Activation of AMP-Activated Protein Kinase by 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside in the Muscle Microcirculation Increases Nitric Oxide …

EA Bradley, EC Eringa, CDA Stehouwer… - … , and vascular biology, 2010 - Am Heart Assoc
EA Bradley, EC Eringa, CDA Stehouwer, I Korstjens, GP van Nieuw Amerongen, R Musters
Arteriosclerosis, thrombosis, and vascular biology, 2010Am Heart Assoc
Objective—To investigate the effects of activation of the AMP-activated protein kinase
(AMPK) on muscle perfusion and to elucidate the mechanisms involved. Methods and
Results—In a combined approach, we studied the vasoactive actions of AMPK activator by 5-
aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) on rat cremaster muscle
resistance arteries (≈ 100 μm) ex vivo and on microvascular perfusion in the rat hindlimb in
vivo. In isolated resistance arteries, AICAR increased Thr172 phosphorylation of AMPK in …
Objective— To investigate the effects of activation of the AMP-activated protein kinase (AMPK) on muscle perfusion and to elucidate the mechanisms involved.
Methods and Results— In a combined approach, we studied the vasoactive actions of AMPK activator by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) on rat cremaster muscle resistance arteries (≈100 μm) 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 (≈60%, P<0.05), as was evidenced by contrast-enhanced ultrasound, without effects on blood pressure, femoral blood flow, or hind leg glucose uptake.
Conclusion— 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.
Am Heart Assoc