The effects of the Na(+)/Ca(++) exchange blocker on osmotic blood-brain barrier disruption

Abstract

Osmotic disruption of the blood-brain barrier (BBB) by mannitol is currently being used to enhance drug delivery in human brains. Despite clinical and experimental interest, to date the time course in the early phase of disruption has not been accurately identified. The mechanism in barrier closure also remains elusive. We first studied the rapid change in cerebrovascular permeability after BBB disruption in rats, and then demonstrated that the Na(+)/Ca(++) exchange blocker (KB-R7943) prolongs osmotic disruption. Osmotic BBB disruption was attained by using intra-arterial infusion of hypertonic mannitol in Sprague-Dawley (SD) rats. To measure the changes in cerebrovascular permeability, perfusate containing [14C]-sucrose was infused intra-arterially at different time points following osmotic stress. Cerebrovascular permeability was then measured with the in situ brain perfusion technique. This is the first in vivo study demonstrating that osmotic disruption is prolonged by the Na(+)/Ca(++) exchange blocker, which did not affect the peak level of BBB disruption. The exact time course of cerebrovascular reversibility was studied and the earliest BBB disruption was seen to occur 5 min after osmotic stress. Histopathological examination after osmotic disruption with the Na(+)/Ca(++) exchange blocker showed no neuronal damage in rat brains. Our findings represent important experimental information regarding pharmacological manipulation of BBB disruption. The possibility of prolonging the transient opening of the BBB has major clinical implications.