title: Rosuvastatin prevents conduit artery endothelial dysfunction induced by ischemia and reperfusion by a cyclooxygenase-2-dependent mechanism.
abstract: OBJECTIVE
  The purpose of this study was to determine whether single-dose rosuvastatin (40 mg) protects against ischemia and reperfusion (IR)-induced endothelial dysfunction in humans and whether this effect is cyclooxygenase (COX)-2 dependent.
  
  
  BACKGROUND
  Animal studies have demonstrated that rosuvastatin can limit damage and improve recovery after IR.
  
  
  METHODS
  In a double-blind, parallel design, 20 volunteers were randomized to a single dose of oral rosuvastatin (40 mg) or placebo. Twenty-four hours later, endothelium-dependent, flow-mediated dilation (FMD) of the radial artery was measured before and after IR (15 min of upper arm ischemia followed by 15 min of reperfusion). In a separate protocol, 18 volunteers received the COX-2 inhibitor celecoxib (200 mg orally twice daily) for 5 days. On day 4, subjects were randomized to single-dose rosuvastatin (40 mg) or placebo and 24 h later underwent the same protocol as described.
  
  
  RESULTS
  Pre-IR FMD was similar between groups (p = NS). IR significantly blunted FMD in the placebo group (FMD pre-IR: 6.4 +/- 1.4%; FMD post-IR: 1.1 +/- 3.8%, [p = 0.002]). Rosuvastatin prevented this impairment (FMD pre-IR: 7.5 +/- 3.1%; FMD post-IR: 6.2 +/- 3.9%, [p = NS] vs. rosuvastatin pre-IR, [p = 0.03] vs. placebo). Pre-treatment with celecoxib completely abolished rosuvastatin's protective effect (FMD pre-IR: 8.0 +/- 2.2%; FMD post-IR: 1.4 +/- 2.0%, [p < 0.001] compared with pre-IR, [p = NS] vs. placebo, [p = 0.002] vs. rosuvastatin alone).
  
  
  CONCLUSIONS
  Rosuvastatin pharmacologically prevents the development of IR-induced conduit artery endothelial dysfunction. This beneficial effect of rosuvastatin is mediated by a COX-2-dependent mechanism, evidence that may also provide potential mechanistic insight into the reported cardiotoxic effects of COX-2 inhibitors.
authors.affiliation: Division of Cardiology, Mount Sinai and University Health Network Hospitals and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Liuni
authors.forename: Mary Clare
authors.initials: MC
authors.lastname: Luca
authors.forename: Tommaso
authors.initials: T
authors.lastname: Gori
authors.forename: John D
authors.initials: JD
authors.lastname: Parker
mesh_terms: D000293:Adolescent; D000328:Adult; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D005464:Fluorobenzenes / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008955:Models, Cardiovascular; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D011292:Premedication; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D017534:Radial Artery / Q000187:drug effects / Q000503:physiopathology; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D051546:Cyclooxygenase 2; D000068579:Celecoxib