caa a22 4500 378855948 CHVBK 20180305123335.0 cr unu---uuuuu 161128e20031225xx s 000 0 eng 10.1515/BC.2003.177 doi (NATIONALLICENCE)gruyter-10.1515/BC.2003.177 A Novel Water-Soluble and Cell-Permeable Calpain Inhibitor Protects Myocardial and Mitochondrial Function in Postischemic Reperfusion [Elektronische Daten] [C. Neuhof, O. Götte, S. Trumbeckaite, M. Attenberger, N. Kuzkaya, F. Gellerich, A. Möller, W. Lubisch, M. Speth, H. Tillmanns, H. Neuhof] 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×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. Copyright © 2003 by Walter de Gruyter GmbH & Co. KG Biochemistry nationallicence Molecular biology nationallicence Cellular biology nationallicence Neuhof C. aut Götte O. aut Trumbeckaite S. aut Attenberger M. aut Kuzkaya N. aut Gellerich F. aut Möller A. aut Lubisch W. aut Speth M. aut Tillmanns H. aut Neuhof H. aut Biological Chemistry Walter de Gruyter 384/12(2003-12-25), 1597-1603 1431-6730 384:12<1597 2003 384 bchm https://doi.org/10.1515/BC.2003.177 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1515/BC.2003.177 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Neuhof C. aut NATIONALLICENCE 700 1- Götte O. aut NATIONALLICENCE 700 1- Trumbeckaite S. aut NATIONALLICENCE 700 1- Attenberger M. aut NATIONALLICENCE 700 1- Kuzkaya N. aut NATIONALLICENCE 700 1- Gellerich F. aut NATIONALLICENCE 700 1- Möller A. aut NATIONALLICENCE 700 1- Lubisch W. aut NATIONALLICENCE 700 1- Speth M. aut NATIONALLICENCE 700 1- Tillmanns H. aut NATIONALLICENCE 700 1- Neuhof H. aut NATIONALLICENCE 773 0- Biological Chemistry Walter de Gruyter 384/12(2003-12-25), 1597-1603 1431-6730 384:12<1597 2003 384 bchm CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter