Life Sciences, Vol. 53, pp. PL 417-420 Pergamon Press Printed in the USA PHARMACOLOGY LETTERS Accelerated Communication INCREASED BLOOD-BRAIN BARRIER PERMEABILITY OF AMINO ACIDS IN CHRONIC HYPERTENSION Jian-ping Tang l, Zhi-Qun Xu t, Frank L. Douglas 2,3, Ashok Rakhit 2,4 and Srikumaran Melethil t ! Schools of Pharmacy and Medicine, University of Missouri-Kansas City, Kansas City, MO 64108 2 Research Department, CIBA-GEIGY Corp., Summit, NJ 07901 (Submitted August 27, 1993; accepted September 8, 1993; received in final form October 11, 1993) Abstract A previous communication from this laboratory reported that brain uptake of libenzapril, a small polar molecule, was enhanced in chronic hypertension (1). The objective of this investigation was to determine if this was a more generalized phenomenon. Therefore, experiments were undertaken to examine the effect of chronic hypertension on the brain uptake of tryptophan (an amino acid with high brain permeability) and glutamic acid (one with low permeability). Brain concentrations of these two amino acids were 5- to 12-fold greater in chronic hypertensive rats, as compared to normotensive rats; the corresponding brain uptake index (BUI) values were 2- to 5-fold higher in the former group. Since blood-brain barrier transport of amino acids involve both saturable (carrier) and non-saturable (most likely, diffusion via pores) mechanisms, data from this study show that hypertension can enhance BBB transport of amino acids by affecting one or both of these pathways. Introduction Very little is known about the effect of chronic hypertension on the blood-brain barrier (BBB) permeability of small (M.W. < 500) polar molecules. Previous studies from our laboratory (1) showed that chronic hypertension increased brain uptake of libenzapril (LZP), a small polar molecule with a lysine side-chain. It has also been reported that BUI of tyrosine increased in chronic hypertension (2). Therefore, the objective of this study was to determine if this was a more generalized phenomenon and applied to other small molecules. As a first step in this direction, the study was extended to include two other amino acids, namely tryptophan and glutamic acid, which represent high and low permeable compound, respectively. Materials and Methods Radioactivity Materials: 3H20 (1 mCi/gm), ~4C-tryptophan (54.8 mCi/mmol) and 14C-glutamic acid (293.3 mCi/mmol) were purchased from New England Nuclear Corp., Boston, MA. Corresponding Author: S. Melethil, Ph.D., M3-209, 2411 Holmes Street, Schools of Pharmacy and Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108 3 Present address: Marion Merrell Dow Inc., Kansas City, MO 64114 4 Present address: Hoffmann-La Roche Inc., Nutley, NJ 07110 0024-3205/93 $6.00 + .00 Copyright © 1993 Pergamon Press Ltd All rights reserved.