A Novel Water-Soluble and Cell-Permeable Calpain Inhibitor Protects Myocardial and Mitochondrial Function in Postischemic Reperfusion
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C. Neuhof
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×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
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- Anti-Mouse GPI-PLD Antisera Highlight Structural Differences between Murine and Bovine GPI-PLDs
- Substrate Specificity of Glutaminyl Cyclases from Plants and Animals
- The Binding of Haptoglobin to Apolipoprotein AI: Influence of Hemoglobin and Concanavalin A
- A Novel Water-Soluble and Cell-Permeable Calpain Inhibitor Protects Myocardial and Mitochondrial Function in Postischemic Reperfusion
- Potent Bivalent Inhibition of Human Tryptase-? by a Synthetic Inhibitor
- Aza-Peptide Epoxides: Potent and Selective Inhibitors of Schistosoma mansoni and Pig Kidney Legumains (Asparaginyl Endopeptidases)
- Semisynthesis and Application of Carboxyfluorescein-Labelled Biologically Active Human Interleukin-8
- Acknowledgment
- Content Index
- Author Index
- Subject Index
Articles in the same Issue
- Metabolic Stability, Receptor Binding, cAMP Generation, Insulin Secretion and Antihyperglycaemic Activity of Novel N-Terminal Glu9-Substituted Analogues of Glucagon-Like Peptide-1
- Characterisation of Human Dipeptidyl Peptidase IV Expressed in Pichia pastoris. A Structural and Mechanistic Comparison between the Recombinant Human and the Purified Porcine Enzyme
- Effects of Iron Limitation on the Respiratory Chain and the Membrane Cytochrome Pattern of the Euryarchaeon Halobacterium salinarum
- Anti-Mouse GPI-PLD Antisera Highlight Structural Differences between Murine and Bovine GPI-PLDs
- Substrate Specificity of Glutaminyl Cyclases from Plants and Animals
- The Binding of Haptoglobin to Apolipoprotein AI: Influence of Hemoglobin and Concanavalin A
- A Novel Water-Soluble and Cell-Permeable Calpain Inhibitor Protects Myocardial and Mitochondrial Function in Postischemic Reperfusion
- Potent Bivalent Inhibition of Human Tryptase-? by a Synthetic Inhibitor
- Aza-Peptide Epoxides: Potent and Selective Inhibitors of Schistosoma mansoni and Pig Kidney Legumains (Asparaginyl Endopeptidases)
- Semisynthesis and Application of Carboxyfluorescein-Labelled Biologically Active Human Interleukin-8
- Acknowledgment
- Content Index
- Author Index
- Subject Index
