Influence of cannabinoids on the delayed rectifier in freshly dissociated smooth muscle cells of the rat aorta.
The influence of the cannabinoids anandamide, methanandamide and WIN 55212-2 on the delayed rectifier K(+) current (I(K(V))) in rat arterial myocytes was investigated. Anandamide caused a concentration-dependent reduction of total peak and late K(+) current (I(K)). The maximal effect (about 50% inhibition of I(K)) was reached with 3 microM, and half-maximal current block was observed at 0.6 microM. Blockade was voltage-independent. Inhibition of I(K) by the cannabinoid was associated with a characteristic increase in the rate of current relaxation. Methanandamide (10 microM), a metabolically more stable analogue of anandamide, decreased I(K) with a similar time course. Current traces in the presence of the drug also showed an acceleration of inactivation. The presence of TEA did not impair the inhibition by anandamide or methanandamide, but inhibition was prevented by pre-exposure to 4-AP, showing that both cannabinoids inhibited I(K(V)) while having no influence on Ca(2+)-dependent K(+) current (I(K(Ca))). The CB(1) receptor antagonist SR141716A (10 microM) did not influence the action of anandamide or methanandamide. Arachidonic acid (1 microM) increased I(K) considerably. However, in the presence of TEA it caused a decrease of I(K(V)) with a characteristic increase in the rate of current relaxation. WIN 55212-2 (20 microM) caused similar inhibition of I(K). Internally applied anandamide (10 microM) or methanandamide (10 microM) was ineffective at influencing I(K). In the dialyzed cells, the additional external application of a cannabinoid promptly initiated inhibition. The results show that anandamide, methanandamide and WIN 55212-2 affect I(K(V)) in a cannabinoid receptor-independent way similar to that of arachidonic acid, which, unlike the cannabinoids, additionally increases a Ca(2+)-activated K(+) current. It is suggested that cannabinoids might bind to an external site on or near the K(v) channel of the vascular smooth muscle cells.
Van den Bossche
I
I
Department of Physiology and Physiopathology, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium.
Vanheel
B
B
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D016718:Arachidonic Acid / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology*; D048588:Benzoxazines; D002186:Cannabinoids / Q000494:pharmacology*; D063388:Endocannabinoids; D005260:Female; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D015221:Potassium Channels / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077285:Rimonabant
D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D015221:Potassium Channels; D011720:Pyrazoles; C088155:methanandamide; D016718:Arachidonic Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant; C078814:anandamide