Ranolazine Improves Cardiac Diastolic Dysfunction Through Modulation of Myofilament Calcium Sensitivity

被引:153
作者
Lovelock, Joshua D. [1 ,2 ,4 ]
Monasky, Michelle M. [3 ]
Jeong, Euy-Myoung [1 ,2 ]
Lardin, Harvey A. [1 ,2 ]
Liu, Hong [1 ,2 ]
Patel, Bindiya G. [3 ]
Taglieri, Domenico M. [3 ]
Gu, Lianzhi [1 ,2 ]
Kumar, Praveen [1 ,2 ]
Pokhrel, Narayan [1 ,2 ]
Zeng, Dewan [5 ]
Belardinelli, Luiz [5 ]
Sorescu, Dan [4 ]
Solaro, R. John [3 ]
Dudley, Samuel C., Jr. [1 ,2 ]
机构
[1] Univ Illinois, Cardiol Sect, Chicago, IL 60612 USA
[2] Jesse Brown VA Med Ctr, Chicago, IL USA
[3] Univ Illinois, Dept Physiol & Biophys, Chicago, IL 60612 USA
[4] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA
[5] Gilead, Palo Alto, CA USA
关键词
diastole; ranolazine; oxidative stress; myofilaments; LATE SODIUM CURRENT; PRESERVED EJECTION FRACTION; RAT VENTRICULAR MYOCYTES; SKELETAL TROPONIN-I; BINDING-PROTEIN-C; HEART-FAILURE; HYDROGEN-PEROXIDE; CONTRACTILE DYSFUNCTION; ANGINA-PECTORIS; FORCE DECLINE;
D O I
10.1161/CIRCRESAHA.111.258251
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 Ca2+ 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, tau, 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 Ca2+ transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca2+ with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca2+ 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. (Circ Res. 2012; 110: 841-850.)
引用
收藏
页码:841 / U114
页数:26
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