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

AbstractINTRODUCTION:
The present study determined whether late-ischemia/early reperfusion therapy with the β(1)-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 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:
Late-ischemia/early reperfusion therapy with esmolol + milrinone additively reduces LV-IS associated with robust activation of myocardial PKA and subsequent Akt-antiapoptotic pathway.
AuthorsMing-He Huang, Yewen Wu, Vincent Nguyen, Saurabh Rastogi, Bradley K McConnell, Cori Wijaya, Barry F Uretsky, Kian-Keong Poh, Huay-Cheem Tan, Kenichi Fujise
JournalCardiovascular drugs and therapy (Cardiovasc Drugs Ther) Vol. 25 Issue 3 Pg. 223-32 (Jun 2011) ISSN: 1573-7241 [Electronic] United States
PMID21562974 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Adrenergic beta-1 Receptor Antagonists
  • Cardiotonic Agents
  • Phosphodiesterase 3 Inhibitors
  • Propanolamines
  • Cyclic AMP-Dependent Protein Kinases
  • Milrinone
  • esmolol
Topics
  • Adrenergic beta-1 Receptor Antagonists (administration & dosage, pharmacology)
  • Animals
  • Apoptosis (drug effects)
  • Cardiotonic Agents (administration & dosage, pharmacology)
  • Cyclic AMP-Dependent Protein Kinases (drug effects, metabolism)
  • Disease Models, Animal
  • In Situ Nick-End Labeling
  • Infusions, Intravenous
  • Milrinone (administration & dosage, pharmacology)
  • Myocardial Reperfusion Injury (physiopathology)
  • Myocardium (metabolism)
  • Myocytes, Cardiac (drug effects, metabolism)
  • Phosphodiesterase 3 Inhibitors (administration & dosage, pharmacology)
  • Propanolamines (administration & dosage, pharmacology)
  • Rats

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