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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/E759    most recent 00141.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bosselaar, M. Articles by Tack, C. J. PubMed PubMed Citation Articles by Bosselaar, M. Articles by Tack, C. J.

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

¹Departments of General Internal Medicine and ²Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen; ³Departments of Human Biology and ⁴Human Movement Sciences, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

Submitted 4 March 2009 ; accepted in final form 12 July 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 AICA-riboside concentrations were assessed. We also combined AICA-riboside infusion (2 mg·min^–1·dl^–1) with the intra-arterial administration of the adenosine receptor antagonist caffeine (90 µg·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.

5-aminoimidazole-4-carboxamide; nitric oxide; forearm blood flow; forearm glucose uptake