title: Carvedilol treatment after myocardial infarct decreases cardiomyocytic apoptosis in the peri-infarct zone during cardioplegia-induced cardiac arrest.
abstract: OBJECTIVE
  In this study, experiments were designed to determine which parts and how carvedilol provided protection of the failed hearts under cardioplegia-induced hypoxia/reperfusion (H/R) insult.
  
  
  BACKGROUND
  Carvedilol could improve the perioperative and postoperative prognosis of the heart failure patients. The mechanism of carvedilol in prevention of the occurrence of cardiomyocytic apoptosis and preservation of cardiac function had been rarely studied.
  
  
  METHODS
  Fifty Sprague-Dawley rats treated with placebo or daily carvedilol after coronary artery ligation were divided into five groups (ligation only-group 2; ligation followed with cardioplegia-induced cardiac arrest-group 3; daily oral carvedilol treatment at 0.1, 1.0, or 10.0 mg/kg after ligation followed with cardioplegia-induced cardiac arrest-groups 4, 5, and 6), whereas another 10 animals received sham operation only (group 1), 30 days before ex vivo H/R injury. Failed hearts were harvested and received 1-h cardiac hypoxia with intermittent cold cardioplegia infusion and followed by 2-h reperfusion with warm oxygenated phosphate-buffered saline solution using a Langendorff apparatus. Perfusate was sampled at various time points. After H/R injury, the myocardium was carefully dissected into infarct, peri-infarct, and remote zones, which were used for further studies. In vitro H/R studies were carried on HL-1 cardiomyocytes to further explore the possible downstream pathways.
  
  
  RESULTS
  Carvedilol could reduce the H/R-induced cardiomyocytic apoptosis and related proteins expression, especially in the peri-infarct zone, in a dose-dependent pattern. Carvedilol could also preserve cardiac contractility via modulation of the tumor necrosis factor α and interleukin 8 mRNA expression and reduction of Bcl-2 and cytochrome c protein production and decrease the occurrence of apoptosis ex vivo. In vitro experiments revealed that carvedilol exerted its antiapoptotic effect by way of phosphatidylinositol 3-kinase and MEK (mitogen-activated protein-kinase kinase), instead of protein kinase A, pathways.
  
  
  CONCLUSIONS
  In the failed heart, pretreatment with carvedilol could preserve cardiac contractility during cardioplegia-induced myocardial H/R injury by lessening inflammation-related genes and expression of cytokines, decreasing apoptosis-related proteins production and diminishing the occurrence of cardiomyocytic apoptosis in the peri-infarct zone. The cardinal pathways of the antiapoptotic mechanism of carvedilol were PI3K- and MEK-related pathways.
authors.affiliation: Division of Thoracic & Cardiovascular Surgery, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan, Republic of China. yehccl@cgmh.org.tw
authors.forename: Chi-Hsiao
authors.initials: CH
authors.lastname: Yeh
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Chen
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Wang
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Fang
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006324:Heart Arrest, Induced; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000473:pathology*; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000319:Adrenergic beta-Antagonists; D015415:Biomarkers; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol