EMD 57033 belongs to a chemical group known as “myofilament calcium sensitizers”. We hypothesize that troponin I (TnI) isoform switching alters the effect of EMD 57033. To test this hypothesis, we studied transgenic mice (TG) overespressing the fetal isoform of TnI: ssTnI.
METHODS: Triton X-100 skinned fiber bundles prepared from left ventricular papillary muscle from non-transgenic mice (NTG) and TG mice were mounted in a force transducer apparatus. Sarcomere length was set at 2 μm. Force was measured in fibers immersed in buffers with increasing calcium concentrations(pCa 8.0-4.5; pCa=-log[Ca2+]) with and without 3μM EMD 57033. Data were analyzed, fitted to a sigmoidal curve and plotted using the GraphPad software.
RESULTS: The figure shows the dependence of force on pCa expressed as% control maximum force for TG and NTG preparations, with and without EMD. TG hearts showed a significant increase in Ca2+ sensitivity [pCa50] is 5.57±0.01 in NTG (n=7) and 5.87±0.01 in TG myofilaments (n=7)]. Hill coefficient was 3.05±0.10 in NTG and 2.20±0.03 in TG hearts. EMD (3 μM) caused a significant increase in pCa50 in both groups (pCa50 of 0.30 in NTG and 0.14 in TG fibers), and a small but significant increase in control maximal force (pCa 4.5) in the TG group.
CONCLUSIONS: The attenuated effect of EMD 57033 observed in TG mouse hearts over-expressing ssTnI suggest that TnI is involved in the mechanism of action of this drug. Furthermore, the effect of EMD may differ between fetal and adult hearts due to developmentally related TnI isoform expression.
(Spon by: George R. Honig)
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Arteaga, G., Wolska, B., Martin, A. et al. The Effect of EMD 57033 is Decreased in Myofilaments from Transgenic Mouse Hearts over-expressing Slow Skeletal Troponin I (ssTnI) • 81. Pediatr Res 43, 17 (1998) doi:10.1203/00006450-199804001-00102