Role of superoxide dismutase and nitric oxide on the interaction between brain and systemic circulation during brain ischemia

Abstract

To elucidate the critical role of superoxide dismutase (SOD) and nitric oxide in brain injury and systemic circulation during brain ischemia, we performed bilateral carotid artery ligation (BCAL) on rats and evaluated the effects of NG-monomethyl-L-arginine (L-NMMA) and a long-acting SOD derivative (SMA-SOD). After administration of L-NMMA, specific inhibitor against nitric oxide synthase (NOS), most of BCAL rats died within 6 h while no BCAL rats without L-NMMA died at all. Administration of SMA-SOD exhibited no effect on the life span of BCAL rats. Magnetic resonance imaging (MRI) and microscopic analysis for the ischemic brain revealed that, although administration of L-NMMA showed no significant effect on the ischemic brain of BCAL rats, SMA-SOD effectively prevented the ischemic changes based on permeability edema in the frontal lobe. Measurement of changes in the blood flow of the ischemic brain revealed that administration of L-NMMA decreased the blood flow in the BCAL rats while no remarkable changes were seen after administration of SMA-SOD. Urinary secretion of NO2-/NO3-, the metabolites of nitric oxide, was increased by challenging BCAL, and the presence of L-NMMA or SMA-SOD diminished this elevation. Blood pressure was increased by performing BCAL to rats, and administration of L-NMMA showed further elevation of the blood pressure. On the contrary, administration of SMA-SOD decreased post-ischemic hypertension. These results suggest that SOD may play a protective role for brain ischemia by suppressing increased vascular permeability, while nitric oxide showed beneficial effect on the ischemic brain by increasing the blood flow in the ischemic brain.