Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system.
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.
Loukogeorgakis
Stavros P
SP
Vascular Physiology Unit, Institute of Child Health, University College London, London, United Kingdom. s.loukogeorgakis@ich.ucl.ac.uk
Panagiotidou
Anna T
AT
Broadhead
Michael W
MW
Donald
Ann
A
Deanfield
John E
JE
MacAllister
Raymond J
RJ
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