Ranolazine Attenuates the Enhanced Reverse Na+-Ca2+ Exchange Current via Inhibiting Hypoxia-Increased Late Sodium Current in Ventricular Myocytes

Abstract

Abstract. Ranolazine (RAN), a novel antianginal agent, inhibits the increased late sodium current (I Na.L ) under many pathological conditions. In this study, the whole-cell patch-clamp technique was used to explore the effects of RAN on I Na.L and reverse Na + /Ca 2+ exchange current (I NCX ) in rabbit ventricular myocytes during hypoxia. Tetrodotoxin (TTX) at 2 mM or RAN at 9 mM decreased significantly I Na.L and reverse I NCX under normoxia and RAN had no further effects on both currents in the presence of TTX. RAN (3, 6, and 9 mM) attenuated hypoxia-increased I Na.L and reverse I NCX in a concentration-dependent manner. Hypoxia-increased I Na.L and reverse I NCX were inhibited by 2 mM TTX, whereas 9 mM RAN applied sequentially did not further decrease both currents. In another group, after both currents were decreased by 9 mM RAN, 2 mM TTX had no further effects in the presence of Ran. In monophasic action potential (MAP) recording, early after-depolarizations (EADs) were suppressed by RAN (9 mM) during hypoxia. In conclusion, RAN decreased reverse I NCX by inhibiting I Na.L in normoxia, concentration-dependently attenuated the increase of I Na.L , which thereby decreased the reverse I NCX , and obviously relieved EADs during hypoxia.

Modulation of late sodium current by Ca2+–calmodulin‐dependent protein kinase II, protein kinase C and Ca2+ during hypoxia in rabbit ventricular myocytes

“…; Wang et al . ). Results of recent studies indicate that increases of [Ca 2+ ] i and I Na,L in ventricular myocytes act in a positive but pathological feedback system, involving PKC and CaMII, to create electrical and mechanical dysfunction (Maltsev & Undrovinas, ; Maltsev et al .…”

Protein kinase C and Ca2+–calmodulin‐dependent protein kinase II mediate the enlarged reverse INCX induced by ouabain‐increased late sodium current in rabbit ventricular myocytes

“…The increase of reverse I NCX induced by hypoxia was inhibited by either 2 μ m TTX or 9 μ m ranolazine, and this effect is believed to be secondary to reductions of I NaL and cytoplasmic Na + loading (Wang et al . ). It is therefore unclear whether stimulation of I NaL is part of the therapeutic response to glycoside or a manifestation of glycoside toxicity, although it is well documented that I NaL can lead to increases of [Na + ] i and I NCX ‐mediated [Ca 2+ ] i overload (Soliman et al .…”