Role of Nitric Oxide in Basal Integrity of the Blood Brain Barrier

Although it is clear that the endothelium, by the synthesis/release of nitric oxide, plays a critical role in basal tone of peripheral and cerebral blood vessels, the role of nitric oxide in maintaining the integrity of the endothelial barrier in peripheral and cerebral vessels remains controversial. A few investigators have suggested that inhibition of NOS (using L-NMMA or L-NAME) increases basal levels of permeability in the peripheral circulation and potentiates agonist-induced increases in peripheral vascular permeability. In contrast, a majority of studies including studies from our laboratory have suggested that inhibition of nitric oxide synthesis using L-NMMA and L-NAME does not influence or decreases basal levels of peripheral microvascular permeability, and inhibits increases in venular permeability of the peripheral microcirculation in response to mechanical stimuli and/or inflammatory mediators. The precise reasons for discrepancies between studies regarding a role for nitric oxide in peripheral microvascular permeability remain elusive, but may relate to regional differences in responses of the microcirculation.

Since many cell types of the central nervous system are capable of the synthesis/release of nitric oxide from the var ious isoforms of NOS it is conceivable that nitric oxide may play a critical role in maintaining the integrity of the blood-brain barrier under physiologic conditions. Unfortunately, no studies have systematically examined the precise role of the various isoforms of nitric oxide on basal integrity of the blood-brain barrier, and studies that have attempted to examine the potential role of nitric oxide, in general, in basal permeability of the blood-brain barrier have reported conflicting results. Studies from our laboratory found that L-NMMA (a nonspecific inhibitor of NOS) and aminoguani-dine (a specific inhibitor of iNOS) did not alter the basal transport of molecules across the blood-brain barrier. In addition, others have not reported any differences in the basal permeability characteristics of the blood-brain barrier between wild-type and nNOS knockout mice. In contrast, others have reported that inhibition of NOS with L-NAME produced an increase in permeability of the blood-brain barrier. However, treatment with L-NAME also produced a significant increase in blood pressure, and the contribution of changes in blood pressure to an increase in the permeability of the blood-brain barrier was not examined. Thus, although the basal synthesis/release of nitric oxide may play a critical role in basal tone of cerebral blood vessels, the role of nitric oxide in maintaining the integrity of the blood-brain barrier during physiologic conditions remains uncertain. Future studies, using a variety of specific inhibitors of NOS and genetically altered models, will be required in order to precisely determine the role of the various isoforms of nitric oxide in basal integrity of the blood-brain barrier.

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Essentials of Human Physiology

Essentials of Human Physiology

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