Summary and Conclusions

Although a significant number of studies have clearly demonstrated an important role for nitric oxide in the regulation of diameter of cerebral blood vessels, there is an overall lack of information regarding the potential role of nitric oxide in permeability of the blood-brain barrier. Future studies must continue to focus on identifying the contribution of the nitric oxide biosynthetic pathway to the permeability of the blood-brain barrier. In addition, while many cellular second-messenger systems have been implicated in contributing to the effects of nitric oxide on peripheral microvascular permeability, the role of these pathways in changes in permeability of the blood-brain barrier under physiologic and pathophysiologic conditions remains unknown. Thus, future studies directed at identifying the precise cellular role of nitric oxide in the permeability of the cerebral microcirculation will be critical. The complementary use of in vitro and in vivo models using innovative pharmacological approaches and unique genetic models will certainly advance our understanding of the role of nitric oxide in basal integrity and pathophysiological^ induced changes in permeability of the blood-brain barrier. The answers provided by these unique studies will provide insights into new therapeutic approaches for the treatment of many neurological and cerebrovascular diseases that produce an increase in the permeability of the blood-brain barrier.

Glossary

Blood-brain barrier: An anatomical and physiological barrier. It is formed by complex interendothelial cell tight junctions that form a continuous sealing. The barrier serves to protect the brain from agents in the blood, but also controls the influx and efflux of numerous substances to maintain proper homeostasis in the brain.

Cerebrovascular disease: Disease processes that involve blood vessels of the brain.

Inflammation: A condition in which tissues react to an injury. Inflammation is marked by vasodilation, leukocyte infiltration, redness, heat and pain.

Nitric oxide: A free radical gas derived from a guanidino nitrogen of L-arginine. Nitric oxide is a major secretory product of many cell types and is a pluripotent biological mediator.

Permeability: A process by which substances penetrate or pass across or through a cell membrane.

Further Reading

Brian, J. E., Faraci, F. M., and Heistad, D. D. (1996). Recent insights into the regulation of the cerebral circulation. Clin. Exp. Pharmacol. Physiol. 23, 449-457.

Faraci, F. M., and Heistad, D. D. (1998). Regulation of the cerebral circulation: Role of endothelium and potassium channels. Physiol. Rev. 78, 53-97.

Iadecola, C. (1997). Bright and dark sides of nitric oxide in ischemia brain injury. Trends Neurol. Sci. 20, 132-139. Krizbai, I. A., and Deli, M. A. (2003). Signalling pathways regulating the tight junction permeability in the blood-brain barrier. Cell. Mol. Biol. 49, 23-31.

Mayhan, W. G. (2001). Regulation of blood-brain barrier permeability.

Microcirculation 8, 89-104. Pardridge, W. M. (1986). Blood-brain barrier: Interface between internal medicine and the brain. Ann. Intern. Med. 105, 82-95. Yuan, S. Y. (2000). Signal transduction pathways in enhanced microvascular permeability. Microcirculation 7, 395-403.

Capsule Bibliography

Dr. William G. Mayhan has been at the University of Nebraska Medical Center since 1989 and is currently a Professor and the Vice-Chair of the Department of Physiology. Recipient of the Young Investigator Award from the Microcirculatory Society in 1983, his research primarily focuses on endothelial control of the cerebral microcirculation during physiologic and pathophysiologic conditions. His work is supported by grants from the National Institutes of Health, American Heart Association and American Diabetes Association.

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