© 1996 American Heart Association, Inc.
Articles |
Intrinsic Myofilament Alterations Underlying the Decreased Contractility of Stunned Myocardium
A Consequence of Ca2+-Dependent Proteolysis?
From the Division of Cardiology (W.D.G., Y.L., E.M.), Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md, and the Department of Pharmacology (R.M.), Medical College of Ohio, Toledo.
Correspondence to Eduardo Marban, MD, PhD, Room 844, Ross Building, 720 Rutland Ave, Baltimore, MD 21205. E-mail marban@welchlink.welch.jhu.edu.
Abstract We investigated the mechanism of the decreased myofilament Ca2+ responsiveness in stunned myocardium. The steady state force-[Ca2+] relationship was measured before and after skinning in thin ventricular trabeculae from control or stunned (20 minutes of ischemia, 20 minutes of reperfusion) rat hearts. [Ca2+]i was determined using microinjected fura 2 salt in intact muscles, whereas the myofilaments of chemically skinned trabeculae were activated directly with solutions of varied [Ca2+]. Maximal Ca2+-activated force (Fmax) before and after skinning was identical within either the control or stunned groups but was markedly depressed in both groups of stunned trabeculae (P<.001). After ischemia and reperfusion, the [Ca2+] required for 50% of maximal activation (Ca50) was increased in both intact (control, 0.60±0.09 µmol/L; stunned, 0.85±0.09 µmol/L; P<.001) and skinned (control, 1.13±0.24 µmol/L; stunned, 1.39±0.21 µmol/L; P=.0025) trabeculae. These data indicate that the decreased Ca2+ responsiveness of stunned myocardium is due to intrinsic alterations of the myofilaments. Therefore, we tested the hypothesis that activation of proteases by reperfusion-induced Ca2+ overload decreases the Ca2+ responsiveness of the cardiac myofilaments. Force-[Ca2+] relations were compared before and 5 to 30 minutes after direct exposure of skinned trabeculae to calpain I (18 µg/mL, 20 minutes at [Ca2+]=10.8 µmol/L), a Ca2+-activated protease that is present in myocardium. Calpain I reduced Fmax from 94.3±8.3 to 56±8.5 mN/mm2 while increasing Ca50 from 0.94±0.11 to 1.36±0.21 µmol/L (P<.01). Calpastatin, a specific calpain inhibitor, prevented the effects of calpain I on skinned trabeculae. The results show that the reduced Ca2+ responsiveness of stunned myocardium reflects alteration of the myofilaments themselves, not of soluble cytosolic factors, which can be faithfully reproduced by exposure to Ca2+-dependent protease.
Key Words: force-[Ca2+] relation • contractile proteins • calpain I • myocardial ischemia/reperfusion
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