Intra-arterial AICA-riboside administration induces NO-dependent vasodilation in vivo in human skeletal muscle.
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 x min(-1) x 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 x min(-1) x dl(-1)) with the intra-arterial administration of the adenosine receptor antagonist caffeine (90 microg x min(-1) x dl(-1); n = 6) and with the endothelial NO synthase inhibitor l-NMMA (0.4 mg x min(-1) x 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 x min(-1) x 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.
Bosselaar
Marlies
M
Dept. of General Internal Medicine, Univ. Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. m.bosselaar@aig.umcn.nl
Boon
Hanneke
H
van Loon
Luc J C
LJ
van den Broek
Petra H H
PH
Smits
Paul
P
Tack
Cees J
CJ
D000328:Adult; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001916:Brachial Artery / Q000187:drug effects / Q000502:physiology; D002110:Caffeine / Q000008:administration & dosage; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005542:Forearm / Q000098:blood supply; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007269:Injections, Intra-Arterial; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D012263:Ribonucleosides / Q000008:administration & dosage / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D055815:Young Adult
D004791:Enzyme Inhibitors; D012263:Ribonucleosides; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D002110:Caffeine; C011651:acadesine; D019331:NG-Nitroarginine Methyl Ester