DEVELOPMENTAL AND REGIONAL DIFFERENCES IN NITRIC-OXIDE SYNTHASE ACTIVITY AND BLOOD-FLOW IN THE SHEEP BRAIN

Nitric oxide synthase (NOS) participates in the regulation of cerebral blood flow and neurotransmitter release and as a second messenger of glutamatergic and cholinergic systems. Developmental differences in NO S activity have been described in the rat, but not in a species with l onger gestation and a larger, lobulated brain at birth. We assayed NOS activity by conversion of [C-14]L-arginine to [C-14]L-citrulline in 5 0-mg tissue samples from eight brain regions in sheep at 70, 92, 110, and 135 days gestation (term = 145 days); newborns (< 7 days); and adu lts to test the hypothesis that NOS activity in the brain is developme ntally regulated from midgestation through adulthood and matures along the neuroaxis in parallel with the known development of cerebral bloo d flow and neuronal activity. Three patterns of maturation of NOS acti vity were evident: increasing to or exceeding adult levels before 70 d ays gestation in the thalamus, cerebellum, and medulla; increasing to adult levels between 70 and 92 days in the hippocampus; and increasing to adult levels after 92 days in the cortex and caudate. Additionally , there were regional differences in cortical NOS activity: at 70 and 92 days of gestation, frontal cortex NOS activity was greater than par ietal or occipital activity, and at 135 days gestation and in the newb orn and adult, cortical and caudate activity exceeded that in most of the more caudal regions. The up to fourfold increase in regional corti cal NOS activity between 92 and 135 days gestation was associated with twofold increases in cerebral blood flow and oxygen consumption durin g this period. Inhibition of NOS activity with administration of 60 mg /kg of N-G-nitro-L-arginine methylester (L-NAME) resulted in 27% and 2 5% reductions in cerebral blood flow at 93 and 133 days gestation. Whi le the associated increases in NOS activity with increases in CBF and CMRO(2) do not appear causative, at various points in gestation the de development of NOS activity may participate in the development of mat ure patterns of cerebral blood flow regulation in parallel with develo pment of synaptic and electrical activity.