on January 6, 2003
Published online before print January 6, 2003, doi: 10.1161/01.CIR.0000046267.16901.E9
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Submitted on July 19, 2002
From the Cardiology Unit, Department of Medicine (T.N., K.J.B., J.A.G., M.M.L., P.V.), and Department of Molecular Physiology and Biophysics (K.A.P., P.V.), University of Vermont, Burlington, Vt, and the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (Y.K.). * To whom correspondence should be addressed. E-mail: vanburen{at}physiology.med.uvm.edu.
Background—Dahl salt-sensitive rats fed a high-salt diet develop compensated left ventricular hypertrophy followed by a transition to myocardial failure. We previously reported an increase in a troponin T isoform (TnT3) and a decrease in TnT phosphorylation in failing Dahl salt-sensitive rat hearts compared with low-salt controls. The present study was undertaken to determine whether the thin filament plays a role in depression of the contractile machinery in this model. Methods and Results—Native thin filaments (NTFs) were isolated intact from rats with compensated left ventricular hypertrophy and failing hearts and compared with age-matched controls. NTF velocity was measured as a function of free calcium in the in vitro motility assay. Maximal velocity was similar in all groups. However, NTFs from failing hearts demonstrated a reduction in calcium sensitivity compared with controls, as reflected in the pCa50 (5.88±0.05 versus 6.22±0.05, respectively, P<0.001). No difference in thin-filament motility (pCa50, Vmax) was observed in rats with compensated left ventricular hypertrophy compared with controls. Protein kinase A treatment of NTFs from control and failing hearts had no effect on thin-filament calcium sensitivity. However, the endothelin receptor blocker bosentan prevented the reduction in thin-filament calcium sensitivity found in failing hearts. Conclusions—The thin filament is a key modulator of contractile performance in the transition to failure in the Dahl salt-sensitive rat model. The alteration in thin-filament function may be mediated by an endothelin-triggered pathway potentially affecting protein kinase C signaling.
Revised on October 14, 2002
Accepted on October 15, 2002
Altered Myocardial Thin-Filament Function in the Failing Dahl Salt-Sensitive Rat Heart. Amelioration by Endothelin Blockade
Teruo Noguchi MD,
Key words: heart failure • endothelin • troponin • phosphorylation • motility
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