Abstract 1086 Neonatal Disease Oriented Research: Molecular Events and Brain Injury Poster Symposium, Tuesday, 5/4
Dysfunctional autoregulation of cerebral blood flow (CBF) appears to contribute to increased blood flow and subsequent intraventricular hemorrhage in premature infants when arterial pressure increases. CBF autoregulation depends on the interaction of metabolic and myogenic factors, and may be modified by neurogenic factors, such as perivascular nerves. Nitric oxide synthase (NOS) is present within endothelium, neurons, glia and perivascular nerves. Thus it was tempting to consider the notion that NO might play a role in CBF autoregulation. Since NO is a potent vasodilator we speculated that NO production would contribute to vasodilation and loss of CBF autoregulation when cerebral perfusion pressure is increased. We hypothesized that NOS inhibition would attenuate the increase in CBF when cerebral perfusion pressure was increased. We examined the effects of non-selective inhibition of endothelial and neuronal NOS by Nω-nitro-L-arginine methylester (L-NAME 50 mg/kg i.v.) and selective inhibition of neuronal NOS by 7-nitroindazole (7-NI 25 mg/kg i.p.). Total brain and regional blood flows (rCBFs) were measured by radiolabelled microspheres in newborn piglets (<14 d) at baseline mean arterial pressure (MAP) of 80-95 mmHg, and after MAP was increased by aortic occlusion and/or norepinephrine infusion to 100-110 mmHg (H1) and 110-125 mmHg (H2). Data were analyzed with 2-way ANOVA with replications. In CONTROL (n=6), flows to the medulla-pons and midbrain-diencephalon did not increase significantly. Flows increased to cerebellum and cortical gray matter at H1 (p <0.01) while at H2 flows increased to the cerebellum (p <0.05), cerebrum, occipital lobe, olfactory-hippocapus, cortical gray matter, and total brain (p < 0.01). In L-NAME (n=6), total brain and regional blood flows did not increase. In 7-NI (n=6), total brain and all regional blood flows increased at both H1 and H2 (p <0.01). Total brain and nearly all rCBFs at H2 were greater in 7-NI compared to CONTROL (p < 0.05). Compared to baseline flows, rCBFs at H1 increased 4-32% in CONTROL and 28-77% in 7-NI, while rCBFs at H2 increased 15-81% in CONTROL and 43-266% in 7-NI. Cerebral oxygen consumption did not change and did not differ between groups. Fractional extraction of oxygen by cerebrum decreased significantly at both H1 and H2 in CONTROL and 7-NI (p <0.01) and at H2 was lower in 7-NI compared to CONTROL (p <0.01). We conclude that (1) non-selective NOS inhibition attenuates increases in total and regional blood flows and (2) selective neuronal NOS inhibition disrupts CBF autoregulation. These results suggest that (1) endothelial NO contributes to loss of CBF autoregulation, and (2) neuronal NO contributes to maintenance of CBF autoregulation as perfusion pressure increases. We speculate that neuronal NO, derived from perivascular nerves, inhibits production of a vasodilator, perhaps endothelial NO or prostaglandins.
Study funded by the Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, D.C.
(Spon by: Val G Hemming)
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Berkenbaugh, J., Larkin, H. & O'Neill, J. Neuronal Nitric Oxide Synthase Inhibition Disrupts Autoregulation of Cerebral Blood Flow during Increased Cerebral Perfusion Pressure in Newborn Piglets. Pediatr Res 45, 186 (1999) doi:10.1203/00006450-199904020-01103