Wilderman M J, Armstead W M
Department of Anesthesia, University of Pennsylvania, Philadelphia 19104, USA.
Am J Physiol. 1996 Mar;270(3 Pt 2):H869-74. doi: 10.1152/ajpheart.1996.270.3.H869.
It has previously been observed that nitric oxide (NO) and the opioids Met- and Leu-enkephalin contribute to hypoxia-induced pial artery dilation in the newborn pig. The present study was designed to investigate the relationship between NO and opioids in hypoxic pial dilation. Piglets equipped with closed cranial windows were used to measure pial artery diameter and collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids. Sodium nitroprusside (SNP; 10(-8) and 10(-6) M) elicited pial dilation that was blunted by the soluble guanylate cyclase inhibitor LY-83583 (10(-5) M; 10 +/- 1 and 23 +/- 1 vs. 3 +/- 1 and 7 +/- 1% for 10(-8) and 10(-6) M SNP before and after LY-83583, respectively). SNP-induced dilation was accompanied by increased CSF Met-enkephalin, and coadministration of LY-83583 with SNP blocked these increases in CSF opioid concentration (1,144 +/- 59, 2,215 +/- 165, and 3,413 +/- 168 vs. 1,023 +/- 16, 1,040 +/- 18, and 1,059 +/- 29 pg/ml for control and 10(-8) and 10(-6) M SNP before and after LY-83583, respectively). SNP-induced release of CSF Leuenkephalin was also blocked by LY-83583. Similar blunted vascular and biochemical effects of SNP were observed with coadministration of the purported guanosine 3', 5'-cyclic monophosphate (cGMP) antagonist, the phosphorothioate analogue of 8-bromo-cGMP (BrcGMP) [(R)-p-BrcGMP[S]; 10(-5) M]. The cGMP analogue, BrcGMP, elicited dilation that was also accompanied by increased CSF Met- and Leu-enkephalin. Vascular and biochemical effects of BrcGMP were blunted by (R)-p-cGMP[S] and unchanged by LY-83583. Hypoxia-induced pial artery dilation was attenuated by N omega-nitro-L-arginine (L-NNA; 10(-6) M), an NO synthase inhibitor (25 +/- 2 vs. 14 +/- 1%). Hypoxic pial dilation was accompanied by increased CSF Met-enkephalin, and these increases were attenuated by L-NNA (1,137 +/- 60 and 3,491 +/- 133 vs. 927 +/- 25 and 2,052 +/- 160 pg/ml for control and hypoxia before and after L-NNA, respectively). Hypoxia also increased CSF Leuenkephalin, and these CSF changes were similarly attenuated by L-NNA. These data show that cGMP increases CSF Met- and Leu-enkephalin. Furthermore, these data suggest that NO contributes to hypoxic dilation, at least in part, via formation of cGMP and the subsequent release of opioids.
此前已有研究观察到，一氧化氮（NO）和阿片类物质甲硫氨酸脑啡肽及亮氨酸脑啡肽可促使新生猪的软脑膜动脉在缺氧时扩张。本研究旨在探讨缺氧性软脑膜扩张时NO与阿片类物质之间的关系。给仔猪安装封闭的颅骨视窗，用于测量软脑膜动脉直径，并收集皮质蛛网膜下腔脑脊液（CSF）以检测阿片类物质。硝普钠（SNP；10⁻⁸和10⁻⁶ M）可引起软脑膜扩张，而可溶性鸟苷酸环化酶抑制剂LY - 83583（10⁻⁵ M）可减弱这种扩张（LY - 83583处理前，10⁻⁸和10⁻⁶ M SNP引起的扩张分别为10±1%和23±1%；处理后分别为3±1%和7±1%）。SNP诱导的扩张伴随着脑脊液中甲硫氨酸脑啡肽增加，LY - 83583与SNP联合给药可阻断脑脊液中阿片类物质浓度的这些增加（对照组、LY - 83583处理前10⁻⁸和10⁻⁶ M SNP组的脑脊液阿片类物质浓度分别为1144±59、2215±165和3413±168 pg/ml；处理后分别为1023±16、1040±18和1059±29 pg/ml）。LY - 83583也可阻断SNP诱导的脑脊液亮氨酸脑啡肽释放。同时给予所谓的鸟苷3',5'-环磷酸（cGMP）拮抗剂8-溴-cGMP的硫代磷酸酯类似物[（R）-p-BrcGMP[S]；10⁻⁵ M]时，观察到SNP对血管和生化的类似减弱作用。cGMP类似物BrcGMP引起扩张的同时也伴随着脑脊液中甲硫氨酸脑啡肽和亮氨酸脑啡肽增加。BrcGMP的血管和生化作用可被（R）-p-cGMP[S]减弱，而LY - 83583对其无影响。一氧化氮合酶抑制剂Nω-硝基-L-精氨酸（L-NNA；10⁻⁶ M）可减弱缺氧诱导的软脑膜动脉扩张（25±2%对14±1%）。缺氧性软脑膜扩张伴随着脑脊液中甲硫氨酸脑啡肽增加，L-NNA可减弱这些增加（对照组、L-NNA处理前缺氧组的脑脊液甲硫氨酸脑啡肽浓度分别为1137±60和3491±133 pg/ml；处理后分别为927±25和2052±160 pg/ml）。缺氧也可增加脑脊液亮氨酸脑啡肽，L-NNA对这些脑脊液变化也有类似的减弱作用。这些数据表明cGMP可增加脑脊液中甲硫氨酸脑啡肽和亮氨酸脑啡肽。此外，这些数据提示NO至少部分通过cGMP的形成及随后阿片类物质的释放而促成缺氧性扩张。
