation may act dynamically to suppress 20-HETE synthesis or downstream signaling and permit EETs-dependent vasodilation. With the chronic loss of neuronal NOS in mice, other mechanisms apparently suppress 20-HETE synthesis or signaling.
一氧化氮（NO）在感觉激活过程中调节大脑皮质的血管舒张。已知NO可抑制20-羟基二十碳四烯酸（20-HETE）的合成，而20-HETE在脑片星形胶质细胞激活期间的小动脉收缩中起作用。我们测试了以下假设：在一氧化氮合酶（NOS）抑制后观察到的对触须刺激的脑血流量（CBF）反应减弱需要20-HETE合成，并且环氧二十碳三烯酸（EETs）拮抗剂降低CBF反应的能力在NOS抑制后减弱，但在同时阻断20-HETE合成后恢复。在麻醉大鼠中，用7-硝基吲唑阻断神经元NOS后，触须刺激期间CBF的增加减弱。随后给予20-HETE合成抑制剂N-羟基-N'-（4-正丁基-2-甲基苯基）甲脒（HET0016）可将CBF反应恢复至对照水平。给予7-硝基吲唑后，EETs拮抗剂14,15-环氧二十碳-5（Z）-烯酸（14,15-EEZE）对CBF反应的抑制作用丧失，而同时给予7-硝基吲唑和HET0016可恢复14,15-EEZE的抑制作用。单独给予HET0016对大鼠诱发的CBF反应只有很小的影响。此外，在神经元NOS（+/+）和NOS（-/-）小鼠中，给予HET0016并未增加对触须刺激的CBF反应。在神经元NOS（+/+）小鼠中，HET0016还阻断了急性NOS抑制所见反应的降低。这些结果表明，20-HETE合成通常不会实质性地限制功能性充血。功能激活期间NO产生增加可能动态地抑制20-HETE合成或下游信号传导，并允许EETs依赖性血管舒张。在小鼠中神经元NOS长期缺失的情况下，其他机制显然会抑制20-HETE合成或信号传导。
