Upregulation of ecto-5'-nucleotidase by rosuvastatin increases the vasodilator response to ischemia.
3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are effective in the primary and secondary prevention of cardiovascular events. Although originally developed to improve lipid profile, statins have demonstrated a surplus of beneficial pleiotropic effects, including improved endothelial function, reduced inflammation, and increased tolerance to ischemia-reperfusion injury. In preclinical studies, increased ecto-5'-nucleotidase activity, the key enzyme in extracellular adenosine formation, plays an important role in these effects. Because human data are absent, we explored the effects of rosuvastatin on ecto-5'-nucleotidase activity and the clinical relevance of increased extracellular adenosine during ischemia in humans in vivo. The forearm vasodilator responses to 3 increasing periods of forearm ischemia (2, 5, and 13 minutes) were determined during placebo and caffeine (an adenosine receptor antagonist) infusion into the brachial artery. At the end of an 8-day treatment period with rosuvastatin (20 mg per day), this whole procedure was repeated. During both experiments, ecto-5'-nucleotidase activity was determined. Vasodilator responses are expressed as the percentage increase in forearm blood flow ratio from baseline. Rosuvastatin increased ecto-5'-nucleotidase activity by 49±17% and enhanced the vasodilator response after 2, 5, and 13 minutes of ischemia in the absence (146±19, 330±26, and 987±133 to 312±77, 566±107, and 1533±267) but not in the presence of caffeine (98±25, 264±54, and 727±111 versus 95±19, 205±34, and 530±62). Rosuvastatin increases extracellular formation of adenosine in humans in vivo probably by enhancing ecto-5'-nucleotidase activity. This action results in the improvement of reactive hyperemia and may further enhance the clinical benefit of statins, in particular in conditions of ischemia.
Meijer
Patrick
P
Departments of Pharmacology-Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Wouters
Constantijn W
CW
van den Broek
Petra H H
PH
de Rooij
Maarten
M
Scheffer
Gert Jan
GJ
Smits
Paul
P
Rongen
Gerard A
GA
D015720:5'-Nucleotidase / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism; D001783:Blood Flow Velocity / Q000187:drug effects; D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D055815:Young Adult
D000697:Central Nervous System Stimulants; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D014665:Vasodilator Agents; D002110:Caffeine; D000068718:Rosuvastatin Calcium; D015720:5'-Nucleotidase; D000241:Adenosine