Armengou Arola, Hurtado Olivia, Leira Rogelio, Obón María, Pascual Carlos, Moro María A, Lizasoain Ignacio, Castillo José, Dávalos Antoni
Department of Neurology, Hospital Doctor Josep Trueta, Girona, Spain.
J Cereb Blood Flow Metab. 2003 Aug;23(8):978-84. doi: 10.1097/01.WCB.0000080651.64357.C6.
There are no useful markers in blood of nitric oxide (NO)-mediated brain damage. Because l-arginine (l-arg) is the only known substrate for NO generation, the authors investigated the plasma profile of l-arg after cerebral ischemia, and the relationship of L-arg concentrations in blood with stroke outcome and infarct volume in a clinical and experimental study. l-Arg levels were determined with high-performance liquid chromatography in blood and CSF samples obtained on admission, and in blood 48 hours after inclusion, in 268 patients admitted with a hemispheric ischemic stroke lasting 8.2 +/- 5.9 hours. Infarct volume was measured by days 4 to 7 using computed tomography. Plasma l-arg profiles were analyzed in a separate group of 29 patients seen within 8 hours of onset (median, 4.5 hours) and in 24 male Fischer rats treated with subcutaneous vehicle or 20-mg/kg 1400W (a specific inducible NO synthase inhibitor) every 8 hours for 3 days after performing sham or permanent middle cerebral artery occlusion. Plasma l-arg concentrations decreased after the ischemic event, both in patients and rats, and peaked between 6 and 24 hours. In patients, there was a highly correlation between l-arg levels in CSF and plasma at 48 hours (r = 0.85, P<0.001). CSF and plasma l-arg concentrations negatively correlated with infarct volume (r = -0.40 and r = -0.35, respectively, P<0.001), and were significantly lower in patients with early neurologic deterioration and in those with poor outcome (Barthel index <85) at 90 days (P<0.001). In rats, the administration of 1400W resulted in a 55% significant reduction of infarct volume measured 72 hours after permanent middle cerebral artery occlusion, an effect that correlated with the inhibition caused by 1400W on the ischemia-induced decrease of plasma l-arg concentrations at 6 to 24 hours after the onset of the ischemia. Taken together, these data indicate that determination of l-arg levels in blood might be useful to evaluate the neurotoxic effects of NO generation. These findings might be helpful to guide future neuroprotective strategies in patients with ischemic stroke.
在血液中没有可用于检测一氧化氮（NO）介导的脑损伤的有效标志物。由于L-精氨酸（L-arg）是已知唯一能生成NO的底物，作者在一项临床和实验研究中，调查了脑缺血后血浆中L-arg的变化情况，以及血液中L-arg浓度与中风预后和梗死体积之间的关系。对268例因半球缺血性中风入院、病程为8.2±5.9小时的患者，在入院时及纳入研究后48小时采集血液和脑脊液样本，用高效液相色谱法测定L-arg水平。在发病8小时内（中位数为4.5小时）就诊的另外29例患者，以及24只雄性Fischer大鼠（在进行假手术或永久性大脑中动脉闭塞后，每8小时皮下注射溶媒或20mg/kg 1400W（一种特异性诱导型NO合酶抑制剂），持续3天）中分析血浆L-arg变化情况。缺血事件后，患者和大鼠的血浆L-arg浓度均下降，并在6至24小时达到峰值。在患者中，48小时时脑脊液和血浆中的L-arg水平高度相关（r = 0.85，P<0.001）。脑脊液和血浆中的L-arg浓度与梗死体积呈负相关（分别为r = -0.40和r = -0.35，P<0.001），在早期神经功能恶化的患者以及90天时预后不良（Barthel指数<85）的患者中显著降低（P<0.001）。在大鼠中，给予1400W可使永久性大脑中动脉闭塞72小时后测量的梗死体积显著减少55%，这一效应与1400W对缺血后6至24小时血浆L-arg浓度缺血诱导性降低的抑制作用相关。综上所述，这些数据表明，测定血液中的L-arg水平可能有助于评估NO生成的神经毒性作用。这些发现可能有助于指导缺血性中风患者未来神经保护策略的制定。
