Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways

ObjectivesAn in situ model was used to test whether and how multiple occlusions at reperfusion can protect rabbit myocardium.BackgroundRecently it was demonstrated that postconditioning in dogs salvaged ischemic myocardium.MethodsControl hearts underwent 30-min regional ischemia/3-h reperfusion, whereas in experimental hearts four postconditioning cycles of 30-s occlusion/30-s reperfusion starting 30 s after release of the index coronary occlusion were added in the presence or absence of various cell signaling antagonists.ResultsPostconditioning decreased infarction from 35.4 ± 2.7% of the risk zone in control hearts to 19.8 ± 1.8% (p < 0.05). Six cycles did not result in greater protection. If postconditioning cycles were begun after 10 min of reperfusion, protection was no longer evident. Either the non-selective KATPchannel closer glibenclamide or the putatively selective mitochondrial KATPchannel antagonist 5-hydroxydecanoate administered 5 min before reperfusion blocked the protection afforded by postconditioning, indicating involvement of the mitochondrial KATPchannel. PD98059, a mitogen-activated protein/extracellular-signal regulated kinase (MEK) 1/2 and therefore extracellular-signal regulated kinase (ERK) inhibitor, and Nω-nitro-l-arginine methyl ester, an antagonist of nitric oxide synthase, infused shortly before reperfusion also aborted the protection afforded by postconditioning. Combined ischemic postconditioning and preconditioning resulted in significantly greater protection than either alone.ConclusionsMultiple, short, regional coronary occlusions immediately after prolonged myocardial ischemia are an effective cardioprotective intervention in the rabbit, and the mechanism of protection involves activation of ERK, production of nitric oxide, and opening of mitochondrial KATPchannels. These observations suggest that a similar approach could be applied in the cardiac catheterization laboratory to protect reperfused myocardium after primary angioplasty in patients with acute myocardial infarction