title: Cardioprotection of the enkephalin analog Eribis peptide 94 in a rat model of ischemia and reperfusion is highly dependent on dosing regimen and timing of administration.
abstract: Eribis Peptide 94 (EP94) is an enkephalin analog with cardioprotective properties in ischemia and reperfusion. The aim of the present study was to define the optimal timing and dosing of the administration of EP94 during ischemia and reperfusion in a rat model. 172 anesthetized and mechanically ventilated male Sprague-Dawley rats were randomly assigned to different administration protocols of EP94 and subjected to 30 or 40 min of coronary artery occlusion followed by 2h of reperfusion. EP94 was administered intravenously at different doses and time intervals. Area at risk (AAR) and infarct size (IS) were determined by staining with Evans Blue (EB) and Triphenyl tetrazolium chloride (TTC), respectively. EP94 reduced IS/AAR when administered as a double bolus (0.5 µg/kg per dose), whereas single (1 μg/kg) or triple boluses (0.5 μg/kg per dose) did not confer any protection. Reduction of IS/AAR was of highest magnitude if EP94 was administered 5 and 0 min before the 30 min ischemic period (47% reduction, P<0.05), with declining cardioprotective effect with later administration during ischemia. When EP94 was administered after 15 and 20 min of a 40-min ischemic period, reduction of IS/AAR was of the same magnitude as when given after 5 and 10 min of a 30-min ischemic period. It is concluded that EP94 confers cardioprotection after double bolus administration. The effects are highly dependent on the timing of administration in relation to ischemia and reperfusion. Time of reperfusion from drug administration seems to be more critical than the total duration of ischemia.
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden. Electronic address: elias.spanos@vgregion.se.
authors.forename: Elias
authors.initials: E
authors.lastname: Spanos
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Lars O
authors.initials: LO
authors.lastname: Karlsson
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Redfors
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Yangzhen
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Elmir
authors.initials: E
authors.lastname: Omerovic
authors.affiliation: Eribis Pharmaceuticals AB, SE-754 50 Uppsala, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Bobrova
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Grip
authors.affiliation: Department of Acute and Cardiovascular Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-423 45 Gothenburg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Bergh
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004745:Enkephalins / Q000008:administration & dosage* / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D002316:Cardiotonic Agents; D004745:Enkephalins
keywords: Enkephalin; Myocardial ischemia; Opioid receptor; Reperfusion injury