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

Abstract

Conclusion: Remote postconditioning (RPostC) is inducible by transient limb ischemia and is as effective as remote ischemic preconditioning (RIPC) for preventing endothelial ischemic–reperfusion (IR) injury. Summary: Ischemic postconditioning and ischemic preconditioning are mechanisms that may protect tissues from injury during IR. In ischemic preconditioning, short periods of IR are applied before a prolonged ischemic insult. In ischemic postconditioning, there is a modified schedule of reperfusion that uses intermediate restoration of flow after prolonged episodes of ischemia (Physiol Rev 2003;83:1113-51; Basic Res Cardiol 2005;100:295-310). Both ischemic preconditioning and ischemic postconditioning share similar mechanisms. In both forms of intervention, survival kinases and mitochondrial adenosine triphosphate (ATP)-sensitive potassium+ (KATP) channels are activated as part of the process of IR tissue protection. It is also known that protection from IR injury can be achieved by application of ischemia to remote sites during an injurious ischemic event. This is termed remote postconditioning (RPostC). In this study, the authors used an in vivo model of endothelial IR injury to determine whether RPostC occurs in humans and if it shares similar mechanisms with RIPC. The authors assessed endothelial function by flow-mediated dilatation before and after 20 minutes of arm ischemia, followed by reperfusion. Remote ischemic preconditioning was induced by conditioning cycles of 5 minutes of ischemia and reperfusion on the contralateral leg or arm before IR. Remote postconditioning induction conditioning cycles were administered during the ischemic phase of IR. The dependence of RIPC and RPostC on KATP was determined with use of oral glibenclamide. Ischemia–reperfusion reduced flow-mediated dilatation in healthy volunteers (baseline, 9.3% ± 1.2% vs post-IR, 3.3% ± 0.7%; P < .0001). Ischemia–reperfusion also caused a significant reduction in flow-mediated dilatation in patients with atherosclerosis (baseline, 5.5% ± 0.6% vs post-IR, 2.3% ± 0.5%; P < .01). These reductions were prevented by RIPC in healthy volunteers (post-IR plus RIPC, 7.2% ± 0.5%, P < .0001 vs post-IR) and in atherosclerotic patients (P < .01 vs post-IR). Reduction was also prevented by RPostC (post-IR plus RpostC, 8.0% ± 0.5%; P < .0001 vs post-IR). Glibenclamide blocked the protective effects of both RPost C and RIPC. Comment: The study may have huge implications. It suggests that in patients undergoing an ischemic event (myocardial infarction, stroke, acute mesentery ischemia or acute limb ischemia), the ischemia–reperfusion injury may be modified by producing transient limb ischemia at a remote site before and after revascularization of the critically ischemic tissue. It should be possible to easily test the effect of this relatively benign stimulus on patients with acute ischemic events.