title: Modulation of programmed forms of cell death by intracoronary levosimendan during regional myocardial ischemia in anesthetized pigs.
abstract: OBJECTIVE
  Powerful mediators of programmed cell death, such as apoptosis and autophagy, can contribute to myocyte cell loss during pathological cardiac conditions. Levosimendan has been shown to exert beneficial hemodynamic effects in presence of global myocardial ischemia and heart failure through vasodilatation and increase of cardiac contractility. Recently, the intracoronary administration of a bolus levosimendan was found to exert favourable cardiac anti-stunning effects without lowering arterial pressure, which limits the use of levosimendan mainly in coronary artery disease. Here we tested whether the intracoronary administration of levosimendan can beneficially modulate programmed cell death in acute regional myocardial ischemia.
  
  
  METHODS
  Acute regional myocardial ischemia was induced in 20 anaesthetized pigs and intracoronary levosimendan 15 min bolus administration was started 4 h afterwards. The effects of levosimendan on coronary blood flow and cardiac function were evaluated and myocardial biopsies were examined for criteria of autophagy and apoptosis.
  
  
  RESULTS
  The administration of levosimendan caused a significant increase of coronary blood flow (p < 0.05) in absence of changes in cardiac function. Moreover, levosimendan prevented the down-regulation of the anti-apoptotic gene, Bcl-2, and the up-regulation of the apoptotic markers Bax and cytochrome c, which resulted in a reduced expression of TUNEL fragmented nuclei (p < 0.05). Furthermore, levosimendan maintained Beclin 1 at 4 h and potentiated LC3 II expression, these results being consistent with autophagy activation.
  
  
  CONCLUSIONS
  Such effects of intracoronary levosimendan bolus administration during regional myocardial ischemia indicate the occurrence of cardio-protection by modulation of programmed form of cell death.
authors.affiliation: Department of Clinical and Experimental Medicine, University of East Piedmont "A. Avogadro", Novara, Italy. grossini@med.unipmn.it
authors.forename: Elena
authors.initials: E
authors.lastname: Grossini
authors.forename: Philippe Primo
authors.initials: PP
authors.lastname: Caimmi
authors.forename: Francesca
authors.initials: F
authors.lastname: Platini
authors.forename: Claudio
authors.initials: C
authors.lastname: Molinari
authors.forename: Francesca
authors.initials: F
authors.lastname: Uberti
authors.forename: Marco
authors.initials: M
authors.lastname: Cattaneo
authors.forename: Guido
authors.initials: G
authors.lastname: Valente
authors.forename: David A S G
authors.initials: DA
authors.lastname: Mary
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vacca
authors.forename: Luciana
authors.initials: L
authors.lastname: Tessitore
mesh_terms: D000758:Anesthesia; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020287:In Situ Nick-End Labeling; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000473:pathology / Q000517:prevention & control; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000077464:Simendan; D034421:Sus scrofa; D014690:Venous Pressure / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002316:Cardiotonic Agents; D006835:Hydrazones; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011724:Pyridazines; D051028:bcl-2-Associated X Protein; D000077464:Simendan; D045304:Cytochromes c