Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity

Joshua D. Lovelock, Michelle M. Monasky, Euy Myoung Jeong, Harvey A. Lardin, Hong Liu, Bindiya G. Patel, Domenico M. Taglieri, Lianzhi Gu, Praveen Kumar, Narayan Pokhrel, Dewan Zeng, Luiz Belardinelli, Dan Sorescu, R. John Solaro, Samuel C. Dudley

Research output: Contribution to journalArticle

Abstract

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; PNa 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.

Original languageEnglish
Pages (from-to)841-850
Number of pages10
JournalCirculation Research
Volume110
Issue number6
DOIs
Publication statusPublished - Mar 16 2012

Keywords

  • diastole
  • myofilaments
  • oxidative stress
  • ranolazine

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Lovelock, J. D., Monasky, M. M., Jeong, E. M., Lardin, H. A., Liu, H., Patel, B. G., Taglieri, D. M., Gu, L., Kumar, P., Pokhrel, N., Zeng, D., Belardinelli, L., Sorescu, D., Solaro, R. J., & Dudley, S. C. (2012). Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity. Circulation Research, 110(6), 841-850. https://doi.org/10.1161/CIRCRESAHA.111.258251