P-450 epoxygenase and NO synthase inhibitors reduce cerebral blood flow response to N-methyl-D-aspartate
P-450 epoxygenase and NO synthase inhibitors reduce cerebral blood flow response to N-methyl-D-aspartate
复制标题
DOI：
10.1152/ajpheart.2000.279.4.h1616
复制
发表时间：
2000-10-01
影响因子：
4.8
通讯作者：
Koehler, RC
中科院分区：
文献类型：
--
作者：
Bhardwaj, A;Northington, FJ;Koehler, RC
环氧二十碳三烯酸是星形胶质细胞中通过细胞色素P-450环氧合酶活性产生的脑血管扩张剂。P-450抑制剂咪康唑减弱谷氨酸引起的脑血流量（CBF）增加。我们评估是否环氧酶活性参与CBF响应激活的N-甲基-D-天冬氨酸（NMDA）受体亚型通过使用两种结构不同的抑制剂，咪康唑和N-甲磺酰基-6-（2-炔丙氧基苯基）己酰胺（MS-PPOH），选择性环氧酶底物抑制剂。通过微透析探针在麻醉大鼠的纹状体中局部递送药物。采用氢清除法测定局部脑血流量，并与接受溶剂的对侧纹状体的脑血流量进行比较。通过在标记精氨酸输注期间回收透析液中的标记瓜氨酸估计，NMDA的微透析灌注使CBF加倍，并增加一氧化氮（NO）的产生。灌注咪康唑或MS-PPOH可阻断CBF的增加，而不会降低瓜氨酸的回收率。灌注N-ω-硝基-L-精氨酸降低基线CBF并抑制CBF对NMDA的反应。灌注MS-PPOH不抑制CBF对硝普钠的反应。我们的结论是，P-450环氧酶和NO合酶途径参与局部CBF响应NMDA受体激活，信号通路可能比简单的NO扩散从神经元到血管平滑肌更复杂。
Epoxyeicosatrienoic acids are cerebral vasodilators produced in astrocytes by cytochrome P-450 epoxygenase activity. The P-450 inhibitor miconazole attenuates the increase in cerebral blood flow (CBF) elicited by glutamate. We evaluated whether epoxygenase activity is involved in the CBF response to activation of the N-methyl-D-aspartate (NMDA) receptor subtype by using two structurally distinct inhibitors, miconazole and N-methylsulfonyl- 6-(2-propargyloxyphenyl) hexanamide (MS-PPOH), a selective epoxygenase substrate inhibitor. Drugs were delivered locally through microdialysis probes in striata of anesthetized rats. Local CBF was measured by hydrogen clearance and compared with CBF in contralateral striatum receiving vehicle. Microdialysis perfusion of NMDA doubled CBF and increased nitric oxide (NO) production estimated by recovery of labeled citrulline in the dialysate during labeled arginine infusion. Perfusion of miconazole or MS-PPOH blocked the increase in CBF without decreasing citrulline recovery. Perfusion of N-omega-nitro-L-arginine decreased baseline CBF and inhibited the CBF response to NMDA. Perfusion of MS-PPOH did not inhibit the CBF response to sodium nitroprusside. We conclude that both the P-450 epoxygenase and NO synthase pathways are involved in the local CBF response to NMDA receptor activation, and that the signaling pathway may be more complex than simply NO diffusion from neurons to vascular smooth muscle.