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1 Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
2 National Institutes of Health, Bethesda, MD, USA
3 Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
* To whom correspondence should be addressed. E-mail: lawrence.young{at}yale.edu.
AMPK is a serine-threonine kinase which regulates cellular metabolism and has an
essential role in activating glucose transport during hypoxia and ischemia. The mechanisms
responsible for AMPK stimulation of glucose transport are uncertain, but may involve
interaction with other signaling pathways or direct effects on glucose transporter (GLUT)
vesicular trafficking. One potential downstream mediator of AMPK signaling is the nitric
oxide pathway. The aim of this study was to examine the extent to which AMPK mediates
glucose transport through activation of the nitric oxide signaling pathway in isolated heart
muscles. Incubation with 1 mM 5-amino-4-imidazolecarboxamide ribofuranoside
(AICAR) activated AMPK (P<0.01), stimulated glucose uptake (P<0.05) and translocation
of the cardiomyocyte glucose transporter GLUT4 to the cell surface (P<0.05). AICAR
treatment increased phosphorylation of endothelial nitric oxide synthase (eNOS) by ~1.8-
fold (P<0.05). eNOS, but not nNOS, co-immunoprecipitated with both the 
2 and 1
AMPK catalytic subunits in heart muscle. Nitric oxide donors also increased glucose
uptake and GLUT 4 translocation (P<0.05). Inhibition of NOS with L-NAME and LNMMA,
reduced AICAR-stimulated glucose uptake by 21 ± 3% (P<0.05) and 25 ± 4%
(P<0.05) respectively. Inhibition of guanylate cyclase with ODQ and LY83583, reduced
AICAR-stimulated glucose uptake by 31 ± 4% (P<0.05) and 22 ± 3% (P<0.05)
respectively, as well as GLUT4 translocation to the cell surface (P<0.05). Taken together,
these results indicate that activation of the nitric oxide/guanylate cyclase pathway contributes
to, but is not the sole mediator of AMPK-stimulation of glucose uptake and GLUT4
translocation in heart muscle.
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