Background: Increased extracellular adenosine formation provides a cholesterol-independent explanation for the therapeutic benefit of statins. This theory was tested in humans in-vivo using dipyridamole-induced vasodilation as a read out for local adenosine formation. Its relevance was explored using a foream model of ischemia-reperfusion injury.

Methods: Twenty-one healthy volunteers were randomly allocated to receive either rosuvastatin (20 mg/day for eight days) or placebo in a double-blind parallel design. The vasodilator response to the nucleoside transport inhibitor dipyridamole was determined in the absence and presence of the adenosine antagonist caffeine. In two additional studies, healthy volunteers were randomly divided in four groups to receive either placebo (n=10), rosuvastatin (20 mg/day for 7 days; n=22), or rosuvastatin combined with intravenous caffeine (4 mg/kg, single dose; n=12). Subsequently, volunteers performed ischemic exercise of the non-dominant forearm. At reperfusion, Tc-99m-labeled annexin A5 was infused intravenously and scintigraphic images were acquired using a gamma camera, providing an early marker of injury.

Results: Rosuvastatin treatment significantly increased the vasodilator response to dipyridamole. This effect was completely abolished by caffeine. Rosuvastatin increased tolerance to ischemia-reperfusion injury, an effect which was attenuated by adenosine receptor blockade.

Conclusion: Rosuvastatin increases extracellular adenosine formation and protects against ischemia-reperfusion injury in humans in-vivo. Our observations prove the concept that statins and dipyridamole interact synergistically whereas caffeine consumption hinders the therapeutic action of statins.