Further characterization of the time-dependent vascular effects of delta9-tetrahydrocannabinol.

We have previously shown that over time (2 h), the active ingredient of cannabis, Delta(9)-tetrahydrocannabinol (THC), produces peroxisome proliferator-activated receptor (PPAR) gamma-mediated vasorelaxation of conduit arteries. We have now investigated whether incubation with THC affects agonist-stimulated contractile (methoxamine) and endothelium-dependent vasorelaxant (acetylcholine) responses in the rat superior mesenteric artery (G0) and aorta by myography. We have also investigated whether similar responses are observed in isolated resistance (G3) vessels of the mesenteric bed. In both the aorta and G0, incubation with 10 microM THC for 2 h, but not 10 min, significantly attenuated the contractile responses to methoxamine. This effect of THC was abolished in the presence of the enzyme catalase, which breaks down H(2)O(2), and was reduced in the presence of the superoxide dismutase inhibitor diethyldithiocarbamate (DETCA), but it was not PPARgamma-mediated. THC also inhibited calcium influx in a H(2)O(2)-dependent manner. In G0, but not the aorta, incubation with 10 muM THC for 2 h significantly enhanced endothelium-dependent vasorelaxation. This was inhibited by a PPARgamma antagonist, 2-chloro-5-nitro-N-phenylbenzamide (GW9662), catalase, and DETCA, but not by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. By contrast, in G3, no time-dependent vasorelaxation of precontracted arteries to THC was observed, and incubation with THC led to potentiation of contractile responses and blunting of vasorelaxation to acetylcholine, which seems to involve inhibition of endothelium-derived hyperpolarizing factor (EDHF) production, and agonist-stimulated production of EDHF. These data demonstrate further the time-dependent vascular actions of THC and also highlight the heterogenous effects of THC in different arterial types.