AUGMENTATION OF NITRIC-OXIDE, SUPEROXIDE, AND PEROXYNITRITE PRODUCTION DURING CEREBRAL-ISCHEMIA AND REPERFUSION IN THE RAT

The effect of ischemia produced by bilateral occlusion of the common c arotid arteries (30 min) followed by 4 hours of reperfusion on total a nd inducible nitric oxide synthase (NOS) activity and the production o f nitric oxide (NO), superoxide and peroxynitrite in the cerebral hemi spheres was determined in the rat. Compared to sham-operated controls, cerebral ischemia-reperfusion resulted in a significant increase in t otal and inducible NOS activity and a significant increase in the prod uction of NO and superoxide in the cerebral hemispheres. The level of NO in the plasma and the peripheral leukocyte count were also signific antly increased. Immunohistochemical staining for nitrotyrosine (a mar ker of peroxynitrite production) showed that ischemia-reperfusion resu lted in increased synthesis of cerebral peroxynitrite. Administration of the irreversible NOS inhibitor, N-omega-nitro-L-arginine (L-NA), in creased superoxide levels in the brain and significantly reduced plasm a NO. Total and inducible NOS activity as well as NO and immunoreactiv e nitrotyrosine, in the cerebral hemispheres were reduced with L-NA ad ministration. The number of leukocytes in the plasma was unaffected by administration of L-NA. These findings suggest that cerebral ischemia -reperfusion causes increased production of reactive oxygen species in the cerebral hemispheres and that the production of peroxynitrite, an d not superoxide, may be dependent upon the availability of NO.