Heart protection by combination therapy with esmolol and milrinone at late-ischemia and early reperfusion

Ming He Huang, Yewen Wu, Vincent Nguyen, Saurabh Rastogi, Bradley K. McConnell, Cori Wijaya, Barry F. Uretsky, Kian Keong Poh, Huay Cheem Tan, Kenichi Fujise

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Introduction: The present study determined whether late-ischemia/early reperfusion therapy with the β1-adrenergic receptor (AR) blocker esmolol and phosphodiesterase III inhibitor milrinone reduced left ventricular (LV) myocardial infarct size (IS). Methods and Results: 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 5min of ischemia to the first 5min 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: Late-ischemia/early reperfusion therapy with esmolol+milrinone additively reduces LV-IS associated with robust activation of myocardial PKA and subsequent Akt-antiapoptotic pathway.

Original languageEnglish (US)
Pages (from-to)223-232
Number of pages10
JournalCardiovascular Drugs and Therapy
Issue number3
StatePublished - Jun 2011
Externally publishedYes


  • Akt
  • Esmolol
  • Milrinone
  • PKA
  • Reperfusion injury

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)


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