Oral therapy with dipyridamole limits ischemia-reperfusion injury in humans.
BACKGROUND
Adenosine receptor stimulation induces several effects that could limit ischemia-reperfusion injury. We hypothesize that treatment with the nucleoside uptake inhibitor dipyridamole increases endogenous adenosine and limits ischemia-reperfusion injury in humans.


METHODS
Ischemia-reperfusion injury was studied in forearm skeletal muscle by technetium Tc 99m-labeled annexin A5 scintigraphy. Ischemia-reperfusion injury was induced by unilateral forearm ischemic exercise. Immediately on reperfusion, annexin A5 labeled with technetium Tc 99m was administered intravenously, and ischemia-reperfusion injury was expressed as the percentage difference in radioactivity between the experimental arm and the control arm 1 and 4 hours after reperfusion. Targeting was quantified in the region of the thenar muscle and forearm flexor muscles. This approach was used in 9 healthy male volunteers after a 1-week treatment with dipyridamole (200 mg, slow release, twice daily) and in 23 control subjects.


RESULTS
Dipyridamole treatment significantly reduced annexin A5 targeting in skeletal muscle compared with the control group (thenar region, 13% +/- 7% versus 22% +/- 15% at 1 hour after reperfusion and 9% +/- 6% versus 27% +/- 13% at 4 hours for dipyridamole and control groups, respectively [P = .01]; flexor region, 4% +/- 8% versus 7% +/- 6% at 1 hour after reperfusion and 1% +/- 4% versus 10% +/- 9% at 4 hours for dipyridamole and control groups, respectively [P = .01]).


CONCLUSIONS
One week of oral treatment with the nucleoside uptake inhibitor dipyridamole (200 mg, slow release, twice daily) significantly limits ischemia-reperfusion injury in humans in vivo, as assessed by technetium Tc 99m-labeled annexin A5 scintigraphy of forearm skeletal muscle.
Department of Pharmacology-Toxicology, Radbound University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands. N.Riksen@aig.umcn.nl
Niels P
NP
Riksen
Wim J G
WJ
Oyen
Bart P
BP
Ramakers
Petra H H
PH
Van den Broek
Richard
R
Engbersen
Otto C
OC
Boerman
Paul
P
Smits
Gerard A
GA
Rongen
D000284:Administration, Oral; D000328:Adult; D017304:Annexin A5 / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D002110:Caffeine / Q000097:blood; D004176:Dipyridamole / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D015444:Exercise; D017079:Exercise Tolerance; D005542:Forearm / Q000098:blood supply / Q000000981:diagnostic imaging; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000000981:diagnostic imaging; D011877:Radionuclide Imaging; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control*; D013667:Technetium / Q000008:administration & dosage; D014529:Uridine / Q000037:antagonists & inhibitors / Q000378:metabolism
D017304:Annexin A5; D002110:Caffeine; D004176:Dipyridamole; D013667:Technetium; D014529:Uridine