Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach.
Date
2015-06Author
Walsh, Sarah K.
Hepburn, Claire Y.
Keown, Oliver
Astrand, Annika
Lindblom, Anna
Ryberg, Erik
Hjorth, Stephan
Leslie, Stephen J.
Greasley, Peter J.
Wainwright, Cherry L.
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WALSH, S. K., HEPBURN, C. Y., KEOWN, O., ASTRAND, A., LINDBLOM, A., RYBERG, E., HJORTH, S., LESLIE, S. J., GREASLEY, P. J. and WAINWRIGHT, C. L., 2015. Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach. Pharmacology Research & Perspectives, [online] 3 (3), article 143. Available from: http://onlinelibrary.wiley.com/doi/10.1111/prp2.2015.3.issue-3/issuetoc [Accessed 9 July 2015]
Abstract
The receptors mediating the hemodynamic responses to cannabinoids are not
clearly defined due to the multifarious pharmacology of many commonly used
cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G
protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic
effects of several atypical cannabinoid ligands. The present studies
attempted to unravel the pharmacology underlying the in vivo hemodynamic
responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1
antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist
profiles of each ligand were determined by ligand-induced GTPcS binding in
membrane preparations expressing rat and mouse CB1 and GPR55 receptors.
Blood pressure responses to ACEA and O-1602 were recorded in anesthetized
and conscious mice (wild type, CB1
/
and GPR55
/
) and rats in the absence
and presence of AM251 and CBD. ACEA demonstrated GTPcS activation at
both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist
activity at CB1 and agonist activity at GPR55, while CBD demonstrated
selective antagonist activity at GPR55. The depressor response to ACEA was
blocked by AM251 and attenuated by CBD, while O-1602 did not induce a
depressor response. AM251 caused a depressor response that was absent in
GPR55
/
mice but enhanced by CBD, while CBD caused a small vasodepressor
response that persisted in GPR55
/
mice. Our findings show that assessment
of the pharmacological profile of receptor activation by cannabinoid
ligands in in vitro studies alongside in vivo functional studies is essential to
understand the role of cannabinoids in hemodynamic control.