Received for publication September 21, 2005.
Revised December 6, 2005.
Accepted for publication December 9, 2005.

Further characterisation of the time-dependent vascular effects of ⁹-tetrahydrocannabinol (THC)

Abstract

We have previously shown that over time (2 h), the active ingredient of cannabis, ⁹-tetrahydrocannabinol (THC) produces peroxisome proliferator-activated receptor gamma (PPAR-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 THC (10 µM) 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 hydrogen peroxide (H₂O₂), and was reduced in the presence of the superoxide dismutase (SOD) inhibitor, DETCA, but was not PPAR-mediated. THC also inhibited calcium influx in a H₂O₂-dependent manner. In G0, but not the aorta, incubation with THC (10 µM, 2 h) significantly enhanced endothelium-dependent vasorelaxation. This was inhibited by a PPAR antagonist (GW9662), catalase and DETCA, but not by the NO synthase inhibitor L-NAME. 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 appears to involve inhibition of endothelium-derived hyperpolarising 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.

Key words: aorta, cannabinoid, delta-9tetrahydrocannabinol, mesenteric artery, vasoconstriction, vasorelaxation

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