Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation.
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.
Soergel
David G
DG
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Georgakopoulos
Dimitrios
D
Stull
Linda B
LB
Kass
David A
DA
Murphy
Anne M
AM
D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009132:Muscles / Q000502:physiology; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology; D009210:Myofibrils / Q000201:enzymology; D011804:Quinolines / Q000494:pharmacology*; D013599:Systole / Q000187:drug effects*; D013829:Thiadiazines / Q000494:pharmacology*; D019210:Troponin I / Q000235:genetics* / Q000494:pharmacology
D002316:Cardiotonic Agents; D011804:Quinolines; D013829:Thiadiazines; D019210:Troponin I; C070609:EMD 53998; D017301:Ca(2+) Mg(2+)-ATPase