EFFECTS OF CENTRAL INHIBITION OF NITRIC-OXIDE SYNTHASE ON FOCAL CEREBRAL-ISCHEMIA IN RATS

We have investigated whether central inhibition of nitric oxide syntha se (NOS) could modify the tissue damage of focal cerebral ischemia pro duced by occlusion of the middle cerebral artery (MCA) in rats. N-G-Ni tro-L-arginine methyl ester (L-NAME) was administered intracerebrovent ricularly at two doses 15 min prior to occlusion of the MCA, as well a s 4 and 24 h following occlusion. After the injection of L-NAME, the c atalytic activity of the constitutive NOS, considered to be mainly neu ronal, was effectively suppressed in the subcortical gray matter bilat erally, but not in the ischemic territory. Seven days after the MCA oc clusion, the brains were evaluated for histopathologic damage. High-do se administration of L-NAME (120 mu g/kg 15 min prior to MCA occlusion , followed by 150 CI mu g/kg 4 and 24 h after occlusion) produced an e nlargement of the infarct area and increased the volume of ischemic da mage. These results indicate that extensive inhibition of NOS by a cen tral route can increase the cerebral infarct size in focal ischemia ev en if NOS is not inhibited in the ischemic tissue and suggest that NO may also play a potentially beneficial role as well as a neurodestruct ive role in the pathophysiological mechanisms of focal cerebral ischem ia.