Introduction The Reperfusion Injury Salvage Kinase (RISK) pathway is the term given to prosurvival kinases such as the phosphatidylinositol-3 kinase (PI3K)–Akt cascade, which confer cardioprotection when specifically activated at the onset of myocardial reperfusion following an infarct. Applying brief ischaemia/reperfusion to a limb either before myocardial ischaemia (remote ischaemic preconditioning; RIPC) or after the onset of myocardial ischaemia (remote ischaemic postconditioning; RIPost) can reduce myocardial infarct size. We hypothesised that RIPC and RIPost limit myocardial infarct size through activation of the RISK pathway.
Methods Mini swine (25–30 kg) were subjected to in situ left anterior descending (LAD) coronary artery ischaemia (60 min) followed by myocardial reperfusion (180 min) at the end of which myocardial infarct size was determined using tetrazolium staining. Animals were randomly assigned to the following experimental protocols: (1) control—no additional intervention; (2) RIPC—four 5-minute cycles of lower limb ischaemia/reperfusion (femoral artery clamping and declamping) were administered before the onset of myocardial ischaemia; (3) RIPC + wort—wortmannin (20 μg/kg, a PI3K inhibitor) was given intravenously 30 s before myocardial reperfusion to RIPC-treated animals; (4) RIPost—four 5-minute cycles of lower limb ischaemia/reperfusion were administered at the end of myocardial ischaemia, one minute before the onset of myocardial reperfusion; (5) RIPost + wort—wortmannin was given 30 s before myocardial reperfusion to RIPost-treated animals.
Results Both RIPC and RIPost significantly reduced myocardial infarct size (13.3 ± 2.2% with RIPC, 18.2 ± 2.0% with RIPost vs 48.8 ± 4.2% in control; p<0.05; N >5). Interestingly, pharmacologically inhibiting the PI3K–Akt pathway at the onset of myocardial reperfusion using wortmannin abolished the infarct-limiting effects of RIPC but not RIPost (33.2 ± 6% with RIPC + wort, 18.0 ± 3.4% with RIPost + wort vs 48.8 ± 4.2% in control; p<0.05; N >6).
Conclusion Remote ischaemic preconditioning using lower limb ischaemia reduces myocardial infarct size by activating the PI3K–Akt component of the RISK pathway. However, remote ischaemic postconditioning does not appear to require activation of this component of the RISK pathway to confer its cardioprotective effect.