title: Cardioprotective effects of intracoronary administration of 4-chlorodiazepam in small and large animal models of ischemia-reperfusion.
abstract: BACKGROUND
  The Translocator Protein (TSPO) of the mitochondrial membrane has been recognized as a potential therapeutic target for mitigation of myocardial ischemia-reperfusion injury. Administration of 4-chlorodiazepam (4-CLD), a TSPO ligand, has been shown to confer acute cardioprotective effects in small animals; however, long-term studies and studies in clinically-relevant large animal models are lacking. In the present study we investigated a potential cardioprotective effect of intracoronary administration of 4-CLD in small and large animal models of ischemia-reperfusion.
  
  
  METHODS
  Acute myocardial infarction was induced in 38 Wistar rats and 29 farm pigs by ligation of the left anterior descending coronary artery, followed by reperfusion. Animals were randomized to undergo intracoronary infusion of 2μM 4-CLD or vehicle just prior (pigs) or immediately after (rats) reperfusion. Infarcted rats were euthanized either after 1h of reperfusion (for histological assessment of the "no reflow" area) or after 60days (for serial evaluation of cardiac function and structure by echocardiography and assessment of infarct size). Infarcted pigs were euthanized after 2h of reperfusion for histological assessment of infarct size and "no reflow" area.
  
  
  RESULTS
  In infarcted rats, intracoronary infusion of 4-CLD resulted in acute reduction of the "no reflow" area and conferred durable long-term structural and functional benefits (reduction in infarct size, attenuation of adverse remodeling, improvement in global systolic function). In infarcted pigs, intracoronary infusion of 4-CLD was well-tolerated from a hemodynamic standpoint and resulted in acute reduction in infarct size, reduction in "no reflow" area and more rapid resolution of ST-segment elevation.
  
  
  CONCLUSIONS
  In a rat model of myocardial infarction, intracoronary administration of 4-CLD attenuated the "no reflow" phenomenon and produced long-term structural and functional benefits. In a porcine model of myocardial infarction intracoronary administration of 4-CLD did not raise safety concerns and conferred acute cardioprotective effects.
authors.affiliation: 3rd Department of Cardiology, University of Athens School of Medicine, Laiko Hospital, Athens, Greece.
authors.forename: Michalis
authors.initials: M
authors.lastname: Tsamatsoulis
authors.affiliation: 3rd Department of Cardiology, University of Athens School of Medicine, Laiko Hospital, Athens, Greece.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Kapelios
authors.affiliation: 3rd Department of Cardiology, University of Athens School of Medicine, Laiko Hospital, Athens, Greece.
authors.forename: Lambros
authors.initials: L
authors.lastname: Katsaros
authors.affiliation: 3rd Department of Cardiology, University of Athens School of Medicine, Laiko Hospital, Athens, Greece.
authors.forename: Stella
authors.initials: S
authors.lastname: Vakrou
authors.affiliation: 3rd Department of Cardiology, University of Athens School of Medicine, Laiko Hospital, Athens, Greece.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Sousonis
authors.affiliation: 3rd Department of Cardiology, University of Athens School of Medicine, Laiko Hospital, Athens, Greece.
authors.forename: Stefania
authors.initials: S
authors.lastname: Sventzouri
authors.affiliation: 3rd Department of Cardiology, University of Athens School of Medicine, Laiko Hospital, Athens, Greece.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Michelinakis
authors.affiliation: Laboratory for Experimental Surgery and Surgical Research "N.S. Christeas", University of Athens School of Medicine, Athens, Greece.
authors.forename: Despoina N
authors.initials: DN
authors.lastname: Perrea
authors.affiliation: 3rd Department of Cardiology, University of Athens School of Medicine, Laiko Hospital, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Anastasiou-Nana
authors.affiliation: 3rd Department of Cardiology, University of Athens School of Medicine, Laiko Hospital, Athens, Greece.. Electronic address: malliaras@gmail.com.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Malliaras
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000008:administration & dosage*; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D003331:Coronary Vessels / Q000000981:diagnostic imaging* / Q000187:drug effects; D004195:Disease Models, Animal; D000960:Hypolipidemic Agents / Q000008:administration & dosage; D007261:Infusions, Intra-Arterial / Q000379:methods; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging* / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D016896:Treatment Outcome
chemical_list: D001570:Benzodiazepinones; D002316:Cardiotonic Agents; D000960:Hypolipidemic Agents; C028513:4'-chlorodiazepam
keywords: Acute myocardial infarction; No reflow phenomenon; Reperfusion injury