The protective effects of 5'-AMP-activated protein kinase (AMPK) on the 
metabolic syndrome may include direct effects on resistance artery vasomotor 
function. However, the precise actions of AMPK on microvessels and their 
potential interaction are largely unknown. Thus, we set to determine the effects 
of AMPK activation on vascular smooth muscle tone and the underlying mechanisms. 
Resistance arteries isolated from hamster and mouse exhibited a pronounced 
endothelium-independent dilation on direct pharmacological AMPK activation by 2 
structurally unrelated compounds (PT1 and A769662). The dilation was associated 
with a decrease of intracellular-free calcium [Ca(2+)]i in vascular smooth 
muscle cell. AMPK stimulation induced activation of BKCa channels as assessed by 
patch clamp studies in freshly isolated hamster vascular smooth muscle cell and 
confirmed by direct proof of membrane hyperpolarization in intact arteries. The 
BKCa channel blocker iberiotoxin abolished the hyperpolarization but only 
partially reduced the dilation and did not affect the decrease of [Ca(2+)]i. By 
contrast, the sarcoplasmic/endoplasmic Ca(2+)-ATPase (SERCA) inhibitor 
thapsigargin largely reduced these effects, whereas combined inhibition of SERCA 
and BKCa channels virtually abolished them. AMPK stimulation significantly 
increased the phosphorylation of the SERCA modulator phospholamban at the 
regulatory T17 site. Stimulation of smooth muscle AMPK represents a new, potent 
vasodilator mechanism in resistance vessels. AMPK directly relaxes vascular 
smooth muscle cell by a decrease of [Ca(2+)]i. This is achieved by calcium 
sequestration via SERCA activation, as well as activation of BKCa channels. 
There is in part a mutual compensation of both calcium-lowering mechanisms. 
However, SERCA activation which involves an AMPK-dependent phosphorylation of 
phospholamban is the predominant mechanism in resistance vessels.