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(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 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 CBI 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. (c) 2005 Elsevier Inc. All rights reserved.