The increase in cerebral blood flow (CBF) during hypoxia in fetal sheep at 0.6 gestation is less than the increase at 0.9 gestation when normalized for differences in baseline CBF and oxygen consumption. Nitric oxide (NO) synthase (NOS) catalytic activity increases threefold during this period of development. We tested the hypothesis that administration of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) decreases the CBF response to systemic hypoxia selectively at 0.9 gestation. We also tested whether any peripheral vasoconstriction during hypoxia is potentiated by L-NAME at 0.9 gestation. Administration of L-NAME increased arterial blood pressure and decreased microsphere-determined CBF during normoxia in fetal sheep at both 0.6 and 0.9 gestation. With subsequent reduction of arterial oxygen content by approximately 50%, the percent increase in forebrain CBF in a control group (57 +/- 11%; +/- SE) and L-NAME-treated group (51 +/- 6%) was similar at 0.6 gestation. Likewise, at 0.9 gestation, the increase in CBF was similar in control (90 +/- 25%) and L-NAME (80 +/- 28%) groups. At 0.9 gestation, L-NAME treatment attenuated the increase in coronary blood flow and increased gastrointestinal vascular resistance during hypoxia. We conclude that NO exerts a basal vasodilatory influence in brain as early as 0.6 gestation in fetal sheep but is not an important mechanism for hypoxic vasodilation in brain at either 0.6 or 0.9 gestation. Thus the developmental increase in NOS catalytic capacity does not appear to be responsible for developmental increases in the CBF response to hypoxia during this period. In contrast, NO modulates the vascular response to hypoxia in heart and gastrointestinal tract.

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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 NOS activity have been described in the rat, but not in a species with longer gestation and a larger, lobulated brain at birth. We assayed NOS activity by conversion of [14C]L-arginine to [14C]L-citrulline in 50-mg tissue samples from eight brain regions in sheep at 70, 92, 110, and 135 days gestation (term = 145 days); newborns (< 7 days); and adults to test the hypothesis that NOS activity in the brain is developmentally regulated from midgestation through adulthood and matures along the neuroaxis in parallel with the known development of cerebral blood flow and neuronal activity. Three patterns of maturation of NOS activity were evident: increasing to or exceeding adult levels before 70 days 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 parietal or occipital activity, and at 135 days gestation and in the newborn and adult, cortical and caudate activity exceeded that in most of the more caudal regions. The up to fourfold increase in regional cortical NOS activity between 92 and 135 days gestation was associated with twofold increases in cerebral blood flow and oxygen consumption during this period. Inhibition of NOS activity with administration of 60 mg/kg of NG-nitro-L-arginine methylester (L-NAME) resulted in 27% and 25% reductions in cerebral blood flow at 93 and 133 days gestation. While the associated increases in NOS activity with increases in CBF and CMRO2 do not appear causative, at various points in gestation the development of NOS activity may participate in the development of mature patterns of cerebral blood flow regulation in parallel with development of synaptic and electrical activity.

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