缺氧和腺苷对仔猪N-甲基-D-天冬氨酸诱导的软脑膜小动脉扩张的抑制作用。

Inhibitory effects of hypoxia and adenosine on N-methyl-D-aspartate-induced pial arteriolar dilation in piglets.

作者信息

Bari F, Thore C R, Louis T M, Busija D W

机构信息

Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.

出版信息

Brain Res. 1998 Jan 12;780(2):237-44. doi: 10.1016/s0006-8993(97)01196-7.

DOI:10.1016/s0006-8993(97)01196-7

PMID:9507150

Abstract

Our previous studies have indicated that oxygen radicals, produced during reoxygenation following short-term arterial hypoxia, lead to sustained suppression of cerebral arteriolar responses to N-methyl-D-aspartate (NMDA). However, whether arteriolar dilator responses to NMDA are reduced during arterial hypoxia has never been examined. In this study, we determined whether hypoxia or hypoxia-related metabolites such as adenosine or nitric oxide (NO) will reduce NMDA-induced arteriolar dilation. We have also determined the location of NMDA receptor- and brain nitric oxide synthase (bNOS)-positive neurons in the cerebral cortex. In anesthetized piglets, pial arteriolar diameters were determined using intravital microscopy. Baseline arteriolar diameters were approximately 100 microns. Topical application of NMDA at concentrations of 10(-5), 5 x 10(-5) and 10(-4) M resulted in dose-dependent vasodilation (9 +/- 2, 18 +/- 2 and 29 +/- 2% above baseline, respectively, n = 21). Administration of theophylline (20 mg/kg, i.v.) had no effect on NMDA-dependent vasodilation, but it did block dilation to hypoxia (inhalation of 8.5% O2). In theophylline-treated animals, NMDA responses were completely abolished during hypoxia (28 +/- 2 vs. 2 +/- 1%, respectively to 10(-4) M, n = 7) while sodium nitroprusside (SNP, 10(-4) M) still dilated pial arterioles normally. NMDA-induced vasodilation was not modified after application and removal of adenosine (10(-4) M; n = 5) or SNP (10(-5) M; n = 4), or when SNP (10(-7) M) was coapplied with NMDA (n = 6). Conversely, coapplication of adenosine (10(-6) M) attenuated NMDA responses (31 +/- 5 vs. 20 +/- 3%, n = 7). We also found that NMDA receptor- and bNOS-containing neurons were located predominantly in layers II/III of the cortex. Proximity of these neurons to the cortical surface is consistent with diffusion of NO to pial arterioles as the mechanism of dilation to NMDA. We conclude that NMDA-induced cerebral arteriolar dilation is inhibited by hypoxia alone and by exogenous adenosine, but not by NO.

摘要

我们之前的研究表明，短期动脉缺氧后再给氧过程中产生的氧自由基会导致脑小动脉对N-甲基-D-天冬氨酸（NMDA）的反应持续受到抑制。然而，动脉缺氧期间小动脉对NMDA的舒张反应是否降低从未得到过研究。在本研究中，我们确定了缺氧或与缺氧相关的代谢产物如腺苷或一氧化氮（NO）是否会降低NMDA诱导的小动脉舒张。我们还确定了NMDA受体和脑一氧化氮合酶（bNOS）阳性神经元在大脑皮层中的位置。在麻醉的仔猪中，使用活体显微镜测定软脑膜小动脉直径。基线小动脉直径约为100微米。局部应用浓度为10⁻⁵、5×10⁻⁵和10⁻⁴ M的NMDA导致剂量依赖性血管舒张（分别比基线高9±2%、18±2%和29±2%，n = 21）。静脉注射氨茶碱（20 mg/kg）对NMDA依赖性血管舒张无影响，但它确实阻断了对缺氧（吸入8.5% O₂）的舒张反应。在氨茶碱处理的动物中，缺氧期间NMDA反应完全消失（对10⁻⁴ M分别为28±2% vs. 2±1%，n = 7），而硝普钠（SNP，10⁻⁴ M）仍能正常舒张软脑膜小动脉。应用并去除腺苷（10⁻⁴ M；n = 5）或SNP（10⁻⁵ M；n = 4）后，或当SNP（10⁻⁷ M）与NMDA联合应用时（n = 6），NMDA诱导的血管舒张未改变。相反，联合应用腺苷（10⁻⁶ M）减弱了NMDA反应（31±5% vs. 20±3%，n = 7）。我们还发现，含有NMDA受体和bNOS的神经元主要位于皮层的II/III层。这些神经元靠近皮层表面与NO扩散到软脑膜小动脉作为对NMDA舒张的机制是一致的。我们得出结论，NMDA诱导的脑小动脉舒张仅受缺氧和外源性腺苷抑制，而不受NO抑制。