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

作者：Bradley Eloise A; Eringa Etto C; Stehouwer Coen D A; Korstjens Iolente; Amerongen Geerten P van Nieuw; Musters Rene; Sipkema Pieter; Clark Michael G; Rattigan Stephen^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2010, 30(6): 1137-1142.

DOI：10.1161/ATVBAHA.110.204404

• AICAR
• AMPK
• microcirculation
• muscle
• hemodynamics

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-beta-D-ribofuranoside (AICAR) on rat cremaster muscle resistance arteries (approximate to 100 mu m) 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 (approximate to 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. (Arterioscler Thromb Vasc Biol. 2010; 30: 1137-1142.)

• 出版日期2010-6