title: Daily ischemic preconditioning provides sustained protection from ischemia-reperfusion induced endothelial dysfunction: a human study.
abstract: BACKGROUND
  It is well established that acute ischemic preconditioning (IPC) protects against ischemia-reperfusion (IR) injury; however, the effectiveness of repeated IPC exposure has not been extensively investigated. We aimed to determine whether daily IPC episodes provide continued protection from IR injury in a human forearm model, and the role of cyclooxygenase-2 in these responses.
  
  
  RESULTS
  Thirty healthy volunteers were randomized to participate in 2 of 3 protocols (IR alone, 1-day IPC, 7-day IPC) in an operator-blinded, crossover design. Subjects in the IR alone protocol underwent flow-mediated dilation (FMD) measurements pre- and post-IR (15' upper-arm ischemia and 15' reperfusion). The 1-day IPC protocol involved FMD measurements before and after 1 episode of IPC (3 cycles of 5' upper-arm ischemia and 5' reperfusion) and IR. Day 7 of the 7-day IPC protocol was identical to the 1-day IPC protocol but was preceded by single daily episodes of IPC for 6 days prior. During each protocol, subjects received a 7-day treatment of either the cyclooxygenase-2 inhibitor celecoxib or placebo. Pre-IR FMD was similar between groups. IR alone reduced FMD post-IR (placebo, ΔFMD: -4.4±0.7%; celecoxib, ΔFMD: -5.0±0.5%). One-day IPC completely prevented this effect (placebo, ΔFMD: -1.1±0.6%; celecoxib, ΔFMD: 0.0±0.7%; P<0.0001). Similarly, 7-day IPC demonstrated persistent endothelial protection post-IR (placebo, ΔFMD: -0.9±0.9%; celecoxib, ΔFMD: 0.0±0.8%; P<0.0001, P<0.0001 for ANOVA effect of IPC protocol). Celecoxib did not alter responses to IR in any protocol.
  
  
  CONCLUSIONS
  Daily episodes of IPC provide sustained protection from IR-induced endothelial dysfunction in humans through a mechanism that appears cyclooxygenase-2-independent.
authors.affiliation: Division of Cardiology, Mount Sinai and University Health Network Hospitals, Toronto, Canada.
authors.forename: Mary Clare
authors.initials: MC
authors.lastname: Luca
authors.forename: Andrew
authors.initials: A
authors.lastname: Liuni
authors.forename: Kelsey
authors.initials: K
authors.lastname: McLaughlin
authors.forename: Tommaso
authors.initials: T
authors.lastname: Gori
authors.forename: John D
authors.initials: JD
authors.lastname: Parker
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000068579:Celecoxib; D018592:Cross-Over Studies; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D006940:Hyperemia / Q000503:physiopathology; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D009864:Ontario; D011720:Pyrazoles / Q000008:administration & dosage; D015427:Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000008:administration & dosage; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D055815:Young Adult
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib