A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea-pig bronchus.
1. In the absence of indomethacin, anandamide did not contract the guinea-pig bronchus at concentrations up to 100 microM. In the presence of indomethacin (10 microM), anandamide induced concentration-related contractions with a pEC(50) value of 5.18+/-0.11. It was significantly less potent than capsaicin (pEC(50) 7.01+/-0.1). The anandamide uptake inhibitor AM404, produced only a 14.1+/-3.22% contraction at 100 microM. All experiments were conducted in the presence of PMSF (20 microM). 2. The vanilloid receptor antagonist, capsazepine (10 microM), significantly attenuated the contractile effect of anandamide, the response to 100 microM anandamide being 40.53+/-7.04% in the presence of vehicle and 1.57+/-8.93% in the presence of 10 microM capsazepine. The contractile actions of anandamide and AM404 were markedly enhanced by the peptidase inhibitor thiorphan. 3. The log concentration-response curve of anandamide was unaltered by the CB1 receptor antagonist, SR141716A. The pEC(50) values for anandamide were 4.88+/-0.08 and 5.17+/-0.19 in the presence of vehicle and SR141716A (1 microM) respectively. 4. The lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid (ETYA) and 5,8,11 eicosatriynoic acid (ETI) reduced the effect of 100 microM anandamide from 34.7+/-1.9% (vehicle) to 7.7+/-5% (ETYA, 10 microM) and from 41.85+/-4.25% (n=6) (vehicle) to 10.31+/-3.54 (n=6) (ETI, 20 microM). Neither inhibitor significantly affected contraction of the tissue by substance P. 5. This study provides evidence that anandamide acts on vanilloid receptors in the guinea-pig isolated bronchus. These data raise the possibility that the contractile action of anandamide may be due, at least in part, to lipoxygenase metabolites of this fatty acid amide that are vanilloid receptor agonists.
Craib
S J
SJ
Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
Ellington
H C
HC
Pertwee
R G
RG
Ross
R A
RA
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006168:Guinea Pigs; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008084:Lipoxygenase / Q000187:drug effects / Q000502:physiology*; D009119:Muscle Contraction / Q000187:drug effects; D010077:Oxazepines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism; D000077285:Rimonabant; D015244:Thiorphan / Q000494:pharmacology
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D003511:Cyclohexanols; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010077:Oxazepines; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D011955:Receptors, Drug; D015117:5,8,11,14-Eicosatetraynoic Acid; C026603:5,8,11-eicosatriynoic acid; C086836:SC 51089; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D015244:Thiorphan; D008084:Lipoxygenase; C071423:capsazepine; D000077285:Rimonabant; D002211:Capsaicin; C078814:anandamide; D007213:Indomethacin