Involvement of a cannabinoid in endothelium-derived hyperpolarizing factor-mediated coronary vasorelaxation.
We have recently proposed that an endocannabinoid is the endothelium-derived hyperpolarizing factor (EDHF) and have now tested this hypothesis in the rat isolated perfused heart. In this preparation bradykinin gave rise to nitric oxide- and prostanoid-independent relaxations, assessed as reductions in coronary perfusion pressure (ED50 = 14.9 +/- 5.9 pmol; Rmax = 25.2 +/- 2.2%), which are thought to be mediated by EDHF. These relaxations were antagonised by both the highly selective cannabinoid antagonist, SR141716A (1 microM) (Rmax = 8.3 +/- 1.2%, P < 0.001) and by the calcium-dependent potassium channel blocker tetrabutylammonium (300 microM) (Rmax = 6.7 +/- 3.4%, P < 0.01) and were abolished by the EDHF inhibitor clotrimazole (3 microM). The endogenous cannabinoid, anandamide, similarly caused coronary vasorelaxation (Rmax = 32.3 +/- 2.3%), which was abolished by clotrimazole (3 microM) and antagonised by both 300 microM tetrabutylammonium (Rmax = 18.2 +/- 2.8%, P < 0.01) and 1 microM SR141716A (Rmax = 16.4 +/- 3.3%, P < 0.01). Accordingly, these results suggest that EDHF-mediated responses in the rat coronary vasculature are due to an endogenous cannabinoid and that anandamide causes vasorelaxation through potassium channel activation. These findings are, therefore, consistent with our recent proposal that EDHF is an endogenous cannabinoid.
Randall
M D
MD
Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre, UK. michael.randall@nottingham.ac.uk
Kendall
D A
DA
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001685:Biological Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D001920:Bradykinin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000037:antagonists & inhibitors*; D003022:Clotrimazole / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D063388:Endocannabinoids; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D011720:Pyrazoles / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D001095:Arachidonic Acids; D001685:Biological Factors; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D000644:Quaternary Ammonium Compounds; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C067410:endothelium-dependent hyperpolarization factor; C009405:tetrabutylammonium; D003022:Clotrimazole; D000077285:Rimonabant; D001920:Bradykinin; C078814:anandamide