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the brief periods of ischemia had “preconditioned” the myocardium to make it more
resistant to the stress of a longer ischemic interval followed by a full reperfusion. IP
was then studied in a variety of animal models and in many independent laborato-
ries, and it became clear that this intervention was a robust cardioprotective strategy
that greatly diminished myocardial infarction after a sustained period of coronary
occlusion followed by reperfusion. In all animal models, brief periods (a few min-
utes) of ischemia, separated from one another by brief periods (a few minutes) of
reperfusion just prior to a prolonged period of ischemia followed by reperfusion
induce the IP protection (see Fig. 2 ). The severity of the I/R injury are limited by IP
and the cardioprotective effects of IP include infarct size reduction, limitation of
apoptosis, reduction of stunning, anti-arrhythmic effects, and vascular precondi-
tioning consisting in reduction of endothelial dysfunction and limitation of endothe-
lial activation with reduction of neutrophil adherence and platelet aggregation.
During the years, it has been reported that many molecules released during the
short periods of preconditioning ischemia are responsible of IP protection trigger-
ing. One of the first molecule demonstrated to be responsible of triggering IP has
been adenosine, which can be released during the brief periods of preconditioning
maneuvers (Liu et al. 1991 ). Several other autacoids were identified as IP triggers,
e.g. bradykinin, platelet activating factor and opioids, produced during the brief
periods of ischemia of IP protocols (Bolli 2001 ; Dawn and Bolli 2002 ; Hausenloy
and Yellon 2007a, 2008 ; Ludman et al. 2010 ; Yellon and Hausenloy 2007 ; Pagliaro
et al. 2001 ; Penna et al. 2008 ; Wink et al. 2003 ). Several studies have identified
many of IP signaling steps. These steps are represented as complex protective path-
ways, which can be divided at least into three phases: (1) a pre-ischemic trigger
phase, (2) a memory phase and (3) a mediation phase, which occurs in early reper-
fusion after the infarcting ischemia.
In the trigger phase the released cardioprotective substances induce the activa-
tion of signal transduction pathways with the final point converging on mitochon-
dria (Fig. 2 ) (Gomez et al. 2007 ; Hausenloy and Yellon 2007b; Juhaszova et al.
2004 ). Actually, the opening of mitochondrial ATP-sensitive potassium channels
(mitoKAT P) is an important step for the cardioprotection by IP achieved by a com-
plex signaling cascade (Carroll et al. 2001 ; Cohen et al. 2001 ; Forbes et al. 2001 ;
Garlid et al. 2003 ; Juhaszova et al. 2004 ; Lim et al. 2007 ; O’Rourke 2000 ; Weiss
et al. 2003 ). In fact, the cardioprotective autacoids via their specific receptor may
activate a molecular pathway which includes the activation of PI3K/Akt, nitric
oxide synthase (NOS), guanylyl cyclase (GC) and Protein Kinase G (PKG),
Nevertheless, this complex cascade can be by-passed by the mitoKAT P opener,
Diazoxide, which pharmacologically preconditions the heart (Juhaszova et al. 2004 ;
Weiss et al. 2003 ). The cardioprotective effect of Diazoxide can be completely
inhibited by the infusion of a free radical scavenger, such as mercaptopropionyl
glycine (MPG) or N-acetyl-cysteine. These results are in line with the observation
that the antioxidant compounds infused during preconditioning ischemia avoid the
protective effects of IP (Juhaszova et al. 2004 ; Weiss et al. 2003 ). Therefore, ROS
step is downstream to mitoKAT P channels.
C. Penna and P. Pagliaro