title: Heart protection by combination therapy with esmolol and milrinone at late-ischemia and early reperfusion.
abstract: BACKGROUND
  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).
  
  
  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.
authors.affiliation: Department of Internal Medicine, Cardiology Division (M-HH, YW, VN, SR, BFU, KF), University of Texas Medical Branch, Galveston, TX, USA. mhuang1458@aol.com
authors.forename: Ming-He
authors.initials: MH
authors.lastname: Huang
authors.forename: Yewen
authors.initials: Y
authors.lastname: Wu
authors.forename: Vincent
authors.initials: V
authors.lastname: Nguyen
authors.forename: Saurabh
authors.initials: S
authors.lastname: Rastogi
authors.forename: Bradley K
authors.initials: BK
authors.lastname: McConnell
authors.forename: Cori
authors.initials: C
authors.lastname: Wijaya
authors.forename: Barry F
authors.initials: BF
authors.lastname: Uretsky
authors.forename: Kian-Keong
authors.initials: KK
authors.lastname: Poh
authors.forename: Huay-Cheem
authors.initials: HC
authors.lastname: Tan
authors.forename: Kenichi
authors.initials: K
authors.lastname: Fujise
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling; D007262:Infusions, Intravenous; D020105:Milrinone / Q000008:administration & dosage / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D002316:Cardiotonic Agents; D058987:Phosphodiesterase 3 Inhibitors; D011412:Propanolamines; D017868:Cyclic AMP-Dependent Protein Kinases; D020105:Milrinone; C036604:esmolol