The effects of cannabidiol and the CB1 antagonist AM251 on the depressor responses to ACEA in vivo and on platelet aggregation ex vivo

Prof. Wainwright, Cherry1, Hepburn, Claire1, Keown, Oliver2, Watt, Suzanne1, Prof. Megson, Ian2, Dr. Leslie, Stephen3, Prof. Kane, Kathleen4. 1The Robert Gordon University School of Pharmacy & Life Sciences, Schoolhill, Aberdeen, AB10 1FR, Great Britain; 2UHI MIllenium Institute Department of Diabetes and Cardiovascular Science, Old Perth Road, Inverness, IV2 3JH, Great Britain; 3Raigmore Hospital Highland Heartbeat Centre, Old Perth Road, Inverness, IV2 3UJ, Great Britain; 4University of Strathclyde Strathclyde Institute of Pharmacy & Biomedical Sciences, 27 Taylor Street, Glasgow, G4 0NR, Great Britain.

Cannabidiol (CBD) is a phytocannabinoid with a complex pharmacology1. At low concentrations CBD is an inverse agonist at CB1, CB2 and non CB1/CB2 receptors, while at μM concentrations it acts as a CB1 and CB2 agonist, an antagonist at the orphan “cannabinoid” receptor GPR55 and inhibits COX and FAAH. We have previously found CBD to modestly reduce platelet aggregation in vitro in response to a range of cannabinoid and non-cannabinoid agonists, but to completely abolish aggregation in the presence of a CB1 antagonist (AM251)2. Since CB1 receptors also mediate vascular relaxation, this study explored the effects of CBD, with and without AM251, on the depressor response to the CB1 agonist ACEA, and on ex vivo platelet aggregation. Male SD rats were anaesthetised with sodium pentobarbitone and cannulated for mean arterial blood pressure (MABP) measurement and i.v. drug administration. Rats were pre-treated with CBD (50μgkg-1i.v.) or saline. Blood pressure responses to ACEA (3mgkg-1) were then recorded before and after increasing doses of AM251 (1 & 3mgkg-1) or 1% EtOH vehicle (n=5). Blood samples taken at the beginning and end of the experimental protocol were subjected to whole blood aggregometry to collagen and ADP. CBD alone caused a small (15-20%) transient reduction in arterial blood pressure. In rats treated with saline, ACEA produced a marked hypotension (-32.3±2.1%) which was completely abolished by both doses of AM251. CBD slightly enhanced the responses to ACEA, while combined treatment with CBD and AM251 resulted in an exacerbation of the depressor response to ACEA (-64.5±6.8%; P<0.05). CBD also unmasked a depressor response to AM251 that was not evident when AM251 was given alone. CBD alone reduced the extent of both collagen and ADP-induced aggregation, while blood from rats given both CBD and AM251 failed to aggregate . These findings further suggest that CBD exerts multiple and opposing actions on both platelets and the vasculature.

Pertwee RG (2005). Pharmacological actions of cannabinoids.Handb Exp Pharmacol 168, 1-51.
Hepburn C, Ariyuku C-L, Bastow T, Wainwright CL (2009). Studies on the Mechanism of Action of the Anti-Platelet Effects of the Phytocannabinoid, Cannabidiol. Arter Thromb Vasc Biol Proceedings Supplement, In Press.