I. Van Den Bossche et B. Vanheel, Influence of cannabinoids on the delayed rectifier in freshly dissociated smooth muscle cells of the rat aorta, BR J PHARM, 131(1), 2000, pp. 85-93
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.