Methotrexate modulates the kinetics of adenosine in humans in vivo

Niels Peter Riksen ^1*, Pilar Barrera ¹, Petra HH van den Broek ¹, Piet van Riel ¹, Paul Smits ¹ and Gerard Rongen ¹

¹ Radboud University Nijmegen Medical Centre, Netherlands

^* To whom correspondence should be addressed. E-mail: n.riksen{at}aig.umcn.nl.

Accepted 19 November 2005

Abstract

Objective: Animal studies suggest that the anti- inflammatory effect of methotrexate (MTX) is mediated by increased adenosine concentrations. We aimed to assess the effect of MTX on the vasodilator effects of adenosine and the nucleoside uptake inhibitor dipyridamole in humans in vivo as a marker for changes in adenosine kinetics.

Methods: Ten patients with active arthritis were treated with MTX (15 mg/week). Measurements were performed before and after 12 weeks of therapy. At these timepoints, activity of adenosine deaminase was measured in isolated lymphocytes, and forearm blood flow (FBF) was determined by venous occlusion plethysmography during administration of adenosine and dipyridamole into the brachial artery.

Results: The Vmax of adenosine deaminase in lymphocytes was reduced by MTX therapy (P<0.05). MTX significantly enhanced vasodilator response to adenosine (0.5 and 1.5 µg/min per dl of forearm tissue; FBF ratio increased from 1.2±0.2 to 1.4±0.2 and 2.2±0.2 before and from 1.3±0.1 to 1.8±0.2 and 3.2±0.5 during MTX therapy, mean ± SE; P<0.05). Also, dipyridamole- induced vasodilation (30 and 100 µg/min/dl) was enhanced by MTX (FBF ratio increased from 1.2±0.2 to 1.5±0.3 and 1.8±0.2 before and from 1.3±0.1 to 1.8±0.2 and 2.4±0.4 during MTX therapy; P<0.05).

Conclusions: MTX therapy inhibits deamination of adenosine and potentiates adenosine-induced vasodilation. Also dipyridamole-induced vasodilation is enhanced by MTX treatment, suggesting an increased extracellular formation of adenosine. This is the first study that shows that MTX therapy affects adenosine kinetics in humans in vivo. These effects probably contribute to the therapeutic efficacy of MTX.

Keywords: adenosine, blood flow, methotrexate

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