title: Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system.
abstract: OBJECTIVE
  The aim of this study was to characterize the time course and neuronal mechanism of remote ischemic preconditioning (RIPC) of the vasculature in humans.
  
  
  BACKGROUND
  Non-lethal ischemia of internal organs induces local (ischemic preconditioning) and systemic (RIPC) resistance to lethal ischemia-reperfusion (IR) injury. Experimental RIPC has two temporal components, is neuronally mediated, is induced by limb ischemia, and reduces infarct size. In humans, RIPC prevents IR-induced vascular injury. Determining the time course and mechanism is a prelude to clinical outcome studies of RIPC.
  
  
  METHODS
  Endothelial IR injury was induced by arm ischemia (20 min) and reperfusion, and measured by flow-mediated dilation. To establish if there are early and late phases, RIPC (three 5-min cycles of ischemia of the contralateral arm) was applied immediately, 4, 24, and 48 h before IR. To determine neuronal involvement, trimetaphan (autonomic ganglion blocker; 1 to 6 mg/min intravenous) was infused during the application of the RIPC stimulus.
  
  
  RESULTS
  Flow-mediated dilation was reduced by IR (8.7 +/- 1.1% before IR, 4.9 +/- 1.2% after IR; p < 0.001), but not when preceded by RIPC (8.0 +/- 0.8% after IR; p = NS); RIPC did not protect after 4 h (4.9 +/- 1.1% after IR; p < 0.001), but protected at 24 (8.7 +/- 1.1% after IR; p = NS) and 48 h (8.8 +/- 1.4% after IR; p = NS). Trimetaphan attenuated early (8.3 +/- 1.1% before IR, 4.2 +/- 0.9% after IR; p < 0.05) and delayed (7.3 +/- 1.0% before IR, 2.3 +/- 0.6% after IR, p < 0.001) RIPC.
  
  
  CONCLUSIONS
  Remote ischemic preconditioning in humans has two phases of protection against endothelial IR injury; an early (short) and late (prolonged) phase, both of which are neuronally mediated. The potential for late phase RIPC to provide prolonged protection during clinical IR syndromes merits investigation.
authors.affiliation: Vascular Physiology Unit, Institute of Child Health, University College London, London, United Kingdom. s.loukogeorgakis@ich.ucl.ac.uk
authors.forename: Stavros P
authors.initials: SP
authors.lastname: Loukogeorgakis
authors.forename: Anna T
authors.initials: AT
authors.lastname: Panagiotidou
authors.forename: Michael W
authors.initials: MW
authors.lastname: Broadhead
authors.forename: Ann
authors.initials: A
authors.lastname: Donald
authors.forename: John E
authors.initials: JE
authors.lastname: Deanfield
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: MacAllister
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001783:Blood Flow Velocity; D015331:Cohort Studies; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D008875:Middle Aged; D011322:Primary Prevention / Q000379:methods*; D011336:Probability; D012016:Reference Values; D015427:Reperfusion Injury / Q000517:prevention & control*; D018570:Risk Assessment; D013997:Time Factors