Activation of AMPK Induces NO-Dependent Vasodilatation and Uncovers Insulin-Mediated Vasodilatation of Skeletal Muscle Resistance Arteries
Abstract Number: 995-P
Authors: ETTO C. ERINGA, COEN D. A. STEHOUWER, GEERTEN P. VAN NIEUW AMERONGEN, PIETER SIPKEMA.
Institutions: Amsterdam, Netherlands; Maastricht, Netherlands.
Results: 5'-AMP-activated protein kinase (AMPK), which is activated by exercise, has been shown to increase whole-body insulin sensitivity and to lower blood pressure, but the mechanisms behind these effects are unknown. 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: In cultured human microvascular endothelial cells (hMVEC) the AMPK agonist AICAR (2 mM) induced a twofold increase in MAPK phosphorylation and a fourfold increase in AMPK activity, which was abolished by the AMPK inhibitor Compound C. In resistance arteries from the rat cremaster muscle AICAR induced a marked vasodilatation (18+5 percent diameter change, P=0.01) that was abolished by Compound C (to 3+3 percent) or inhibition of NO synthesis with N-G-nitro-L-arginine (LNA; to -9+3 percent). Furthermore, AICAR uncovered insulin-mediated vasodilatation (Insulin (272 μU/ml) -AICAR: 0+3 percent diameter change; Ins+AICAR: 20+5 percent, P<0.05). This vasodilatation was abolished by pretreatment with LNA (to 3+1 percent). In the absence of AICAR, insulin induced dose-dependent vasoconstriction during NOS inhibition (-26+2 percent at 272 μU/ml, P<0.01 vs. Ins+LNA), showing that AICAR inhibits vasoconstrictor effects of insulin. Western blot analysis showed that this inhibition was accompanied by an inhibition of insulin-mediated activation of 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 insulin's ERK1/2-dependent vasoconstrictor effects. These data provide a new mechanism by which exercise increases insulin sensitivity and lowers blood pressure.