¹King's College London, Cardiovascular Division, New Hunt's House, Guy's Campus, London SE1 1UL

Correspondence: Paul A. Fraser, E-mail: paul.fraser@kcl.ac.uk

²Current address: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, U.K. E-mail: deh11@cam.ac.uk

³Current address: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2. E-mail: Alexander.Easton@Dal.Ca

Received 31 March 2005; Revised 13 June 2005; Accepted 23 June 2005; Published online 1 August 2005.

Abstract

1. We have examined the role of TRPV1 activation in disrupting the blood–brain barrier by measuring the permeability of single pial venular capillaries in anaesthetized rats.
2. Capsaicin application to the brain surface resulted in increased permeability, maximal 2.10.12 10^-6 cm s^-1 (means.e.m.) with log EC₅₀ -4.50.10. Substance P methyl ester gave a similar response (maximal 2.00.07, n=6, log EC₅₀ -4.80.07), but the selective NK₂ agonist, -Ala₈-NKA_4–10 peptide, had no effect. Although CGRP decreased the permeability of venules (log EC₅₀ 10.30.11), its receptor antagonist CGRP_8–37 had no effect on the response to capsaicin.
3. The TRPV1 antagonist capsazepine (1 mM) reduced the response to capsaicin (100 M), from 1.780.15 to 0.630.10 (n=4). The NK₁ receptor antagonists GR205171 (100 M) and SDZ NKT 376 (1 mM) also reduced the response to capsaicin (from 1.750.14 to 0.460.08; n=6, and from 1.850.13 to 0.480.05; n=5, respectively), indicating that capsaicin acts via TRPV1 in series with NK₁.
4. Starch microspheres were used to produce transient focal ischaemia. Permeability was increased on reperfusion to a greater extent and more rapidly in vessels with diameter greater than 40 m than those less than 15 m. Capsazepine given intraperitoneally during ischaemia reduced the permeability increase in small venules from 5.90.3 to 2.40.1, and from 11.40.8 to 5.10.9 in large venules.
5. In conclusion, the TRPV1 receptor is active in the brain microvasculature and has its permeability-increasing effect via substance P. It also plays a role in the immediate blood–brain barrier disruption following ischaemia–reperfusion.