Cannabinoid CB1 receptors fail to cause relaxation, but couple via Gi/Go to the inhibition of adenylyl cyclase in carotid artery smooth muscle.
1. The aim of the current study was to characterize which cannabinoid receptors, if any, are present on rat carotid artery smooth muscle. Additionally, the effects of cannabinoids on carotid artery tone, on cyclic AMP accumulation and on forskolin-induced relaxation were examined in the same tissue. 2. Stimulation of carotid arteries with forskolin (10 microM) significantly increased cyclic AMP accumulation, an effect that was inhibited in a concentration-dependent manner by the cannabinoid receptor agonist, methanandamide. 3. Similar inhibition was seen with the CB1 agonist HU-210 but this inhibition was not mimicked by the CB2 agonist, WIN 55,2212-2. 4. The inhibitory effect of methanandamide on cyclic AMP accumulation was prevented by incubation of the arteries with pertussis toxin and was significantly 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 phenylephrine, but inhibited forskolin-induced relaxation of these arteries. This functional inhibition of relaxation by methanandamide was inhibited by CB1-selective (LY320135 and SR 141716A), but not a CB2-selective antagonist (SR 144528). 6. These data demonstrate the presence of functional G protein-linked cannabinoid receptors of the CB1 subtype in the rat carotid artery, but show that these receptors inhibit cyclic AMP accumulation rather than cause relaxation.
Holland
M
M
Department of Cell Physiology and Pharmacology, Maurice Shock Medical Sciences Building, University of Leicester, P.O. Box 138, Leicester, LE1 9HN.
John Challiss
R A
RA
Standen
N B
NB
Boyle
J P
JP
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D000067956:Adenylyl Cyclase Inhibitors; D001095:Arachidonic Acids; C469526:Cnr2 protein, rat; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C088155:methanandamide; D005576:Colforsin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins