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

Abstract

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.

Comparison of cardioprotective and anti-inflammatory effects of ischemia pre- and postconditioning in rats with myocardial ischemia–reperfusion injury

“…In addition, Ren et al [22] found that the protective effect of the limb remote IPC depended on numbers and duration of the limb ischemic stimulus. In the study of Loukogeorgakis et al [23], moreover, the strength of the protective effect afforded by the limb remote IPOC is related to the tissue volume exposed to the ischemic stimulus. A possible mechanism for this effect is that the inferior stimulus does not make the trigger tissue release enough humoral factors to completely activate the signal transduction pathways eliciting cardioprotection.…”

Postconditioning in Reperfusion Injury: A Status Report

“…They found that remote Postcon applied in an arm or leg at the onset of reperfusion significantly preserves flow-mediated vasodilatation. Protection was blocked by a non-selective K ATP channel blocker, glibenclamide [103]. A recent clinical observation reported by Bøtker et al at the American College of Cardiology 58th Annual Scientific Session in 2009 demonstrated that upper-limb ischemia with four 5/5 min inflation/deflation using a standard blood pressure cuff initiated during ambulance transfer (named as remote perconditioning) reduces myocardial infarct size measured by SPECT imaging after 30 days of standard PCI in STEMI patients.…”

Preconditioning and its clinical potential

“…In stroke and myocardial infarct patients, prompt application of remote IPC could limit the extent of infarct damage, especially considering the recent findings of ''post-conditioning'' [57].…”