Anandamide has been widely shown to cause vasorelaxation through numerous pathways (see Randall et al., 2002). By contrast, the vascular effects of ⁹-tetrahydrocannabinol (THC) have remained largely neglected. Early research showed that THC produced vasorelaxation of cerebral vessels (Ellis et al., 1995), but also vasoconstriction in the perfused mesenteric bed (Wagner et al., 1999). This study aimed to investigate further the effects of THC in rat mesenteric arteries.

Male Wistar rats (200-300 g) were killed by cervical dislocation. Small mesenteric resistance arteries (G3) or the superior mesenteric artery (G0) were isolated, cut into 2 mm lengths and mounted on a Mulvany-Halpern myograph. Vessels were bathed in oxygenated Krebs’ solution at 37^OC. Vessels were set to a baseline tone of 5 mN, and U46619 was added to increase tension by at least 5 mN.

THC caused concentration-dependent vasorelaxation of precontracted G3 vessels which was less potent than that of anandamide (anandamide R_max 95.0 ± 10.8 % relaxation, pEC₅₀ 6.43 ± 0.22 mean ± SEM; THC R max 66.8 ± 7.6 % relaxation, pEC₅₀ 5.31 ± 0.20, P<0.05, Student’s t-test). Anandamide also relaxed the superior mesenteric artery (R_max 31.4 ± 5.2 % relaxation, pEC₅₀ 5.39 ± 0.29), but THC had no effect up to 10 µM, and at 100 µM, produced an additional 14.3 ± 6.4 % contraction. Vasorelaxation to THC in G3 vessels was not inhibited by the CB₁ receptor antagonist AM251 (100 nM), pre-treatment with the vanilloid receptor agonist capsaicin (10 µM), the vanilloid receptor antagonist capsazepine (10 µM), or removal of the endothelium. Vasorelaxation to THC was inhibited by pertussis toxin (400 ng/ml, 2 hours, R_max 38.1 ± 4.3 % relaxation, n=7, P<0.01). The contractile response to the re-introduction of Ca²⁺ in Ca²⁺ free, high K⁺ Kreb’s was inhibited by 10 µM THC (control pEC₅₀ 3.22 ± 0.05, n=8; THC pEC₅₀ 2.75 ± 0.06, n=7, P<0.01). Vasorelaxation to THC was inhibited by 100 nM ChTX (pEC₅₀ 4.85 ± 0.09, n=6, P<0.01), by 500 nM apamin (R_max 48.2 ± 3.5 % relaxation, P<0.05, pEC 50 5.05 ± 0.14, n=6, P<0.01) and by 30 µM barium chloride (pEC 50 4.85 ± 0.15, n=6, P<0.01). Vasorelaxation to THC was not inhibited by glibenclamide (10 µM) or 4-aminopyridine (1 mM). Vasoconstriction to 100 µM THC in G0 vessels was reversed by de-endothelialisation (11.5 ± 2.2 % relaxation, P<0.05), and was opposed by the CB₁ receptor antagonist SR141716A (100 nM, 1.3 ± 5.3 % relaxation).

In summary, THC does not cause vasorelaxation through the same receptors identified for anandamide, but acts via an as yet unidentified site(s) of action. The mechanisms by which THC causes vasorelaxation include inhibition of calcium channels and activation of calcium-activated K⁺ channels and voltage-dependent inward rectifier K⁺ channels. The heterogeneous vascular effects between arterial vessel types may help reconcile previous conflicting findings of both constrictor and relaxant effects of THC.

Randall et al. (2002). Pharm. Ther. 95, 191-202
Ellis et al. (1995) Am. J. Physiol.269, H1859-64
Wagner et al. (1999) Hypertension.33, 429-34

This study was funded by the British Heart Foundation (PG2001/150)