Recent studies suggest that the AMP-activated protein kinase (AMPK) inhibits BK_Ca channels in type I cells of rat carotid bodies (1). It has also been shown recently that AMPK could phosphorylate myosin light chain kinase in macrovascular smooth muscle (2), a mechanism resulting in decreased calcium sensitivity. While the earlier mechanism, when expressed in smooth muscle, would lead to vasoconstriction and inhibition of EDHF mediated dilation, the latter would lead to a vasodilation. We investigated whether a novel activator of the AMPK (3) A769662 (A76), affects microvascular tone and EDHF-dependent dilator pathways in hamster resistance arteries in which we have characterised EDHF mediated dilations on the molecular level (4). Small resistance arteries (about 250 mm in diameter, n= 17 in total) were isolated from hamster gracilis muscle, cannulated and the smooth muscle layer loaded with the calcium indicator Fura2-AM as described previously (5). Vascular diameters were anlysed by videomicroscopy. All microvessels were pre-treated with the COX inhibitor indomethacin (30μM) and the NOS inhibitor L-NAME (30μM). When exposed to A76 (10^-6 to 10^-4 M), resistance arteries (pre-constricted with 0.3 μM norepinephrine) showed a dose dependent vasodilatation (94.5 ± 4.0 % at 10-4M, mean ±SEM) associated with a decrease of [Ca⁺⁺]_i (94.5 ± 10.9% at 10^-4M) This vasodilation was not endothelium dependent. In arteries pre-constricted with 100mM potassium, A76 (10^-4 M), induced neither relaxation nor decreased smooth muscle calcium. There was also no calcium independent dilation during an observation period of 15 min. Neither inhibition of IK_Ca / BK_Ca potassium channels with CTX (1μM) – which has been shown to inhibit EDHF mediated dilations previously – nor IBTX(10^-7 M), a specific inhibitor of IK_Ca did alter maximal effects of A76 significantly whereas the K_ATP inhibitor glibenclamide (0,1mM) reduced dilation to 10.6 ±5.0 % as well as the decrease of [Ca⁺⁺]_i to 35.1 ± 0.5 %. These results suggest that AMPK is a potent dilator of small resistance arteries in the hamster. The results obtained with glibenclamide suggest that K_ATP channels may be a target of AMPK in microvascular smooth muscle. In potassium depolarized vessels, no functional evidence has been found so far for a role of the AMPK in reducing calcium sensitivity as recently described in macrovessels.