Combined local ischemic postconditioning and remote perconditioning recapitulate cardioprotective effects of local ischemic preconditioning.

Ischemic postconditioning (PostC) and perconditioning (PerC) provide practical methods for protecting the heart against ischemia-reperfusion (l/R) injury, but their combined effects have not been studied in detail. Using an in vivo rat hR model, we tested 1) whether additive effects were produced when local PostC was preceded by varying doses of remote PerC, and whether the optimal PostC+PerC regime is additive to local ischemic preconditioning (IPC), and 2) how combined PostC+PerC alters the activity of the reperfusion injury salvage kinase pathway. The optimal combination of PerC and PostC therapy was produced by PerC delivered with four cycles of 5 mm of limb ischemia followed by 5-mm reperfusion. This resulted in lower infarct size (22.56 ± 4.45%) compared with rats with PostC alone (29.39 ± 3.66%) and PerC alone (33.49 ± 5.81%) and complementary differences in the generation of reactive oxygen species and apoptotic signaling. However, this optimal combination of PostC+PerC resulted in protection similar to local 1PC alone (18.8 ± 2.54%, P = 0. 13), and when added to IPC there was no additional protection (19.62 ± 2.89%, P = 0.675). Akt and ERKI/2 phosphorylation was induced by PostC and PerC and maximally by combined PostC+PerC treatment, and protection was abolished by phosphatidylinositol 3-kinase or ERKI/2 inhibitors. This study shows that neither PostC nor a maximized "dose" of PerC leads to optimal kinase signaling or cardioprotection compared with IPC alone. However, combined PostC+PerC may result in complementary effects on kinase signaling to recapitulate the effects of local IPC. Finally, combined PostC+PerC is not additive to IPC, suggesting that each works via a common pathway. [ABSTRACT FROM AUTHOR]