Abstract
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. Oxidative stress in the DOCA-salt model may increase late I(Na), resulting in diastolic dysfunction amenable to treatment with ranolazine. 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. 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.
Highlights
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. (Circ Res. 2012;110:841-850.)
Diastolic dysfunction is characterized by prolonged relaxation of the myocardium, and, untreated, can lead to the clinical syndrome of heart failure with preserved ejection fraction (HFpEF)
Ca2ϩ is removed from the cytosol during diastole by the sarcoplasmic reticular Ca2ϩ-ATPase (SERCA) and the Naϩ/Ca2ϩ exchanger (NCX)
Summary
An expanded Methods section is available in the online-only Data Supplement.Generation of DOCA-Salt Mouse ModelPreviously, we have shown that this model leads to mild hypertension, myocardial oxidative stress, and diastolic dysfunction.[20]. An expanded Methods section is available in the online-only Data Supplement. We have shown that this model leads to mild hypertension, myocardial oxidative stress, and diastolic dysfunction.[20] A gradual and mild elevation in blood pressure was induced by unilateral nephrectomy, subcutaneous implantation of a controlledrelease DOCA pellet (0.7 mg/d; Innovative Research of America, Sarasota, FL) and substituting drinking water with 1.05% saline. Control animals underwent a sham operation, had placebo pellet implantation, and received water without salt. Noninvasive echocardiography, and myocyte isolation were done on postoperative day 14 –18 for DOCA-salt and control mice. All experiments were approved by the University of Illinois at Chicago Animal Care and Use Committee
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