Submitted on December 15, 2005
Accepted on April 28, 2006
Effects of Acute Hyperosmolality on Blood-Brain Barrier Function in Ovine Fetuses and Lambs
Barbara S. Stonestreet1*, Grazyna B Sadowska1, Joanne Leeman2, R Choudary Hanumara2, Katherine H Petersson1, and Clifford S Patlak3
1 Pediatrics, Brown University Medical School, Providence, Rhode Island, United States
2 Department of Computer Science and Statistics, University of Rhode Island, Kingston, Rhode Island, United States
3 Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: bstonestreet{at}wihri.org.
We examined the effects of hyperosmolality on blood-brain barrier (BBB) permeability during development to test the vulnerability of the immature barrier to stress. The BBB response to hyperosmolality was quantified using the blood-to-brain transfer constant (Ki) with 
-aminoisobutyric acid in fetuses at 60% and 90% gestation, premature, newborn, and older lambs. Ki plotted against osmolality increased as a function of increases in osmolality in all groups and brain regions. The relationship was described (P<0.05) by a segmented regression model. At lower osmolalities, changes in Ki were minimal but after a break point (threshold) was reached, the increase (P<0.05) was linear. We examined the responses of Ki to hyperosmolality within each brain region by comparing the thresholds and slopes of the second regression segment. Lower thresholds and higher slopes imply greater vulnerability to hyperosmolality in the younger groups. Thresholds increased (P<0.05) with development in the thalamus, superior colliculus, pons and spinal cord and slopes of the second regression segment decreased (P<0.05) in the cerebellum, hippocampus, inferior colliculus, medulla and spinal cord. BBB resistance to hyperosmolality increased (P<0.05) with development in most brain regions. The pattern of the Ki plotted against osmolality was (P<0.05) heterogenous among brain regions in fetuses, premature and newborn lambs, but not in older lambs. We conclude that (1) BBB permeability increased as a function of changes in osmolality, (2) the barrier becomes more resistant to hyperosmolality during development, and (3) the permeability response to hyperosmolality is heterogenous among brain regions in fetuses, premature and newborn lambs.
