Wilderman M J, Armstead W M
Department of Anesthesia, University of Pennsylvania, The Children's Hospital of Philadelphia 19104, USA.
J Cereb Blood Flow Metab. 1998 May;18(5):531-8. doi: 10.1097/00004647-199805000-00008.
Nitric oxide (NO) contributes to hypoxia-induced pial artery dilation, at least in part, through the formation of cGMP and the subsequent release of methionine enkephalin and leucine enkephalin in the newborn pig. In separate studies, these opioids also were observed to elicit NO-dependent pial artery dilation, whereas light/dye endothelial injury reduced hypoxic pial dilation. The current study was designed to investigate the role of the endothelial isoform of NO synthase in hypoxic pial dilation, associated opioid release, and opioid dilation in piglets equipped with a closed cranial window. N-iminoethyl-L-ornithine (L-NIO) (10(-6) mol/L), an antagonist that may have greater endothelial NO synthase inhibitory selectivity, had no effect on dilation elicited by hypoxia (PO2 approximately 35 mm Hg) (24 +/- 2 versus 24 +/- 2% in the absence and presence of L-NIO, respectively, n = 8). Hypoxic dilation was accompanied by increased CSF cGMP, which also was unchanged in the presence of L-NIO (394 +/- 19 and 776 +/- 63 versus 323 +/- 13 and 739 +/- 25 fmol/mL for control and hypoxia in the absence and presence of L-NIO, respectively, n = 6). Additionally, hypoxic pial dilation was associated with increased CSF methionine enkephalin, which also was unchanged in the presence of L-NIO (992 +/- 73 and 2469 +/- 197 versus 984 +/- 18 and 2275 +/- 185 pg/mL, respectively, n = 6). In contrast, methionine enkephalin-induced dilation was blocked by L-NIO (6 +/- 1, 10 +/- 1, and 16 +/- 1 versus 1 +/- 1, 1 +/- 1, and 2 +/- 1% for 10(-10), 10(-8), 10(-6) mol/L methionine enkephalin, respectively, before and after L-NIO, n = 8). Substance P-induced pial dilation was blunted by L-NIO, whereas responses to sodium nitroprusside and N-methyl-D-aspartate were unchanged. These data indicate that endothelial NO synthase contributes to opioid-induced pial artery dilation but not hypoxia-induced dilation. Additionally, these data suggest that neuronally derived NO contributes to hypoxic pial dilation.
一氧化氮（NO）至少部分地通过环磷酸鸟苷（cGMP）的形成以及新生猪体内蛋氨酸脑啡肽和亮氨酸脑啡肽的随后释放，促成缺氧诱导的软脑膜动脉扩张。在另外的研究中，还观察到这些阿片类物质可引发依赖NO的软脑膜动脉扩张，而光/染料诱导的内皮损伤则可减弱缺氧性软脑膜扩张。本研究旨在探讨在配备闭合式颅窗的仔猪中，内皮型一氧化氮合酶在缺氧性软脑膜扩张、相关阿片类物质释放及阿片类物质介导的扩张中的作用。N-亚氨基乙基-L-鸟氨酸（L-NIO）（10⁻⁶ mol/L）是一种可能具有更高内皮型一氧化氮合酶抑制选择性的拮抗剂，对缺氧（PO₂约35 mmHg）引起的扩张无影响（分别在不存在和存在L-NIO的情况下，扩张率为24±2%和24±2%，n = 8）。缺氧性扩张伴随着脑脊液中cGMP的增加，在存在L-NIO的情况下其也未发生变化（分别在不存在和存在L-NIO的情况下，对照和缺氧时脑脊液中cGMP水平分别为323±13和739±25 fmol/mL、394±19和776±63 fmol/mL，n = 6）。此外，缺氧性软脑膜扩张与脑脊液中蛋氨酸脑啡肽增加有关，在存在L-NIO的情况下其也未发生变化（分别为992±73和2469±197 pg/mL、984±18和2275±185 pg/mL，n = 6）。相反，L-NIO可阻断蛋氨酸脑啡肽诱导的扩张（对于10⁻¹⁰、10⁻⁸、10⁻⁶ mol/L的蛋氨酸脑啡肽，L-NIO处理前后的扩张率分别为6±1%、10±1%、16±1%和1±1%、1±1%、2±1%，n = 8）。P物质诱导的软脑膜扩张被L-NIO减弱，而对硝普钠和N-甲基-D-天冬氨酸的反应未改变。这些数据表明，内皮型一氧化氮合酶促成阿片类物质诱导的软脑膜动脉扩张，但不参与缺氧诱导的扩张。此外，这些数据提示神经元源性NO促成缺氧性软脑膜扩张。
