Graded reversible opening of the rat blood-brain barrier by intracarotid infusion of sodium caprate

The fatty acid salt, sodium caprate (C10) is a well recognized drug absorption enhancer in intestine because of its ability to widen tight junctions in the epithelial cell lining. Caprate's potential usefulness to similarly alter the blood-brain barrier (BBB) tight junctions of brain vasculature and enhance CNS drug delivery has undergone little investigation. Adult SD rats were anesthetized and C10 was infused into the left internal carotid artery (dosing parameters: 10-30 mM, 1 or 2 ml min(-1), for 0.5-1.5 min). Beginning 5 or 60 min after infusion an i.v. bolus of [H-3]mannitol was allowed to circulate for 30 min and degree of BBB leakiness measured as magnitude of the transfer constant (Ki, nl g(-1) s(-1)) for blood to brain mannitol permeation determined front brain and plasma samples. In initial experiments identical C10 infusions caused dramatic BBB opening in some rats, e.g., 10-fold increase in Ki, but not in others. Higher dosing produced consistent opening measured 5-35 or 60-90 min post-infusion but was also toxic as shown by severe brain edema and cardio-respiratory failure. The variable effect of moderate doses was attributed to the fact that arterial blood pressure markedly increased during C10 infusion and may have altered the flow dynamics of cerebrovascular caprate distribution from rat to rat. We modified the procedure by temporarily withdrawing blood to produce hypovolemia and systemic arterial hypotension during C10 infusion. Caprate infusions of 15-25 mM, 2 ml min(-1) for 1 min, produced reliable dose-related openings that lasted as much as an hour, were reversible, and accompanied by little or moderate edema, depending on dose. These findings confirm ail earlier report showing that intracarotid caprate infusion opens the BBB but also show that control of the temporary hypertensive response produced by intracarotid caprate infusion is key to tailoring the dosage to consistently achieve graded, reversible BBB opening, Crown Copyright (c) 2007 Published by Elsevier B.V. All rights reserved.