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Am J Physiol Heart Circ Physiol (December 23, 2003). doi:10.1152/ajpheart.00170.2003
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Submitted on February 21, 2003
Accepted on December 18, 2003

Augmented Systolic Response to the Calcium Sensitizer EMD 57033 in a Transgenic Model with Troponin I Truncation

David G. Soergel1, Dimitrios Georgakopoulos2, Linda B. Stull3, David A. Kass2, and Anne M. Murphy1*

1 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: murphy{at}jhmi.edu.

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. Mice expressing the same proteolytic TnI fragment (TnI1-193) demonstrate cardiac depression with a decreased maximal calcium activated tension. We therefore hypothesized that TnI1-193 mice would preferentially improve with the calcium sensitizing drug, EMD 57033. Both TnI1-193 and non-transgenic myofibrils exhibited significant sensitization to calcium in Mg ATPase assays following 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 TnI1-193 muscle such that it was comparable to non-transgenic cardiac muscle. EMD 57033 enhanced in vivo systolic function modestly in controls, but had a marked effect in transgenic mice, with an almost 3 fold greater leftward shift of the endsystolic pressure volume relationship (p = 0.0005). These data indicate a targeted efficacy of EMD 57033 in offsetting the contractile defect in TnI1-193 mice, and this may have therapeutic implications in models displaying this myofilament defect.




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