Intra-arterial AICA-riboside administration induces NO-dependent vasodilation in vivo in human skeletal muscle

Bosselaar M, Boon H, van Loon LJ, van den Broek PH, Smits P, Tack CJ. Intra-arterial AICA-riboside administration induces NO-dependent vasodilation in vivo in human skeletal muscle. Am J Physiol Endocrinol Metab 297: E759-E766, 2009. First published July 14, 2009; doi: 10.1152/ajpendo.00141.2009.-In animal models, administration of the adenosine analog AICA-riboside has shown beneficial effects on ischemia-reperfusion injury and glucose homeostasis. The vascular and/or metabolic effects of AICA-riboside administration in humans remain to be established. AICA-riboside was infused intra-arterially in four different dosages up to 8 mg.min(-1).dl(-1) in 24 healthy subjects. Forearm blood flow (FBF) and glucose uptake and plasma glucose, free fatty acid, and AICAriboside concentrations were assessed. We also combined AICAriboside infusion (2 mg.min(-1).dl(-1)) with the intra-arterial administration of the adenosine receptor antagonist caffeine (90 mu g.min(-1).dl(-1); n = 6) and with the endothelial NO synthase inhibitor L-NMMA (0.4 mg.min(-1).dl(-1); n = 6). Additional in vitro experiments were performed to explain our in vivo effects of AICA-riboside in humans. AICA-riboside increased FBF dose dependently from 2.0 +/- 0.2 to 13.2 +/- 1.9 ml.min(-1).dl(-1) maximally (P < 0.05 for all dosages). The latter was not reduced by caffeine administration but was significantly attenuated by L-NMMA infusion. Despite high plasma AICA-riboside concentrations, forearm glucose uptake did not change. In vitro experiments showed rapid uptake of AICA-riboside by the equilibrative nucleoside transporter in erythrocytes and subsequent phosphorylation to AICA-ribotide. We conclude that AICA-riboside induces a potent vasodilator response in humans that is mediated by NO. Despite high local plasma concentrations, AICA-riboside does not increase skeletal muscle glucose uptake.