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1 Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
* To whom correspondence should be addressed. E-mail: ksmark{at}u.arizona.edu.
Ischemic stroke from a reduction in blood flow to the brain microvasculature results in a subsequent decreased delivery of oxygen (i.e., hypoxia) and vital nutrients to endothelial, neuronal, and glial cells. Hypoxia associated with stroke has been shown to increase paracellular permeability of the blood-brain barrier, leading to the release of cellular mediators and brain tissue injury (5, 18, 25, 26, 40). While reperfusion does not occur in all ischemic strokes, increased permeability has been seen in post-hypoxic reoxygenation (43, 48). Currently, it is unknown whether these deleterious effects result from cellular mechanisms stimulated by decreased oxygen during stroke or post-hypoxic reoxygenation stress. This study used primary bovine brain microvessel endothelial cells (BBMECs) to examine the involvement of nitric oxide (NO) as a mediator in hypoxia-induced permeability changes. Hypoxia-induced increased transport of [14C]sucrose across BBMEC monolayers compared to normoxia was attenuated by either post-hypoxic reoxygenation or inhibition of nitric oxide synthase (NOS). The hypoxia-induced permeability effect was further reduced when NOS inhibition was combined with post-hypoxic reoxygenation. Additionally, a significant increase in total NO was seen in BBMECs following hypoxic exposure. This correlation was supported by the increased [14C]sucrose permeability observed when BBMECs were exposed to the NO donor, DETANONOate. Western blot analyses of NOS isoforms showed a significant increase in the inducible isoform following hypoxic exposure with a subsequent reduction in expression upon reoxygenation. Results from this study suggest that hypoxia-induced BBB breakdown can be diminished by inhibition of nitric oxide synthesis, decreased concentration of NO metabolites, and/or reoxygenation.
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