O210	Activation of 5'-AMP-activated protein kinase induces nitric oxide-dependent vasodilatation and uncovers insulin-mediated vasodilatation of skeletal muscle resistance arteries.
1E.C.Eringa, 2C.D.A.Stehouwer, 1G.P.van Nieuw Amerongen, 1P.Sipkema
1Laboratory for Physiology, Institute for Cardiovascular Research, VU University medical centre, Amsterdam, NL; 2Department of internal medicine, Academic Hospital Maastricht, Maastricht, NL.

Background: Exercise stimulates blood flow and insulin-mediated glucose uptake in muscle, but the underlying mechanisms are unknown. 5'-AMP-activated protein kinase (AMPK), which regulates whole-body insulin sensitivity, has been proposed to mediate these effects. We have previously shown that insulin exerts vasodilator as well as vasoconstrictor effects on skeletal muscle resistance arteries1, which may be differentially affected by AMPK. Objective: To study the effects of AMPK activation on vascular tone, insulin-mediated vasoreactivity and insulin-mediated cell signaling in skeletal muscle resistance arteries. Methods/Results: To study effects of AMPK activation, resistance arteries from the rat cremaster muscle were stimulated in vitro with the AMPK agonist 5-amino-4-imidazolecarboxamide riboside (AICAR; 2 mM). AICAR induced a marked vasodilatation of resistance arteries (18 +/- 5 percent diameter change, P = 0.01) that was abolished by inhibition of AMPK activity with Compound C2 (to 3 +/- 3 percent) or inhibition of NO synthesis with N-G-nitro-L-arginine (L-NA; to –9 +/- 3 percent). To study effects of AMPK activation on insulin-mediated vasoreactivity of skeletal muscle resistance arteries, vasoreactivity to insulin (4-3400 microU/ml) was studied in the absence and presence of AICAR. In the absence of AICAR, insulin did not induce vasodilatation (0 +/- 3 percent diameter change at 272 microU/ml). In contrast, insulin induced vasodilatation in the presence of AICAR (20 +/- 5 percent at 272 microU/ml, P < 0.05 vs. insulin). This vasodilatation was abolished by pretreatment with L-NA (to 3 +/- 1 percent). In contrast, insulin induced dose-dependent vasoconstriction in the absence of AICAR (-26 +/- 2 percent at 272 microU/ml), showing that AICAR inhibits vasoconstrictor effects of insulin. Western blot analysis showed that this inhibition was accompanied by an inhibition of insulin-mediated activation extracellular-regulated kinase 1/2 (ERK1/2). Conclusions: Activation of AMPK induces NO-mediated vasodilatation of skeletal muscle resistance arteries and uncovers insulin-induced, NO-dependent vasodilatation. This interaction of AMPK with insulin-mediated vasoreactivity is achieved by inhibition of insulins ERK1/2-dependent vasoconstrictor effects. These data provide a new mechanism by which exercise improves endothelial function and insulin-mediated glucose uptake in muscle.

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