Hamada J, Greenberg J H, Croul S, Dawson T M, Reivich M
Department of Neurology, University of Pennsylvania, Philadelphia 19104-6063, USA.
J Cereb Blood Flow Metab. 1995 Sep;15(5):779-86. doi: 10.1038/jcbfm.1995.98.
We have investigated whether central inhibition of nitric oxide synthase (NOS) could modify the tissue damage of focal cerebral ischemia produced by occlusion of the middle cerebral artery (MCA) in rats. NG-Nitro-L-arginine methyl ester (L-NAME) was administered intracerebroventricularly at two doses 15 min prior to occlusion of the MCA, as well as 4 and 24 h following occlusion. After the injection of L-NAME, the catalytic activity of the constitutive NOS, considered to be mainly neuronal, was effectively suppressed in the subcortical gray matter bilaterally, but not in the ischemic territory. Seven days after the MCA occlusion, the brains were evaluated for histopathologic damage. High-dose administration of L-NAME (120 micrograms/kg 15 min prior to MCA occlusion, followed by 150 micrograms/kg 4 and 24 h after occlusion) produced an enlargement of the infarct area and increased the volume of ischemic damage. These results indicate that extensive inhibition of NOS by a central route can increase the cerebral infarct size in focal ischemia even if NOS is not inhibited in the ischemic tissue and suggest that NO may also play a potentially beneficial role as well as a neurodestructive role in the pathophysiological mechanisms of focal cerebral ischemia.
我们研究了中枢抑制一氧化氮合酶（NOS）是否能改变大鼠大脑中动脉（MCA）闭塞所致局灶性脑缺血的组织损伤。在MCA闭塞前15分钟以及闭塞后4小时和24小时，经脑室内给予两种剂量的NG-硝基-L-精氨酸甲酯（L-NAME）。注射L-NAME后，被认为主要是神经元型的组成型NOS的催化活性在双侧皮质下灰质中被有效抑制，但在缺血区域未被抑制。MCA闭塞7天后，对大脑进行组织病理学损伤评估。高剂量给予L-NAME（MCA闭塞前15分钟给予120微克/千克，随后在闭塞后4小时和24小时给予150微克/千克）导致梗死面积扩大和缺血损伤体积增加。这些结果表明，即使在缺血组织中NOS未被抑制，通过中枢途径广泛抑制NOS也会增加局灶性缺血中的脑梗死大小，并提示NO在局灶性脑缺血的病理生理机制中可能既发挥潜在的有益作用，也发挥神经破坏作用。
