Intrinsic Myofilament Alterations Underlying the Decreased Contractility of Stunned Myocardium: A Consequence of Ca2+-Dependent Proteolysis?

Wei Dong Gao, Yongge Liu, Ronald Mellgren, Eduardo Marban

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)455-465
Number of pages11
JournalCirculation research
Volume78
Issue number3
DOIs
StatePublished - Mar 1996

Keywords

  • Calpain I
  • Contractile proteins
  • Force-[Ca] relation
  • Myocardial ischemia/reperfusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Intrinsic Myofilament Alterations Underlying the Decreased Contractility of Stunned Myocardium: A Consequence of Ca<sup>2+</sup>-Dependent Proteolysis?'. Together they form a unique fingerprint.

Cite this