Methotrexate modulates the kinetics of adenosine in humans in vivo.
BACKGROUND
Animal studies suggest that the anti-inflammatory effect of methotrexate (MTX) is mediated by increased adenosine concentrations.


OBJECTIVE
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 treatment. At these time points, the 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 treatment (p<0.05). MTX significantly enhanced vasodilator response to adenosine (0.5 and 1.5 microg/min/dl of forearm tissue; mean (SE) FBF ratio increased from 1.2 (0.2) to 1.4 (0.2) and 2.2 (0.2) ml/dl/min, respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 3.2 (0.5) ml/dl/min during MTX treatment; p<0.05). Also, dipyridamole-induced vasodilatation (30 and 100 microg/min/dl) was enhanced by MTX (FBF ratio increased from 1.2 (0.2) to 1.5 (0.3) and 1.8 (0.2), respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 2.4 (0.4) during MTX treatment; p<0.05).


CONCLUSIONS
MTX treatment inhibits deamination of adenosine and potentiates adenosine-induced vasodilatation. Also dipyridamole-induced vasodilatation is enhanced by MTX treatment, suggesting an increased extracellular formation of adenosine. These effects on the adenosine kinetics in humans may contribute to the therapeutic efficacy of MTX.
Riksen
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NP
Department of Pharmacology-Toxicology 149, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21, 6525 EZ Nijmegen, The Netherlands. N.Riksen@aig.umcn.nl
Barrera
P
P
van den Broek
P H H
PH
van Riel
P L C M
PL
Smits
P
P
Rongen
G A
GA
D000241:Adenosine / Q000494:pharmacology*; D000243:Adenosine Deaminase / Q000097:blood; D058892:Adenosine Deaminase Inhibitors; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005542:Forearm / Q000098:blood supply; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D008875:Middle Aged; D012039:Regional Blood Flow / Q000187:drug effects; D012720:Severity of Illness Index; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D058892:Adenosine Deaminase Inhibitors; D018501:Antirheumatic Agents; D014665:Vasodilator Agents; D004176:Dipyridamole; D000243:Adenosine Deaminase; D000241:Adenosine; D008727:Methotrexate