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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 297; no. 3; pp. E759 - E766
• Main Authors: Bosselaar, Marlies, Boon, Hanneke, van Loon, Luc J. C, van den Broek, Petra H. H, Smits, Paul, Tack, Cees J
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.09.2009
• Subjects: 5-Aminoimidazole-4-carboxamide; Adult; Aminoimidazole Carboxamide - administration & dosage; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; Animal models; Brachial Artery - drug effects; Brachial Artery - physiology; Caffeine; Caffeine - administration & dosage; Cells, Cultured; Effects; Enzyme Inhibitors - administration & dosage; Erythrocytes; Fatty acids; Female; Forearm - blood supply; Forearm blood flow; Forearm glucose uptake; Glucose; Hemodynamics - drug effects; Humans; Injections, Intra-Arterial; Male; Muscle, Skeletal - blood supply; Muscle, Skeletal - drug effects; Musculoskeletal system; NG-Nitroarginine Methyl Ester - administration & dosage; Nitric oxide; Nitric Oxide - pharmacology; Plasma; Regional Blood Flow - drug effects; Ribonucleosides - administration & dosage; Ribonucleosides - pharmacology; Vasodilation - drug effects; Young Adult
• ISSN: 0193-1849; 1522-1555; 1522-1555
• DOI: 10.1152/ajpendo.00141.2009

1 Departments of General Internal Medicine and 2 Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen; 3 Departments of Human Biology and 4 Human 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 Address for reprint requests and other correspondence: M. Bosselaar, Dept. of General Internal Medicine, 463 Radboud Univ. Nijmegen Medical Centre, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands (e-mail: m.bosselaar{at}aig.umcn.nl )