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Cardiovascular Research 1997 35(1):60-67; doi:10.1016/S0008-6363(97)00099-0
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

MDL-28170, a membrane-permeant calpain inhibitor, attenuates stunning and PKC{varepsilon} proteolysis in reperfused ferret hearts

Ferdinand Urthalera,*, Paul E Wolkowicza, Stanley B Digernessb, Kevin D Harrisb and Alfred A Walkera

aDivision of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Zeigler Research Building, 703 South 19th Street, Birmingham, AL 35294, USA
bCardiovascular and Thoracic Surgery, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

* Corresponding author. Tel. +1 205 934-4622, Fax +1 205 975-6237.

Objectives: This paper tests the hypothesis that calpains are activated in the ischemic (I)/reperfused (R) heart and contribute to myocardial stunning. Methods: Isolated ferret hearts were Langendorff perfused isovolumically, and subjected to 20 min of global I followed by 30 min of R in the presence or absence of 0.2 µM MDL-28170, a membrane-permeant calpain inhibitor. Right trabeculae then were isolated from these hearts, skinned chemically, and pCa2+-force curves obtained. Samples of left ventricle were extracted, subjected to SDS-PAGE, and Western analyzed for PKC{varepsilon} and PKM{varepsilon}. Results: Perfused ferret hearts exhibit a 43% decline in left ventricular developed pressure during R. Pre-treatment of hearts with MDL-28170 prior to I significantly improves function during R. Trabecular myofilaments from normal hearts have a KD for Ca2+ of 6.27±0.06; I/R decreased the KD to 6.09±0.04; trabeculae from I/R hearts pre-treated with MDL-28170 have a KD of 6.28±0.04. Western analysis shows ferret hearts to contain a single {approx}96 kDa species of PKC{varepsilon}. I/R hearts contain the native PKC{varepsilon} and a {approx}25 kDa smaller species of PKC{varepsilon}, which corresponds to PKM{varepsilon}, the calpain proteolyzed form of PKC{varepsilon}. Pre-treatment of I/R hearts with MDL-28170 markedly diminishes PKM{varepsilon} in reperfused hearts. Conclusions: Mechanical stunning during R is sensitive to MDL-28170. Depressed mechanical function is reflected in a hyposensitization of trabecular myofilaments to Ca2+. Western analysis shows that PKM{varepsilon} is present in R hearts.

KEYWORDS Ferret; Calpain; Calpain inhibitors; MDL-28170; Stunning; PKC{varepsilon}; PKM{varepsilon}


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