RATIONALE: Previously, we demonstrated that a deoxycorticosterone acetate 
(DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and 
diastolic dysfunction with preserved systolic function. Oxidative stress has 
been shown to increase late inward sodium current (I(Na)), reducing the net 
cytosolic Ca(2+) efflux.
OBJECTIVE: Oxidative stress in the DOCA-salt model may increase late I(Na), 
resulting in diastolic dysfunction amenable to treatment with ranolazine.
METHODS AND RESULTS: Echocardiography detected evidence of diastolic dysfunction 
in hypertensive mice that improved after treatment with ranolazine (E/E':sham, 
31.9 ± 2.8, sham+ranolazine, 30.2 ± 1.9, DOCA-salt, 41.8 ± 2.6, and 
DOCA-salt+ranolazine, 31.9 ± 2.6; P=0.018). The end-diastolic pressure-volume 
relationship slope was elevated in DOCA-salt mice, improving to sham levels with 
treatment (sham, 0.16 ± 0.01 versus sham+ranolazine, 0.18 ± 0.01 versus 
DOCA-salt, 0.23 ± 0.2 versus DOCA-salt+ranolazine, 0.17 ± 0.0 1 mm Hg/L; 
P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with 
ranolazine (DOCA-salt, 0.18 ± 0.02, DOCA-salt+ranolazine, 0.13 ± 0.01, sham, 
0.11 ± 0.01, sham+ranolazine, 0.09 ± 0.02 seconds; P=0.0004). Neither late I(Na) 
nor the Ca(2+) transients were different from sham myocytes. Detergent extracted 
fiber bundles from DOCA-salt hearts demonstrated increased myofilament response 
to Ca(2+) with glutathionylation of myosin binding protein C. Treatment with 
ranolazine ameliorated the Ca(2+) response and cross-bridge kinetics.
CONCLUSIONS: Diastolic dysfunction could be reversed by ranolazine, probably 
resulting from a direct effect on myofilaments, indicating that cardiac 
oxidative stress may mediate diastolic dysfunction through altering the 
contractile apparatus.