title: A novel water-soluble and cell-permeable calpain inhibitor protects myocardial and mitochondrial function in postischemic reperfusion.
abstract: The effects of the novel calpain inhibitor A-705239 were studied in isolated perfused rabbit hearts subjected to 45 min of global ischemia, followed by 60 min of reperfusion. During 15 min of perfusion the inhibitor accumulated in myocardial tissue up to 16 times the concentration in the perfusate. Almost complete recovery and survival of heart function (90%) was seen with an inhibitor concentration of 10(-8) M in the perfusion fluid when the compound was administered prior to ischemia. Left ventricular pressure amplitude and coronary flow showed significantly higher values during reperfusion in the presence of the inhibitor. A-705239 significantly reduced the release of creatine kinase, from 166+/-49 U/l in untreated hearts to 44+/-10 U/l, and diminished the release of lactate dehydrogenase from 118+/-20 U/l in untreated hearts to 63+/-4 U/l. Mitochondrial dysfunction following ischemia and reperfusion was markedly attenuated by the inhibitor. Thus, the state 3 respiration rate only decreased to 4.2 in contrast to 2.6 nmol O2/(min x mg s.w.) in untreated hearts, reflecting a reduced damage of oxidative phosphorylation. Furthermore, in the presence of the inhibitor the inner mitochondrial membranes became less permeable as indicated by a smaller leak respiration. The excellent properties of A-705239 should make this compound a valuable tool for further pharmacological studies.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University of Giessen, Klinikstrasse 36, D-35392 Giessen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Neuhof
authors.forename: Oliver
authors.initials: O
authors.lastname: Götte
authors.forename: Sonata
authors.initials: S
authors.lastname: Trumbeckaite
authors.forename: Markus
authors.initials: M
authors.lastname: Attenberger
authors.forename: Nermin
authors.initials: N
authors.lastname: Kuzkaya
authors.forename: Frank
authors.initials: F
authors.lastname: Gellerich
authors.forename: Achim
authors.initials: A
authors.lastname: Möller
authors.forename: Wilfried
authors.initials: W
authors.lastname: Lubisch
authors.forename: Maria
authors.initials: M
authors.lastname: Speth
authors.forename: Harald
authors.initials: H
authors.lastname: Tillmanns
authors.forename: Heinz
authors.initials: H
authors.lastname: Neuhof
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D001278:Atractyloside / Q000494:pharmacology; D001549:Benzamides / Q000032:analysis / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D045304:Cytochromes c / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: C490161:A 705239; D001549:Benzamides; D001278:Atractyloside; D000244:Adenosine Diphosphate; D000968:Antimycin A; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D002154:Calpain