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Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia

¹Department of Neurology, Baylor College of Medicine and the Michael E. DeBakey Veterans Affairs Medical Center Stroke Program, Houston; and ²Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas

Submitted 9 March 2007 ; accepted in final form 28 July 2008

Decreased cerebral blood flow (CBF) has been observed following the resuscitation from neonatal hypoxic-ischemic injury, but its mechanism is not known. We address the hypothesis that reduced CBF is due to a change in nitric oxide (NO) and superoxide anion O₂^– balance secondary to endothelial NO synthase (eNOS) uncoupling with vascular injury. Wistar rats (7 day old) were subjected to cerebral hypoxia-ischemia by unilateral carotid occlusion under isoflurane anesthesia followed by hypoxia with hyperoxic or normoxic resuscitation. Expired CO₂ was determined during the period of hyperoxic or normoxic resuscitation. Laser-Doppler flowmetry was used with isoflurane anesthesia to monitor CBF, and cerebral perivascular NO and O₂^– were determined using fluorescent dyes with fluorescence microscopy. The effect of tetrahydrobiopterin supplementation on each of these measurements and the effect of apocynin and N-nitro-L-arginine methyl ester (L-NAME) administration on NO and O₂^– were determined. As a result, CBF in the ischemic cortex declined following the onset of resuscitation with 100% O₂ (hyperoxic resuscitation) but not room air (normoxic resuscitation). Expired CO₂ was decreased at the onset of resuscitation, but recovery was the same in normoxic and hyperoxic resuscitated groups. Perivascular NO-induced fluorescence intensity declined, and O₂^–-induced fluorescence increased in the ischemic cortex after hyperoxic resuscitation up to 24 h postischemia. L-NAME treatment reduced O₂^– relative to the nonischemic cortex. Apocynin treatment increased NO and reduced O₂^– relative to the nonischemic cortex. The administration of tetrahydrobiopterin following the injury increased perivascular NO, reduced perivascular O₂^–, and increased CBF during hyperoxic resuscitation. These results demonstrate that reduced CBF follows hyperoxic resuscitation but not normoxic resuscitation after neonatal hypoxic-ischemic injury, accompanied by a reduction in perivascular production of NO and an increase in O₂^–. The finding that tetrahydrobiopterin, apocynin, and L-NAME normalized radical production suggests that the uncoupling of perivascular NOS, probably eNOS, due to acquired relative tetrahydrobiopterin deficiency occurs after neonatal hypoxic-ischemic brain injury. It appears that both NOS uncoupling and the activation of NADPH oxidase participate in the changes of reactive oxygen concentrations seen in cerebral hypoxic-ischemic injury.

apocynin; neonatal rat; vasculature; N-nitro-L-arginine methyl ester

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