Cannabinoid activation of recombinant and endogenous vanilloid receptors.
The effects of three structurally related cannabinoids on human and rat recombinant vanilloid VR1 receptors expressed in human embryonic kidney (HEK293) cells and at endogenous vanilloid receptors in the rat isolated mesenteric arterial bed were studied. In the recombinant cells, all three were full agonists, causing concentration-dependent increases in [Ca(2+)](i) (FLIPR), with a rank order of potency relative to the vanilloids capsaicin and olvanil, of olvanil> or =capsaicin>AM404 ((allZ)-N-(4-hydroxyphenyl)-5,8,11,14-eicosatetraenamide)>anandamide>methanandamide. These responses were inhibited by the vanilloid VR1 receptor antagonist, capsazepine. In the mesenteric arterial bed, vasorelaxation was evoked by these ligands with a similar order of potency. The AM404-induced vasorelaxation was virtually abolished by capsaicin pretreatment. AM404 inhibition of capsaicin-sensitive sensory neurotransmission was blocked by ruthenium red, but not by cannabinoid CB(1) and CB(2) receptor antagonists. AM404 had no effect on relaxations to calcitonin gene-related peptide. These data demonstrate that the vasorelaxant and sensory neuromodulator properties of AM404 in the rat isolated mesenteric arterial bed are mediated by vanilloid VR1 receptors.
Ralevic
V
V
School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. vera.ralevic@nottingham.ac.uk
Kendall
D A
DA
Jerman
J C
JC
Middlemiss
D N
DN
Smart
D
D
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D006801:Humans; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012428:Ruthenium / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D001095:Arachidonic Acids; D001572:Benzofurans; D002121:Calcium Channel Blockers; D001892:Camphanes; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C110630:SR 144528; D014665:Vasodilator Agents; C088155:methanandamide; C054256:olvanil; D012428:Ruthenium; C110158:LY 320135; D015740:Calcitonin Gene-Related Peptide; D000109:Acetylcholine; D002211:Capsaicin; D002118:Calcium; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide