Published Online
on August 27, 2007

A more recent version of this article appeared on September 18, 2007

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Submitted on August 15, 2006
Accepted on July 5, 2007

Transient Limb Ischemia Induces Remote Preconditioning and Remote Postconditioning in Humans by a K_ATP Channel–Dependent Mechanism

Stavros P. Loukogeorgakis MBBS, BSc, PhD^*, Rupert Williams MBBS, BSc, Anna T. Panagiotidou MBBS, BSc, Shyamsunder K. Kolvekar MBBS, MS, MCh, FRCS, FRCSTh, Ann Donald AVS, Tim J. Cole BA, BPhil, MA, PhD, ScD, Derek M. Yellon PhD, DSc, Hon FRCP, John E. Deanfield BA, BChir, MB, FRCP, and Raymond J. MacAllister MA, MD, FRCP

From the Vascular Physiology Unit, Institute of Child Health (S.P.L., R.W., A.T.P., A.D., J.E.D.), MRC Centre of Epidemiology for Child Health, Institute of Child Health (T.J.C.), Hatter Cardiovascular Institute and Centre for Cardiology (D.M.Y.), and Centre for Clinical Pharmacology and Therapeutics (S.P.L.), University College London; and Department of Cardiothoracic Surgery, UCL Hospitals NHS Foundation Trust (S.K.K.), London, United Kingdom.

^* To whom correspondence should be addressed. E-mail: s.loukogeorgakis{at}ich.ucl.ac.uk.

Background—Transient limb ischemia administered before a prolonged ischemic insult has systemic protective effects against ischemia-reperfusion (IR) injury (remote ischemic preconditioning [RIPC]). It has been demonstrated that protection from IR can be achieved by brief periods of ischemia applied at a remote site during an injurious ischemic event (remote postconditioning [RPostC]). Using an in vivo model of endothelial IR injury, we sought to determine whether RPostC occurred in humans and whether it shared mechanistic similarities with RIPC.

Methods and Results—Endothelial function was assessed by flow-mediated dilation before and after IR (20 minutes of arm ischemia followed by reperfusion). RIPC was induced by conditioning cycles of 5 minutes of ischemia and reperfusion on the contralateral arm or leg before IR. For RPostC induction, conditioning cycles were administered during the ischemic phase of IR. Oral glibenclamide was used to determine the dependence of RIPC and RPostC on K_ATP channels. IR caused a significant reduction in flow-mediated dilation in healthy volunteers (baseline, 9.3±1.2% versus post-IR, 3.3±0.7%; P<0.0001) and patients with atherosclerosis (baseline, 5.5±0.6% versus post-IR, 2.3±0.5%; P<0.01). This reduction was prevented by RIPC (post-IR+RIPC: healthy volunteers, 7.2±0.5% [P<0.0001 versus post-IR]; patients, 4.5±0.3% [P<0.01 versus post-IR]) and RPostC (post-IR+RPostC: 8.0±0.5%; P<0.0001 versus post-IR). The protective effects of RIPC and RPostC were blocked by glibenclamide.

Conclusions—This study demonstrates for the first time in humans that RPostC can be induced by transient limb ischemia and is as effective as RIPC in preventing endothelial IR injury. RIPC and RPostC share mechanistic similarities, with protection being dependent on K_ATP channel activation. These results suggest that remote conditioning stimuli could be protective in patients with acute ischemia about to undergo therapeutic reperfusion.

Key words: ischemia • ischemic preconditioning • potassium channels • reperfusion injury

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