Anandamide-induced relaxation of sheep coronary arteries: the role of the vascular endothelium, arachidonic acid metabolites and potassium channels.
1. The effects of the endocannabinoid, anandamide, and its metabolically stable analogue, methanandamide, on induced tone were examined in sheep coronary artery rings in vitro. 2. In endothelium-intact rings precontracted to the thromboxane A(2) mimetic, U46619, anandamide (0.01 - 30 microM) induced slowly developing concentration-dependent relaxations (pEC(50) [negative log of EC(50)]=6.1+/-0.1; R(max) [maximum response]=81+/-4%). Endothelium denudation caused a 10 fold rightward shift of the anandamide concentration-relaxation curve without modifying R(max). Methanandamide was without effect on U46619-induced tone. 3. The anandamide-induced relaxation was unaffected by the cannabinoid receptor antagonist, SR 141716A (3 microM), the vanilloid receptor antagonist, capsazepine (3 and 10 microM) or the nitric oxide synthase inhibitor, L-NAME (100 microM). 4. The cyclo-oxygenase inhibitor, indomethacin (3 and 10 microM) and the anandamide amidohydrolase inhibitor, PMSF (70 and 200 microM), markedly attenuated the anandamide response. The anandamide transport inhibitor, AM 404 (10 and 30 microM), shifted the anandamide concentration-response curve to the right. 5. Precontraction of endothelium-intact rings with 25 mM KCl attenuated the anandamide-induced relaxations (R(max)=7+/-7%), as did K(+) channel blockade with tetraethylammonium (TEA; 3 microM) or iberiotoxin (100 nM). Blockade of small conductance, Ca(2+)-activated K(+) channels, delayed rectifier K(+) channels, K(ATP) channels or inward rectifier K(+) channels was without effect. 6. These data suggest that the relaxant effects of anandamide in sheep coronary arteries are mediated in part via the endothelium and result from the cellular uptake and conversion of anandamide to a vasodilatory prostanoid. This, in turn, causes vasorelaxation, in part, by opening potassium channels.
Grainger
J
J
Institute of Pharmacy and Chemistry, University of Sunderland, Dale Building, Sunderland SR1 3SD.
Boachie-Ansah
G
G
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology*; D001464:Barium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008825:Miconazole / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010455:Peptides / Q000494:pharmacology; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011188:Potassium / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D011955:Receptors, Drug / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D012756:Sheep; D019789:Tetraethylammonium / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D065607:Cytochrome P-450 Enzyme Inhibitors; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D010455:Peptides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011720:Pyrazoles; D011955:Receptors, Drug; D014662:Vasoconstrictor Agents; C088155:methanandamide; D001030:Apamin; D001464:Barium; D016718:Arachidonic Acid; C047008:17-octadecynoic acid; D010664:Phenylmethylsulfonyl Fluoride; D019789:Tetraethylammonium; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C064719:iberiotoxin; D008825:Miconazole; D015761:4-Aminopyridine; D019001:Nitric Oxide Synthase; C071423:capsazepine; D000077285:Rimonabant; D011188:Potassium; D002211:Capsaicin; D005905:Glyburide; C078814:anandamide; D019331:NG-Nitroarginine Methyl Ester; C107594:N-(4-hydroxyphenyl)arachidonylamide; D007213:Indomethacin