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Title: Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

Abstract

Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251 (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects ofmore » cannabis may be mediated by nuclear receptors.« less

Authors:
 [1];  [2];  [2];  [2];  [2]
  1. School of Biomedical Sciences, E Floor, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom). E-mail: Saoirse.o'sullivan@nottingham.ac.uk
  2. School of Biomedical Sciences, E Floor, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom)
Publication Date:
OSTI Identifier:
20713453
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 337; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2005.09.121; PII: S0006-291X(05)02135-2; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AORTA; ENDOTHELIUM; GENES; GTP-ASES; IN VITRO; INCUBATION; LIGANDS; LUCIFERASE; NITRIC OXIDE; RATS; RECEPTORS; STIMULATION; SUPEROXIDE DISMUTASE; SYNTHESIS; TIME DEPENDENCE

Citation Formats

O'Sullivan, Saoirse E., Tarling, Elizabeth J., Bennett, Andrew J., Kendall, David A., and Randall, Michael D.. Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. United States: N. p., 2005. Web. doi:10.1016/j.bbrc.2005.09.121.
O'Sullivan, Saoirse E., Tarling, Elizabeth J., Bennett, Andrew J., Kendall, David A., & Randall, Michael D.. Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. United States. doi:10.1016/j.bbrc.2005.09.121.
O'Sullivan, Saoirse E., Tarling, Elizabeth J., Bennett, Andrew J., Kendall, David A., and Randall, Michael D.. Fri . "Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma". United States. doi:10.1016/j.bbrc.2005.09.121.
@article{osti_20713453,
title = {Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma},
author = {O'Sullivan, Saoirse E. and Tarling, Elizabeth J. and Bennett, Andrew J. and Kendall, David A. and Randall, Michael D.},
abstractNote = {Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251 (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.},
doi = {10.1016/j.bbrc.2005.09.121},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 337,
place = {United States},
year = {Fri Nov 25 00:00:00 EST 2005},
month = {Fri Nov 25 00:00:00 EST 2005}
}