Influence of cannabinoids on the delayed rectifier in freshly dissociated smooth muscle cells of the rat aorta

1 The influence of the cannabinoids anandamide, methanandamide and WIN 5521 2-2 on the delayed rectifier K+ current (I-K(V)) in rat arterial myocytes w as investigated. 2 Anandamide caused a concentration-dependent reduction of total peak and l ate K+ current (IK) The maximal effect (about 50% inhibition of I-K) was re ached with 3 mu M, and half-maximal current block was observed at 0.6 mu M. Blockade was voltage-independent. Inhibition of I-K by the cannabinoid was associated with a characteristic increase in the rate of current relaxatio n. 3 Methanandamide (10 mu M), a metabolically more stable analogue of anandam ide, decreased I-K with a similar time course. Current traces in the presen ce of the drug also showed an acceleration of inactivation. 4 The presence of TEA did not impair the inhibition by anandamide or methan andamide, but inhibition was prevented by pre-exposure to 4-AP, showing tha t both cannabinoids inhibited I-K(V) while having no influence on Ca2+-depe ndent K+ current (TK(Ca)) 5 The CB1 receptor antagonist SR141716A (10 mu M) did not influence the act ion of anandamide or methanandamide. 6 Arachidonic acid (1 mu M) increased I-K considerably. However, in the pre sence of TEA it caused a decrease of I-K(V), with a characteristic increase in the rate of current relaxation. 7 WIN 55212-2 (20 mu M) caused similar inhibition of I-K 8 Internally applied anandamide (10 mu M) or methanandamide (10 mu M) was i neffective at influencing I-K In the dialyzed cells, the additional externa l application of a cannabinoid promptly initiated inhibition. 9 The results show that anandamide, methanandamide and WIN 55212-2 affect I -K(V), in a cannabinoid receptor-independent way similar to that of arachid onic acid, which, unlike the cannabinoids, additionally increases a Ca2+-ac tivated K+ current. It is suggested that cannabinoids might bind to an exte rnal site on or near the K-v channel of the vascular smooth muscle cells.