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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:963.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

Rosuvastatin Increases Extracellular Adenosine Formation in Humans In Vivo

A New Perspective on Cardiovascular Protection

Patrick Meijer; Wim J.G. Oyen; Douwe Dekker; Petra H.H. van den Broek; Constatijn W. Wouters; Otto C. Boerman; Gert Jan Scheffer; Paul Smits; Gerard A. Rongen

From the Department of Pharmacology-Toxicology (P.M., D.D., P.H.H.v.d.B., C.W.W., P.S., G.A.R.), Anesthesiology (P.M., G.J.S.), Nuclear Medicine (W.J.G.O., O.C.B.), Cardiologie (C.W.W.), and Internal Medicine (D.D., P.S., G.A.R.), Radboud University Nijmegen Medical Centre, The Netherlands.

Correspondence to Gerard Rongen, Radboud University Nijmegen Medical Centre, Department of Pharmacology and Toxicology, Geert Grooteplein 21-Noord, 6525 EZ, Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail G.Rongen{at}pharmtox.umcn.nl

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.

Methods and 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.

In healthy volunteers, oral treatment with rosuvastatin significantly augmented dipyridamole-induced vasodilation and prevented annexin A5 targeting to the ischemically exercised forearm. Both actions were inhibited by the adenosine receptor antagonist caffeine. These results provide for the first time pharmacological evidence that rosuvastatin augments extracellular formation of adenosine in humans in vivo.

Key Words: adenosine • human • ischemia • rosuvastatin • annexin A5