title: Reduction of myocardial infarction by calpain inhibitors A-705239 and A-705253 in isolated perfused rabbit hearts.
abstract: Two novel calpain inhibitors (A-705239 and A-705253) were studied in isolated perfused rabbit hearts subjected to 60-min occlusion of the ramus interventricularis of the left coronary artery (below the origin of the first diagonal branch), followed by 120 min of reperfusion. The inhibitors were added to the perfusion fluid in various final concentrations from the beginning of the experiments before the coronary artery was blocked. Hemodynamic monitoring and biochemical analysis of perfusion fluid from the coronary outflow were carried out. Myocardial infarct size and the area at risk (transiently non-perfused myocardium) were determined from left ventricular slices after a special staining procedure with Evans blue and 2,3,5-triphenyltetrazolium chloride. The infarcted area (dead myocardium) was 77.9+/-2.3% of the area at risk in untreated controls ( n =12). The infarct size was significantly reduced in the presence of both calpain inhibitors. The best effect was achieved with 10 -8 M A-705253 ( n =8), which reduced ( p <0.001) the infarcted area to 49.3+/-3.9% of the area at risk, corresponding to an infarct reduction of 61.8%. No statistical difference was observed between the experimental groups in coronary perfusion, left ventricular pressure, and in the release of lactate dehydrogenase and creatine kinase from heart muscle.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Justus-Liebig-University of Giessen, D-35392 Giessen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Neuhof
authors.forename: Verena
authors.initials: V
authors.lastname: Fabiunke
authors.forename: Karin
authors.initials: K
authors.lastname: Deibele
authors.forename: Maria
authors.initials: M
authors.lastname: Speth
authors.forename: Achim
authors.initials: A
authors.lastname: Möller
authors.forename: Wilfried
authors.initials: W
authors.lastname: Lubisch
authors.forename: Hans
authors.initials: H
authors.lastname: Fritz
authors.forename: Harald
authors.initials: H
authors.lastname: Tillmanns
authors.forename: Heinz
authors.initials: H
authors.lastname: Neuhof
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000517:prevention & control*; D011188:Potassium / Q000378:metabolism; D011817:Rabbits
chemical_list: C490161:A 705239; C500488:A-705253; D001549:Benzamides; D004791:Enzyme Inhibitors; D002154:Calpain; D011188:Potassium