Rosuvastatin increases extracellular adenosine formation in humans in vivo: a new perspective on cardiovascular protection.
OBJECTIVE
Statins may increase extracellular adenosine formation from adenosine monophosphate by enhancing ecto-5'-nucleotidase activity. This theory was tested in humans using dipyridamole-induced vasodilation as a read-out for local adenosine formation. Dipyridamole inhibits the transport of extracellular adenosine into the cytosol resulting in increased extracellular adenosine and subsequent vasodilation. In addition, we studied the effect of statin therapy in a forearm model of ischemia-reperfusion injury.


RESULTS
Volunteers randomly received rosuvastatin or placebo in a double-blind parallel design (n=21). The forearm vasodilator response to intraarterial dipyridamole was determined in the absence and presence of the adenosine antagonist caffeine. During a separate visit the vasodilator response to nitroprusside and adenosine was established. In addition, healthy men were randomly divided in 3 groups to receive either placebo (n=10), rosuvastatin (n=22), or rosuvastatin combined with intravenous caffeine (n=12). Subsequently, volunteers performed forearm ischemic exercise. At reperfusion, Tc-99m-labeled annexin A5 was infused intravenously and scintigraphic images were acquired, providing an early marker of cell injury. Rosuvastatin treatment significantly increased the vasodilator response to dipyridamole, which was prevented by caffeine. Rosuvastatin did not influence the response to either sodium nitroprusside or adenosine indicating a specific interaction between rosuvastatin and dipyridamole, which does not result from an effect of rosuvastatin on adenosine clearance nor adenosine-receptor affinity or efficacy. Rosuvastatin increased tolerance to ischemia-reperfusion injury, which was attenuated by caffeine.


CONCLUSIONS
Rosuvastatin increases extracellular adenosine formation, which provides protection against ischemia-reperfusion injury in humans in vivo. Therefore, statins and dipyridamole may interact synergistically.
Radboud University Nijmegen Medical Centre, Department of Pharmacology and Toxicology, Nijmegen, The Netherlands.
Patrick
P
Meijer
Wim J G
WJ
Oyen
Douwe
D
Dekker
Petra H H
PH
van den Broek
Constatijn W
CW
Wouters
Otto C
OC
Boerman
Gert Jan
GJ
Scheffer
Paul
P
Smits
Gerard A
GA
Rongen
D000241:Adenosine / Q000008:administration & dosage / Q000378:metabolism*; D000284:Administration, Oral; D017304:Annexin A5 / Q000378:metabolism; D002110:Caffeine / Q000008:administration & dosage; D004176:Dipyridamole / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007261:Infusions, Intra-Arterial; D008297:Male; D009599:Nitroprusside / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011877:Radionuclide Imaging; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage
D017304:Annexin A5; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D014665:Vasodilator Agents; D009599:Nitroprusside; D002110:Caffeine; D004176:Dipyridamole; D000068718:Rosuvastatin Calcium; D000241:Adenosine