Role of Endothelial Nitric Oxide Synthase (eNOS) in in vivo Cardioprotection Mediated by Ischemic Preconditioning (IPC) and Ischemic Postconditioning (IPostC) in Mice and Rats

Abstract

The role of eNOS in IPC remains highly controversial. Questions also remain regarding the cardioprotective effect of IPostC and the role of eNOS. Therefore, we performed in vivo studies in wild-type (WT) and eNOS-knockout (eNOS−/−) mice, and SD rats to evaluate whether the infarct limiting effect of IPC and IPostC depends on eNOS. IPC was induced by 3-cycles of 5-min coronary ischemia (I) separated by 5-min reperfusion (R), and was followed by control I/R (30-min I and 24-hr R). IPostC was induced by 3-cycles of 10-sec of R separated by 10-sec I at the beginning of 24-hr R. Protection was evaluated by myocardial infarction (MI) measured 24-hr after RP, and correlated with postischemic myocardial eNOS protein. There was no difference in the area at risk between different groups; however, MI was significantly smaller in IPC and IPostC hearts compared to control I/R in mice or rats. NOS inhibition with L-NAME pretreatment in WT mice or absence of eNOS increased MI following I/R and abolished the cardioprotective effects of IPC or IPostC. Postischemic myocardial eNOS was well preserved by IPC and IPostC compared to control I/R in rats. Thus, this data provides compelling evidence that IPostC can protect the hearts against in vivo myocardial I/R injury in mice and rats though IPC confers more robust protection. Importantly, the in vivo cardioprotective effect of IPC and IPostC is mediated by functional/preserved myocardial eNOS.