Armstead W M
Department of Anesthesia, University of Pennsylvania, Philadelphia, USA.
J Cereb Blood Flow Metab. 1997 Jan;17(1):100-8. doi: 10.1097/00004647-199701000-00013.
Previously, it had been observed that nitric oxide (NO) contributes to hypoxia-induced pial artery dilation in the newborn pig. Additionally, it was also noted that activation of ATP-sensitive K+ channels (KATP) contribute to cGMP-mediated as well as to hypoxia-induced pial dilation. Although somewhat controversial, adenosine is also thought to contribute to hypoxic cerebrovasodilation. The present study was designed to investigate the role of NO, cyclic nucleotides, and activation of KATP channels in the elicitation of adenosine's vascular response and relate these mechanisms to the contribution of adenosine to hypoxia-induced pial artery dilation. The closed cranial window technique was used to measure pial diameter in newborn pigs. Hypoxia-induced artery dilation was attenuated during moderate (PaO2 approximately 35 mm Hg) and severe hypoxia (PaO2 approximately 25 mm Hg) by the adenosine receptor antagonist 8-phenyltheophylline (8-PT) (10(-5) M) (26 +/- 2 vs. 19 +/- 2 and 34 +/- 2 vs. 22 +/- 2% for moderate and severe hypoxia in the absence vs. presence of 8-PT, respectively). This concentration of 8-PT blocked pial dilation in response to adenosine (8 +/- 2, 16 +/- 2, and 23 +/- 2 vs. 2 +/- 2, 4 +/- 2, and 6 +/- 2% for 10(-8), 10(-6), and 10(-4) M adenosine before and after 8-PT, respectively). Similar data were also obtained using adenosine deaminase as a probe for the role of adenosine in hypoxic pial dilation. Adenosine-induced dilation was associated with increased CSF cGMP concentration (390 +/- 11 and 811 +/- 119 fmol/ml for control and 10(-4) M adenosine, respectively). The NO synthase inhibitor, L-NNA, and the cGMP antagonist, Rp 8-bromo cGMPs, blunted adenosine-induced pial dilation (8 +/- 1, 14 +/- 1, and 20 +/- 3 vs. 3 +/- 1, 5 +/- 1, and 8 +/- 3% for 10(-8), 10(-6), and 10(-4) M adenosine before and after L-NNA, respectively). Adenosine dilation was also blunted by glibenclamide, a KATP antagonist (9 +/- 2, 14 +/- 3, 21 +/- 4 vs. 4 +/- 1, 8 +/- 2, and 11 +/- 2% for 10(-8), 10(-6), and 10(-4) M adenosine before and after glibenclamide, respectively). Finally, it was also observed that adenosine-induced dilation was associated with increased CSF cAMP concentration and the cAMP antagonist, Rp 8-bromo cAMPs, blunted adenosine pial dilation. These data show that adenosine contributes to hypoxic pial dilation. These data also show that NO, cGMP, cAMP, and activation of KATP channels all contribute to adenosine induced pial dilation. Finally, these data suggest that adenosine contributes to hypoxia-induced pial artery dilation via cAMP and activation of KATP channels by NO and cGMP.
此前观察到，一氧化氮（NO）有助于新生猪缺氧诱导的软脑膜动脉扩张。此外，还注意到ATP敏感性钾通道（KATP）的激活有助于cGMP介导的以及缺氧诱导的软脑膜扩张。尽管存在一定争议，但腺苷也被认为有助于缺氧性脑血管扩张。本研究旨在探讨NO、环核苷酸以及KATP通道激活在引发腺苷血管反应中的作用，并将这些机制与腺苷对缺氧诱导的软脑膜动脉扩张的作用联系起来。采用封闭颅窗技术测量新生猪的软脑膜直径。腺苷受体拮抗剂8-苯基茶碱（8-PT）（10⁻⁵ M）可减弱中度（动脉血氧分压约35 mmHg）和重度缺氧（动脉血氧分压约25 mmHg）期间缺氧诱导的动脉扩张（中度缺氧时，无8-PT和有8-PT时分别为26±2%和19±2%；重度缺氧时分别为34±2%和22±2%）。该浓度的8-PT可阻断腺苷引起的软脑膜扩张（10⁻⁸、10⁻⁶和10⁻⁴ M腺苷在8-PT处理前后，软脑膜扩张分别为8±2%、16±2%、23±2%和2±2%、4±2%、6±2%）。使用腺苷脱氨酶作为腺苷在缺氧性软脑膜扩张中作用的探针也获得了类似数据。腺苷诱导的扩张与脑脊液cGMP浓度升高相关（对照组和10⁻⁴ M腺苷时分别为390±11和811±119 fmol/ml）。一氧化氮合酶抑制剂L-NNA和cGMP拮抗剂Rp 8-溴cGMP可减弱腺苷诱导的软脑膜扩张（10⁻⁸、10⁻⁶和10⁻⁴ M腺苷在L-NNA处理前后，软脑膜扩张分别为8±1%、14±1%、20±3%和3±1%、5±1%、8±3%）。KATP拮抗剂格列本脲也可减弱腺苷扩张（10⁻⁸、10⁻⁶和10⁻⁴ M腺苷在格列本脲处理前后，软脑膜扩张分别为9±2%、14±3%、21±4%和4±1%、8±2%、11±2%）。最后，还观察到腺苷诱导的扩张与脑脊液cAMP浓度升高相关，cAMP拮抗剂Rp 8-溴cAMPs可减弱腺苷引起的软脑膜扩张。这些数据表明腺苷有助于缺氧性软脑膜扩张。这些数据还表明NO、cGMP、cAMP以及KATP通道激活均有助于腺苷诱导软脑膜扩张。最后，这些数据提示腺苷通过cAMP以及NO和cGMP对KATP通道的激活作用，有助于缺氧诱导的软脑膜动脉扩张。
