ATTENUATED NEUROTRANSMITTER RELEASE AND SPREADING DEPRESSION-LIKE DEPOLARIZATIONS AFTER FOCAL ISCHEMIA IN MUTANT MICE WITH DISRUPTED TYPE-INITRIC-OXIDE SYNTHASE GENE

Nitric oxide (NO) plays a complex role in the pathophysiology of cereb ral ischemia. In this study, mutant mice with disrupted type I (neuron al) NO synthase (nNOS) were compared with wild-type littermates after permanent focal ischemia. Cerebral blood flow in the central and perip heral zones of the ischemic distribution were measured with laser dopp ler flowmetry. Simultaneously, microdialysis electrodes were used to m easure extracellular amino acid concentrations and DC potential in the se same locations. Blood flow was reduced to <25 and 60% of baseline l evels in the central and peripheral zones, respectively; there were no differences in nNOS mutants versus wildtype mice. Within the central ischemic zone, DC potentials rapidly shifted to -20 mV in all mice. In the ischemic periphery, spreading depression (SD)-like waves of depol arization were observed. SD-like events were significantly fewer in th e nNOS mutant mice. Concurrent with these hemodynamic and electrophysi ological perturbations, extracellular elevations in amino acids occurr ed after ischemia. There were no detectable differences between wild-t ype and mutant mice in the ischemic periphery. However, in the central zone of ischemia, elevations in glutamate and GABA were significantly lower in the nNOS mutants. Twenty-four hour infarct volumes in the nN OS mutant mice were significantly smaller than in their wild-type litt ermates. Overall, the number of SD-like depolarizations and the integr ated efflux of glutamate were significantly correlated with. infarct s ize. These results suggest that NO derived from the nNOS isoform contr ibutes to tissue damage after focal ischemia by amplifying excitotoxic amino acid release in the core and deleterious waves of SD-like depol arizations in the periphery.