Effects of Ranolazine on Norepinephrine-Induced Cell Death by Inhibition of
the β-adrenoceptor Signal Pathway in Cardiomyocytes
Authors
Kyung-Eun Kim ; Heesang Song ; Hye-Jung Kim ; Min-Ji Cha ; Byeong-Wook Song ; Eunju Choi ; Onju Ham ; ChangYeon Lee ; SeongYong Choi ; Se-Yeon Lee ; Yangsoo Jang ; Tae Woong Kim ; Ki-Chul Hwang
Citation
TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Vol.6(12) : 1148-1158, 2009
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