Effects of ranolazine on norepinephrine-induced cell death by inhibition of the β-adrenoceptor signal pathway in cardiomyocytes

Kyung Eun Kim, Heesang Song, Hye Jung Kim, Min Ji Cha, Byeong Wook Song, Eunju Choi, Onju Ham, Chang Yeon Lee, Seong Yong Choi, Se Yeon Lee, Yangsoo Jang, Tae Woong Kim, Ki Chul Hwang

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Abstract

Ranolazine blocks the intracellular sodium and calcium overload accompanying myocardial ischemia and is used in antianginal therapy. The effects of ranolazine on the β-adrenoceptor signal transduction system are poorly understood. The present study was designed to confirm whether the mechanism was associated with a β-adrenoceptor antagonist activity of ranolazine on norepinephrine (NE)-induced cardiomyocytes. After cardiomyocytes were preincubated with propranolol and ranolazine, cells were treated with NE for 24 hours. The phosphorylation of ERK was decreased by ranolazine treatment, in comparison with NE-only treated cells. Intracellular Ca2+and Na + levels decreased by 40±3% and 17±0.5%, respectively, compared to control. Ranolazine decreased expression of Ca2+/ calmodulin-dependent protein kinase II (CaMKII) by 57±4%, the Na +-Ca2+exchanger (NCX) by 21±0.5%, and the ryanodine receptor 2 (RyR2) by 47±1.5%, compared with NE-only treated control cells. Ranolazine also increased expression of the L-type Ca2+channel (LTCC) by 48±3.5%, phospholamban (PLB) levels by 45±2%, and the sarcoplasmic reticulum Ca2+ATPase 2a (SERCA2a) by 36±0.5%, compared to levels in NE-only stimulated cells. The number of annexin V/PI-positive cells fell by 39±1.5% after ranolazine treatment, compared with levels in NE-only treated control cells. Ranolazine also inhibited apoptosis by regulating the levels of the pro-apoptotic factor Bax, the anti-apoptotic factor Bcl-2, and cytochrome C release. These results demonstrate that ranolazine had an effect on NE-induced cell death through inhibition of the β-adrenoceptor signal pathway in cardiomyocytes.

Original languageEnglish
Pages (from-to)1148-1158
Number of pages11
JournalTissue Engineering and Regenerative Medicine
Volume6
Issue number12
Publication statusPublished - 2009 Sep

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Biomedical Engineering

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    Kim, K. E., Song, H., Kim, H. J., Cha, M. J., Song, B. W., Choi, E., Ham, O., Lee, C. Y., Choi, S. Y., Lee, S. Y., Jang, Y., Kim, T. W., & Hwang, K. C. (2009). Effects of ranolazine on norepinephrine-induced cell death by inhibition of the β-adrenoceptor signal pathway in cardiomyocytes. Tissue Engineering and Regenerative Medicine, 6(12), 1148-1158.