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In Gao et al. (
31
) dose-response study, darbepoetin (DA) 2, 7, 11,
and 30 mg/kg or vehicle was administered as a single i.v. bolus at the
start of 30-min ischemia. To determine the time window of potential
cardioprotection, a single high dose of DA (30 mg/kg) was given at
either the initiation or the end of ischemia or at 1 or 24 h after reperfu-
sion. After 3 days, cardiac function and infarct size were assessed. DA
significantly reduced infarct size in a dose-dependent manner.
Treatment with DA up to 24 h after the beginning of reperfusion still
demonstrated a significant reduction in infarct size. Consistent with
infarction data, DA improved in vivo cardiac reserve compared with
vehicle, as assessed by left ventricular d
P
/d
t
at increasing doses of
isoproterenol. Finally, DA significantly decreased myocyte apoptosis
and caspase-3 activity after ischemia-reperfusion.
Baker et al. (
32
), found that a single intravenous darbepoetin
treatment immediately before 30 min of regional ischemia in the
rat reduced myocardial necrosis following 120 min of reperfusion
in a dose-dependent manner. Optimal protection with darbepoe-
tin-alfa against MI was manifest at a dose of 2.5 mg/kg among
doses ranging from 0.25 to 30 mg/kg. Darbepoetin was cardiopro-
tective when administered after the onset of ischemia and at the
start of reperfusion. Darbepoetin-alfa (2.5 mg/kg) also reduced
infarct size and Troponin I leakage 24 h after reperfusion. Inhibition
of p42/44 MAPK (PD98059), p38 MAPK (SB203580), mito-
chondrial ATP-dependent potassium (KATP) channels (5-HD),
sarcolemmal KATP channels (HMR 1098), but not phosphati-
dylinositol-3 (PI3) kinase/Akt (Wortmannin and LY 294002)
abolished darbepoetin-alfa-induced cardioprotection.
Toma et al. (
33
) randomized to darbepoetin 30 mg/kg i.v. or
saline at the time of reperfusion after 60 min ischemia 16 domestic
pigs. Ischemia was induced by inflating an angioplasty balloon in
the proximal left circumflex artery. Darbepoetin did not reduce
infarct size, but a limited decrease in interstitial fibrosis, increased
capillary area and regional functional improvement in darbepoetin-
treated animals was observed. However, this did not translate to
improved wall thickening of the left ventricle.
Singh et al. (
34
) induced ventricular fibrillation electrically and
maintained it, untreated, for 10 min. Chest compression and ven-
tilation were then started and electrical defibrillation was attempted
8 min later. Rats were randomized to receive rhEPO (5,000 U/
kg) in the right atrium at baseline, 15 min before induction of VF
(rhEPOBL −15-min), or at 10 min of VF, immediately before the
start of chest compression (rhEPOVF 10-min), or to receive saline
(control). Post-resuscitation, rats in the rhEPOVF 10-min group
displayed higher mean aortic pressure associated with numerically
higher cardiac index, stroke work index, and systemic vascular
resistance index. In this model of short lasting global in vivo car-
diac ischemia followed by reperfusion, rhEPO may rapidly induce
myocardial protection.
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