EXCESS NO SYNTHESIS IMPAIRS AUTOREGULATION (AR) OF CEREBRAL BLOOD FLOW (CBF) IN NEWBORN (NB) PIGS: Role and ontogeny of e- and n-NO synthase (NOS). • 188

The inability of CBF of the NB to remain constant when blood pressure (BP) increases predisposes to intraventricular hemorrhage (IVH). We postulated that increased cerebrovascular synthesis of the vasodilator NO in NB curtails the necessary vasoconstriction for enhanced CBF AR. CBF (microspheres) and cerebrovascular nitrite levels (stable product of NO, assayed from sagittal sinus plasma) were measured as a function of increasing mean BP (MBP; by inflation of balloon-tipped catheters in descending aorta) in 1 day old and young adult (4-6 week old) pigs treated with the non-selective NOS inhibitor L-NMMA (3 mg/kg iv) or saline. In saline-treated NB CBF rose with MBP from its upper limit of AR of 85 mm Hg (r=0.61, p<0.01), and this was associated with a concomitant increase in sagittal sinus nitrite levels; in contrast, L-NMMA reduced nitrite concentrations and maintained CBF constant up to 137 mm Hg (r=0.06, p>0.7). In adult pigs treated with saline or L-NMMA CBF and nitrite levels were constant over MBP studied (till 130 mm Hg). Furthermore, NOS activity (conversion of [³H]arginine to [³H]citrulline), as well as e-NOS protein and mRNA were 2-3 fold greater in cerebral microvessels of NB than of adult. Because the autonomic nervous system is important in setting the upper limit of CBF AR and NO from n-NOS is produced by this system, we examined the role of n-NOS in CBF AR of the NB using the selective n-NOS inhibitor 7-NINA (3 mg/kg iv). 7-NINA did not affect basal CBF and, like L-NMMA as well as the autonomic ganglion blocker hexamethonium (1 mg/kg iv), maintained CBF constant beyond MBP 125 mm Hg (r=0.31, p<0.01); 7-NINA also prevented increased sagittal sinus nitrite during hypertension. Finally, n-NOS mRNA was ≈2 fold greater in NB than adult cerebral microvessels. In conclusion: 1) increased cerebrovascular NO synthesis in NB, compared to that of adult, curtails CBF AR by masking cerebral vasoconstrictor response to a rise in perfusion perfusion; and 2) n-NOS, likely through activation of the autonomic nervous system and apparently in a concerted manner with e-NOS, exerts a major role in setting the upper limit of CBF AR of the NB. Reduced activity of constitutive NOS in the preterm NB may decrease IVH.