In an
ischemia/reperfusion rat model (30-min
ischemia/4-hr reperfusion),
esmolol,
milrinone or
esmolol +
milrinone were intravenous (IV) infused over 10 min (from the last 5 min of
ischemia to the first 5 min of reperfusion). LV-IS were 48.9 ± 8.9%, 41.5 ± 5.4%, 25.8 ± 7.7% and 16.8 ± 7.3% for saline,
esmolol,
milrinone, and
esmolol +
milrinone, respectively (n = 12/group).
Esmolol +
milrinone further reduced LV-IS compared with
esmolol or
milrinone alone (p < 0.05). LV-IS-reduction induced by
esmolol +
milrinone was eliminated in the presence of
protein kinase A-(
PKA)-inhibitor (
Rp-cAMPS) or Akt-inhibitor (AKT 1/2
kinase inhibitor). In mixed rat ventricular cardiomyocyte cultures, intra-ischemic application of
esmolol,
milrinone or
esmolol +
milrinone reduced myocyte death rates by 5.5%, 13.3%, and 16.8%, respectively, compared with saline (p < 0.01). This cell protective effect by
esmolol +
milrinone was abrogated in the presence of
PKA-inhibitor or Akt-inhibitor.
Esmolol,
milrinone or
esmolol +
milrinone increased myocardial PKA activity by 22%, 28% and 59%, respectively, compared with saline (n = 6, p < 0.01). No non-specific adverse effect of
Rp-cAMPS on myocytes was identified in a purified myocyte preparation during
hypoxia/re-oxygenation. Antiapoptotic pathways were assessed by measuring myocardial phosphorylated Akt (pAkt) levels combined with terminal dUTP nick-end labelling staining analysis. Ten minutes following infusion of
esmolol,
milrinone or
esmolol +
milrinone, there were 1.7-, 2.7-, and 6-fold increase in tissue pAkt levels, respectively. This
esmolol +
milrinone induced pAkt activation was abolished in the presence of
PKA inhibitor.
Esmolol,
milrinone and
esmolol +
milrinone reduced myocyte apoptosis rates by 22%, 37% and 60%, respectively, compared with saline (p < 0.01).
CONCLUSIONS: