Abstract
We have previously shown that over time (2 h), the active ingredient of cannabis, Δ9-tetrahydrocannabinol (THC), produces peroxisome proliferator-activated receptor (PPAR) γ-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 μM 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 H2O2, and was reduced in the presence of the superoxide dismutase inhibitor diethyldithiocarbamate (DETCA), but it was not PPARγ-mediated. THC also inhibited calcium influx in a H2O2-dependent manner. In G0, but not the aorta, incubation with 10 μM THC for 2 h significantly enhanced endothelium-dependent vasorelaxation. This was inhibited by a PPARγ antagonist, 2-chloro-5-nitro-N-phenylbenzamide (GW9662), catalase, and DETCA, but not by the NO synthase inhibitor NG-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.
Footnotes
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This study was funded by the British Heart Foundation Grant PG2001/150.
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doi:10.1124/jpet.105.095828.
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ABBREVIATIONS: THC, Δ9-tetrahydrocannabinol; PPAR, peroxisome proliferator-activated receptor; GW9662, 2-chloro-5-nitro-N-phenylbenzamide; l-NAME, NG-nitro-l-arginine methyl ester; SOD, superoxide dismutase; DETCA, diethyldithiocarbamate; EDHF, endothelium-derived hyperpolarizing factor; ChTX, charybdotoxin; Veh, vehicle.
- Received September 19, 2005.
- Accepted December 9, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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