Mohammadi Mohammad T, Shid-Moosavi S Mostafa, Dehghani Gholam A
Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran.
Pathophysiology. 2012 Feb;19(1):13-20. doi: 10.1016/j.pathophys.2011.07.003. Epub 2011 Aug 17.
Endogenous level of nitric oxide (NO) is increased in the brain following the stroke, and deactivation of NO synthase has been shown to attenuate its destructive actions in animal stroke models using middle cerebral artery occlusion (MCAO) procedures. However, little is known about the effects of NO in cerebral vascular integrity and edema during acute cerebral ischemia. Here we investigated whether NO plays any role in the progression of blood-brain barrier (BBB) disruption and edema formation in ischemia/reperfusion injury. Intraperitoneal administration of NO substrate l-arginine (300mg/kg), or NOS inhibitor (l-NAME, 1mg/kg), was done in normal rats at 20min before a 60-min MCAO. Mean arterial blood pressures (MAP) and regional cerebral blood flow (rCBF) were continuously recorded during experiment. Neurological deficit score (NDS) was evaluated 12h after termination of MCAO followed with evaluations of cerebral infarction volume (CIV), edema formation and cerebral vascular permeability (CVP), as determined by the Evans blue dye extravasations (EBE) technique. No significant changes were observed in the values of MAP and rCBF with l-arginine or l-NAME during ischemia or reperfusion periods. There was a 75-85% reduction in rCBF in during MCAO which returned back to its pre-occlusion level during reperfusion. Acute cerebral ischemia with or without l-arginine augmented NDS (4.00±0.44 and 3.00±0.30), in conjunction with increased CIV (518±57mm(3) and 461±65mm(3)), provoked edema (3.09±0.45% and 3.30±0.49%), and elevated EBE (8.28±2.04μg/g and 5.09±1.41μg/g). Inhibition of NO production by l-NAME significantly improved NDS (1.50±0.22), diminished CIV (248±56mm(3)), edema (1.18±0.58%) and EBE (1.37±0.12μg/g). This study reconfirms the cerebroprotective properties of reduced tissue NO during acute ischemic stroke, and it also validates the deleterious actions of increased NOS activity on the disruption of cerebral microvascular integrity and edema formation of ischemia/reperfusion injuries in normal rat, without changing arterial blood pressure or blood flows to ischemic regions.
中风后大脑中一氧化氮（NO）的内源性水平会升高，并且在使用大脑中动脉闭塞（MCAO）程序的动物中风模型中，已证明抑制一氧化氮合酶可减弱其破坏作用。然而，关于急性脑缺血期间NO对脑血管完整性和水肿的影响知之甚少。在这里，我们研究了NO在缺血/再灌注损伤中血脑屏障（BBB）破坏和水肿形成的进展中是否起作用。在60分钟MCAO前20分钟，对正常大鼠腹腔注射NO底物L-精氨酸（300mg/kg）或NOS抑制剂（L-NAME，1mg/kg）。实验过程中持续记录平均动脉血压（MAP）和局部脑血流量（rCBF）。在MCAO终止12小时后评估神经功能缺损评分（NDS），随后通过伊文思蓝染料外渗（EBE）技术评估脑梗死体积（CIV）、水肿形成和脑血管通透性（CVP）。在缺血或再灌注期间，L-精氨酸或L-NAME处理后MAP和rCBF值未观察到显著变化。MCAO期间rCBF降低75 - 85%，再灌注期间恢复到闭塞前水平。无论有无L-精氨酸，急性脑缺血都会增加NDS（分别为4.00±0.44和3.00±0.30），同时增加CIV（分别为518±57mm³和461±65mm³），引发水肿（分别为3.09±0.45%和3.30±0.49%），并升高EBE（分别为8.28±2.04μg/g和5.09±1.41μg/g）。L-NAME抑制NO生成可显著改善NDS（1.50±0.22），减少CIV（248±56mm³）、水肿（1.18±0.58%）和EBE（1.37±0.12μg/g）。本研究再次证实了急性缺血性中风期间组织NO减少的脑保护特性，并且还验证了在正常大鼠中，NOS活性增加对缺血/再灌注损伤的脑微血管完整性破坏和水肿形成具有有害作用，而不改变动脉血压或缺血区域的血流量。
