Mechanisms of anandamide‐induced vasorelaxation in rat isolated coronary arteries

• Published in: British journal of pharmacology 2001-10, Vol.134 (4), p.921-929
• Main Authors: White, Richard, Vanessa Ho, W ‐S, Bottrill, Fiona E, Ford, William R, Hiley, C Robin
• Format: Article
• Language: English
• Subjects: anandamide; Animals; Arachidonic Acids - metabolism; Arachidonic Acids - pharmacology; Biological and medical sciences; Blood vessels and receptors; cannabinoid receptors; cannabinoids; capsaicin; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Coronary artery (rat); Coronary Vessels - drug effects; Coronary Vessels - physiology; Dose-Response Relationship, Drug; Endocannabinoids; Endothelium, Vascular - physiology; Ethanolamines; Fundamental and applied biological sciences. Psychology; Gap Junctions - drug effects; Glycyrrhetinic Acid - pharmacology; In Vitro Techniques; Indoles - pharmacology; Indomethacin - pharmacology; Male; Palmitic Acids - pharmacology; Peptides - pharmacology; Piperidines - pharmacology; Polyunsaturated Alkamides; Potassium Channel Blockers; Pyrazoles - pharmacology; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug - antagonists & inhibitors; sensory nerves; Serotonin - pharmacology; Tetraethylammonium - pharmacology; vanilloid receptors; Vasodilation - drug effects; Vertebrates: cardiovascular system
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704333

The cannabinoid arachidonyl ethanolamide (anandamide) caused concentration‐dependent relaxation of 5‐HT‐precontracted, myograph‐mounted, segments of rat left anterior descending coronary artery. This relaxation was endothelium‐independent, unaffected by the fatty acid amide hydrolase inhibitor, arachidonyl trifluoromethyl ketone (10 μM), and mimicked by the non‐hydrolysable anandamide derivative, methanandamide. Relaxations to anandamide were attenuated by the cannabinoid receptor antagonist, SR 141716A (3 μM), but unaffected by AM 251 (1 μM) and AM 630 (1 μM), more selective antagonists of cannabinoid CB1 and CB2 receptors respectively. Palmitoylethanolamide, a selective CB2 receptor agonist, did not relax precontracted coronary arteries. Anandamide relaxations were not affected by inhibition of sensory nerve transmission with capsaicin (10 μM) or blockade of vanilloid VR1 receptors with capsazepine (5 μM). Nevertheless capsaicin relaxed coronary arteries in a concentration‐dependent and capsazepine‐sensitive manner, confirming functional sensory nerves were present. In contrast, capsazepine and capsaicin did inhibit anandamide relaxations in methoxamine‐precontracted rat small mesenteric arteries. Relaxations to anandamide were inhibited by TEA (1 mM) or iberiotoxin (50 nM), blockers of large conductance, Ca2+‐activated K+ channels (BKCa). Gap junction inhibition with 18α‐glycyrrhetinic acid (100 μM) did not affect anandamide relaxations. This study shows anandamide relaxes the rat coronary artery by a novel mechanism. Anandamide‐induced relaxations do not involve the endothelium, degradation into active metabolites, or activation of cannabinoid CB1 or CB2 receptors, but may involve activation of BKCa. Vanilloid receptor activation also has no role in the effects of anandamide in coronary arteries, even though functional sensory nerves are present. British Journal of Pharmacology (2001) 134, 921–929; doi:10.1038/sj.bjp.0704333