Introduction: The regulation of artery diameter (i.e.,resistance), to changes in pressure is an intrinsic property of resistance arteries (RA), termed the myogenic response (MR). This response is primarily mediated by sphingosine-1-phosphate (S1P). The AMP-activated protein kinase (AMPK), an enzyme crucial to energy homeostasis, may inhibit the import of S1P via the cystic fibrosis transmembrane conductance regulator (CFTR) for subsequent intracellular degradation. Therefore, we hypothesized that AMPK activation acutely reduces the MR. Methods: Isolated hamster gracilis RA (n=6) were mounted on a pressure myograph for functional tests. They were maintained in MOPS buffer (37°C), and those with good control responses were used. Results: We found an increase in transmural pressure induced a robust MR (190±40.8% reversal of pressure-induced distension, RID). Incubation with the AMPK inhibitor Compound C (80 mM) removed the MR (p<0.05) and inhibited the constrictory-response to norepinephrine (NEPI) (0% RID; p<0.05). This suggested that both the MR and a-adrenergic signaling involves AMPK. The AMPK activator AICAR (1 mM) abrogated the MR (n=6; p<0.05), but this effect was reversed by the nitric oxide synthase (NOS) inhibitor L-NNA (30mM). A real time iodide efflux assay with baby hamster kidney (BHK) cells expressing WT human CFTR demonstrated that Compound C alone can induce some iodide efflux (n=3), demonstrating that AMPK-inhibition opens the CFTR channel. Conclusions: Together, these experiments suggest that (i)AMPK-inhibition promotes S1P-degradation through CFTR-mediated transport, eliminating the MR;(ii) AMPK-activation inhibits S1P degradation via CFTR and (iii) AMPK-activation inhibits the MR by NOS stimulation. Future work will examine the effects of transmural pressure on AMPK phosphorylation in RA.