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Lipsic et al. (
21
) studied the effect of timing of EPO
administration on cardio protection during cardiac ischemia-reper-
fusion. Male Sprague-Dawley rats were subjected to 45 min of cor-
onary occlusion, followed by 24 h of reperfusion. Animals were
randomized to receive saline or single dose of EPO (5,000 IU/kg
i.p.) either 2 h before ischemia-reperfusion, at the start of ischemia,
or after the onset of reperfusion. Administration of EPO at all three
time points resulted in a significant 19-23% reduction in the infarct
area/area at risk after24-h reperfusion, which was accompanied by
a trend toward better left ventricular hemodynamic parameters only
in EPO at start of ischemia and right after reperfusion groups. The
same two experimental groups showed a significant decrease in
apoptosis, while the decrease was not statistically significant in the
group pretreated with EPO. These results suggest that cardiac pro-
tection by EPO does not need pretreatment with EPO.
Rui et al. (
22
) showed that EPO can ameliorate the myocardial
inflammatory response in both in vitro and in vivo murine models
of ischemia-reperfusion, in agreement with what shown in central
nervous system injury. In vivo, in wild type mice, 5,000 U/kg i.p.
of rhEPO given 24 h before 30 min ischemia followed by 2 h rep-
erfusion prevented ischemia-reperfusion-induced increase in myo-
cardial myeloperoxidase activity (indicative of polymorphonuclear
cells infiltration). With the help of in vitro experiments, the authors
attribute this beneficial effect of EPO to the production of NO by
eNOS via aPI3-kinase-dependent activation of the nuclear tran-
scription factor AP-1.
Hirata et al. (
23
) occluded the canine left anterior descending
coronary artery for 90 min followed by 6 h of reperfusion. EPO
administered (i.v. 100-1,000 IU/kg) just before reperfusion
reduced in a dose-dependent way infarct size and the incidence of
ventricular fibrillation via the PI3 kinase-dependent pathway in
canine hearts. In fact these effects of EPO were abolished by the
treatment with wortmannin, an inhibitor of PI3-kinase.
Xu et al. (
24
) used a rat model of 30 min ischemia followed by
2 h of reperfusion to assess mechanisms of the anti-inflammatory
action of recombinant human EPO (rhEPO). A single i.p. injec-
tion of 3,000 IU/kg of rhEPO 24 h pre-ligation enhanced the
expression of Heat shock protein 70 (Hsp70) and diminished the
expression of NF-kB in rat myocardium, and reduced markedly
myocardial infarct size, compared to control rats.
Bullard et al. (
25
) administered 5,000 IU/kg i.v. at the start of
reperfusion to rats after 40 min ischemia. Infarct size at 24 h was
significantly attenuated in EPO-treated animals. Likewise, wort-
mannin abrogated EPO-mediated protection, thus suggesting that
the protective action of EPO is mediated by ERK and PI3K.
Kristensen et al. (
26
) tested the effects of rhEPO in a closed
chest, catheter-based, porcine coronary occlusion model (45 min
of occlusion of the left anterior descending artery). EPO was given
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