Comparative pharmacology of endothelium-derived hyperpolarizing factor and anandamide in rat isolated mesentery.
We have recently proposed that anandamide, or a related cannabinoid, is the endothelium-derived hyperpolarizing factor (EDHF) and have now compared EDHF-mediated responses (induced by carbachol in the presence of both nitric oxide and prostanoid synthesis inhibitors) with those induced by anandamide in the rat isolated superior mesenteric arterial bed. Both EDHF-mediated and anandamide-induced relaxations were inhibited in the presence of high K+ (60 mM) and opposed by blockade of K+ channels with 10 mM tetraethylammonium. The cytochrome P450 inhibitors, and putative EDHF inhibitors, clotrimazole (10 microM) and proadifen (SKF 525A) (10 microM), opposed both anandamide-induced and EDHF-mediated relaxations and also relaxant responses to the K+ channel activator levcromakalim. Therefore, EDHF-mediated and anandamide-induced vasorelaxations show very similar pharmacological characteristics, with both responses being mediated via K+ channel activation. Further, the actions of EDHF and anandamide are both sensitive to proadifen and clotrimazole, EDHF antagonists which appear to act through K+ channel inhibition. Accordingly, these results support our proposal that an endocannabinoid is an EDHF.
Randall
M D
MD
Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre, UK. michael.randall@nottingham.ac.uk
McCulloch
A I
AI
Kendall
D A
DA
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001685:Biological Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000494:pharmacology*; D003022:Clotrimazole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D018721:Muscarinic Agonists / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011188:Potassium / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019789:Tetraethylammonium / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D001095:Arachidonic Acids; D001685:Biological Factors; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D019789:Tetraethylammonium; D011335:Proadifen; D003022:Clotrimazole; D011188:Potassium; C078814:anandamide; D019331:NG-Nitroarginine Methyl Ester