Altered myocardial thin-filament function in the failing Dahl salt-sensitive rat heart: Amelioration by endothelin blockade

Abstract

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.