Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space
Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space
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DOI：
10.1097/00004647-199809000-00007
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发表时间：
1998-09-01
影响因子：
6.3
通讯作者：
Dirnagl, U
中科院分区：
文献类型：
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作者：
Dreier, JP;Körner, K;Dirnagl, U
我们研究了脑局部K+浓度增加和一氧化氮(NO)减少的联合作用。一氧化氮清除或一氧化氮合酶(NOS)抑制局部脑血流量和蛛网膜下腔直流(DC)电位所致的水平。采用硫喷妥钠麻醉雄性Wistar大鼠闭合颅窗准备，脑局部灌流NO。清除剂血红蛋白(Hb；2 mmoL/L)和人工脑脊液中KF浓度升高(35 mmoL/L)导致突发性自发性短暂性脑缺血事件，脑血流量较基线(100%)下降14+/-7%(n=4)。缺血事件持续53+/-17分钟，并伴有49+/-12分钟的蛛网膜下腔DC负移-7.3+/-0.6 mV。一氧化氮合酶抑制剂N-硝基-L-精氨酸(L-NA，1 mmoL/L)与[K+](Acsf)以35 mmoL/L的速度联合应用，在13只大鼠上引起类似的自发性短暂性脑缺血事件。用KCl5 mm距离诱导皮质扩散性抑制时，生理性人工脑脊液(n=5)或含有升高[K+](ACSF)的人工脑脊液(ACSF)分别以20 mmol/L(n=4)、3 mmol/L(n=4)或[K+](ACSF)3 mmol/L联合L钠(n=10)进行脑局部灌流时，在闭合的颅窗处可观察到典型的皮质扩张性充血(CSH)和负DC漂移。[K+](ACSF)10 mm ol/L+L-NA(5只)或[K+](3 mm o l/L+Hb)(3只)。脑组织灌流[K+](20 mm o l/L)+Hb(脑血流量下降至20+/-20%，持续25+/-21 m in，n=4)或[K+](n=19)[K+](n=19)联合L-NA灌流(n=19)，皮质弥漫性抑制可诱导长时间的短暂性脑缺血，而非CSH。一氧化氮合酶抑制和[K+](ACSF20 mmol/L)诱导的短暂性脑缺血以3.4+/-0.6 mm/min的速度传播，提示皮质扩散性脑缺血。虽然CSH没有改变氧自由基的产生，通过在体的荧光素增强的化学发光法在线测量，CSI导致了典型的脑缺血再灌注自由基产生模式，提示脑损伤(n=4)。尼莫地平(2微克/公斤体重/分钟静脉注射)将CSI转化为CSH(n=4)。车辆对CSI无影响(n=4)。我们的数据表明，NO减少的组合。水平和蛛网膜下腔KC水平升高可导致弥漫性抑郁和急性缺血性脑血流反应。因此，代谢和脑血流的紊乱耦合可导致缺血。我们推测CSI可能与蛛网膜下腔出血后迟发性脑缺血有关，这是一种临床情况，即红细胞释放Hb和K+，创造与本文研究类似的微环境。
We investigated the combined effect of increased brain topical K+ concentration and reduction of the nitric oxide (NO.) level caused by nitric oxide scavenging or nitric oxide synthase (NOS) inhibition on regional cerebral blood flow and subarachnoid direct current (DC) potential. Using thiopental-anesthetized male Wistar rats with a closed cranial window preparation, brain topical superfusion of a combination of the NO. scavenger hemoglobin (Hb; 2 mmol/L) and increased Kf concentration in the artificial cerebrospinal fluid ([K+](ACSF)) at 35 mmol/L led to sudden spontaneous transient ischemic events with a decrease of CBF to 14 +/- 7% (n = 4) compared with the baseline (100%). The ischemic events lasted for 53 +/- 17 minutes and were associated with a negative subarachnoid DC shift of -7.3 +/- 0.6 mV of 49 +/- 12 minutes' duration. The combination of the NOS inhibitor N-nitro-L-arginine (L-NA, 1 mmol/L) with [K+](ACSF) at 35 mmol/L caused similar spontaneous transient ischemic events in 13 rats. When cortical spreading depression was induced by KCl at a 5-mm distance, a typical cortical spreading hyperemia (CSH) and negative DC shift were measured at the closed cranial window during brain topical superfusion with either physiologic artificial CSF(n = 5), or artificial CSF containing increased [K+](ACSF) at 20 mmol/L (n = 4), [K+](ACSF) at 3 mmol/L combined with L-NA (n = 10), [K+](ACSF) at 10 mmol/L combined with L-NA (five of six animals) or [K+](ACSF) at 3 mmol/L combined with Hb (three of four animals). Cortical spreading depression induced long-lasting transient ischemia instead of CSH, when brain was superfused with either [K+](ACSF) at 20 mmol/L combined with Hb (CBF decrease to 20 +/- 20% duration 25 +/- 21 minutes, n = 4), or [K+](ACSF) at 20 mmol/L combined with L-NA (n = 19). Transient ischemia induced by NOS inhibition and [K+](ACSF) at 20 mmol/L propagated at a speed of 3.4 +/- 0.6 mm/min, indicating cortical spreading ischemia (CSI). Although CSH did not change oxygen free radical production, as measured on-line by in vivo lucigenin-enhanced chemiluminescence, CSI resulted in the typical radical production pattern of ischemia and reperfusion suggestive of brain damage (n = 4). Nimodipine (2 mu g/kg body weight/min intravenously) transformed CSI back to CSH (n = 4). Vehicle had no effect on CSI (n = 4). Our data suggest that the combination of decreased NO. levels and increased subarachnoid KC levels induces spreading depression with acute ischemic CBF response. Thus, a disturbed coupling of metabolism and CBF can cause ischemia. We speculate that CSI may be related to delayed ischemic deficits after subarachnoid hemorrhage, a clinical condition in which the release of Hb and K+ from erythrocytes creates a microenvironment similar to the one investigated here.