Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside in the muscle microcirculation increases nitric oxide synthesis and microvascular perfusion.
OBJECTIVE
To investigate the effects of activation of the AMP-activated protein kinase (AMPK) on muscle perfusion and to elucidate the mechanisms involved.


RESULTS
In a combined approach, we studied the vasoactive actions of AMPK activator by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) on rat cremaster muscle resistance arteries ( approximately 100 mum) ex vivo and on microvascular perfusion in the rat hindlimb in vivo. In isolated resistance arteries, AICAR increased Thr172 phosphorylation of AMPK in arteriolar endothelium, which was predominantly located in microvascular endothelium. AICAR induced vasodilation (19+/-4% at 2 mmol/L, P<0.01), which was abolished by endothelium removal, inhibition of NO synthase (with N-nitro-L-arginine), or AMPK (with compound C). Smooth muscle sensitivity to NO, determined by studying the effects of the NO donor S-nitroso-N-acetylpenicillamine (SNAP), was not affected by AICAR except at the highest dose. AICAR increased endothelial nitric oxide synthase activity, as indicated by Ser1177 phosphorylation. In vivo, infusion of AICAR markedly increased muscle microvascular blood volume (approximately 60%, P<0.05), as was evidenced by contrast-enhanced ultrasound, without effects on blood pressure, femoral blood flow, or hind leg glucose uptake.


CONCLUSIONS
Activation of AMPK by AICAR activates endothelial nitric oxide synthase in arteriolar endothelium by increasing its Ser1177 phosphorylation, which leads to vasodilation of resistance arteries and recruitment of microvascular perfusion in muscle.
Bradley
Eloise A
EA
Menzies Research Institute, University of Tasmania, Hobart, Australia.
Eringa
Etto C
EC
Stehouwer
Coen D A
CD
Korstjens
Iolente
I
van Nieuw Amerongen
Geerten P
GP
Musters
Rene
R
Sipkema
Pieter
P
Clark
Michael G
MG
Rattigan
Stephen
S
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006614:Hindlimb; D007262:Infusions, Intravenous; D008833:Microcirculation / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000098:blood supply*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012265:Ribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D012694:Serine; D013912:Threonine; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D011720:Pyrazoles; D011743:Pyrimidines; D012265:Ribonucleotides; D014665:Vasodilator Agents; C516138:dorsomorphin; D019335:Nitroarginine; D013912:Threonine; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D012694:Serine; D026423:S-Nitroso-N-Acetylpenicillamine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide