Open AccessPharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach
Author(s) -
Walsh Sarah K.,
Hepburn Claire Y.,
Keown Oliver,
Åstrand Annika,
Lindblom Anna,
Ryberg Erik,
Hjorth Stephan,
Leslie Stephan J.,
Greasley Peter J.,
Wainwright Cherry L.
Publication year - 2015
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.143
Subject(s) - agonist , cannabinoid receptor , cannabinoid , pharmacology , antagonist , chemistry , receptor , in vivo , biology , biochemistry , microbiology and biotechnology
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 CB 1 and TRPV 1 receptors are implicated, G protein‐coupled receptor 55 ( GPR 55) 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 ( CB 1 agonist), O‐1602 ( GPR 55 agonist), AM 251 ( CB 1 antagonist), and cannabidiol ( CBD ; GPR 55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand‐induced GTP γ S binding in membrane preparations expressing rat and mouse CB 1 and GPR 55 receptors. Blood pressure responses to ACEA and O‐1602 were recorded in anesthetized and conscious mice (wild type, CB 1 −/− and GPR 55 −/− ) and rats in the absence and presence of AM 251 and CBD . ACEA demonstrated GTP γ S activation at both receptors, while O‐1602 only activated GPR 55. AM 251 exhibited antagonist activity at CB 1 and agonist activity at GPR 55, while CBD demonstrated selective antagonist activity at GPR 55. The depressor response to ACEA was blocked by AM 251 and attenuated by CBD , while O‐1602 did not induce a depressor response. AM 251 caused a depressor response that was absent in GPR 55 −/− mice but enhanced by CBD , while CBD caused a small vasodepressor response that persisted in GPR 55 −/− 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.