Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation

David G. Soergel, Dimitrios Georgakopoulos, Linda B. Stull, David A. Kass, Anne M. Murphy

Research output: Contribution to journalArticlepeer-review

Abstract

Myocardial stunning is a form of acute reversible cardiac dysfunction that occurs after brief periods of ischemia and reperfusion. In several animal models, stunning is associated with proteolytic truncation of troponin I (TnI). Mice expressing the same proteolytic TnI fragment [TnI-(1-193)] demonstrate cardiac depression with a decreased maximal calcium-activated tension. We therefore hypothesized preferential improvement in mice expressing TnI-(1-193) treated with the calcium-sensitizing drug EMD-57033. TnI-(1-193) and nontransgenic myofibrils exhibited significant sensitization to calcium in Mg-ATPase assays after EMD-57033 exposure. However, only transgenic myofibrils exhibited an increase in maximal activity (P = 0.023). EMD-57033 also increased maximal calcium-activated force in TnI-(1-193) muscle, such that it was comparable to nontransgenic cardiac muscle. EMD-57033 enhanced in vivo systolic function modestly in controls but had a marked effect in transgenic mice, with an almost threefold greater leftward shift of the end-systolic pressure-volume relation (P = 0.0005). These data indicate a targeted efficacy of EMD-57033 in offsetting the contractile defect in TnI-(1-193) mice, and this may have therapeutic implications in models displaying this myofilament defect.

Original languageEnglish (US)
Pages (from-to)H1785-H1792
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume286
Issue number5 55-5
DOIs
StatePublished - May 2004

Keywords

  • Contractile function
  • Heart failure
  • Inotropic agents
  • Myocardial stunning

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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