Cannabinoid CB1 receptors fail to cause relaxation, but couple via G(i)/G(o) to the inhibition of adenylyl cyclase in carotid artery smooth muscle

1 The aim of the current study was to characterize which cannabinoid recept ors, if any, are present on rat carotid artery smooth muscle. Additionally, the effects of cannabinoids on carotid artery tone, on cyclic AMP accumula tion and on forskolin-induced relaxation were examined in the same tissue. 2 Stimulation of carotid arteries with forskolin (10 mu M) significantly in creased cyclic AMP accumulation, an effect that was inhibited in a concentr ation-dependent manner by the cannabinoid receptor agonist, methanandamide. 3 Similar inhibition was seen with the CB1 agonist HU-210 but this inhibiti on was not mimicked by the CB2 agonist, WIN 55,2212-2. 4 The inhibitory effect of methanandamide on cyclic AMP accumulation was pr evented by incubation of the arteries with pertussis toxin and was signific antly reduced by LY320135, a selective CB1 antagonist, but not by SR 144528 , a CB2-selective antagonist. 5 Methanandamide failed to relax carotid arteries pre-contracted with pheny lephrine, but inhibited forskolin-induced relaxation of these arteries. Thi s functional inhibition of relaxation by methanandamide was inhibited by CB 1-selective (LY320135 and SR 141716A), but not a CB2-selective antagonist ( SR 144528). 6 These data demonstrate the presence of functional G protein-linked cannab inoid receptors of the CB1 subtype in the rat carotid artery, but show that these receptors inhibit cyclic AMP accumulation rather than cause relaxati on.