The efficacy of Ranolazine on E1784K is altered by temperature and calcium

Scientific Reports
Mena AbdelsayedPeter C Ruben

Abstract

E1784K is the most common mixed syndrome SCN5a mutation underpinning both Brugada syndrome type 1 (BrS1) and Long-QT syndrome type 3 (LQT3). The charge reversal mutant enhances the late sodium current (INa) passed by the cardiac voltage-gated sodium channel (NaV1.5), delaying cardiac repolarization. Exercise-induced triggers, like elevated temperature and cytosolic calcium, exacerbate E1784K late INa. In this study, we tested the effects of Ranolazine, the late INa blocker, on voltage-dependent and kinetic properties of E1784K at elevated temperature and cytosolic calcium. We used whole-cell patch clamp to measure INa from wild type and E1784K channels expressed in HEK293 cells. At elevated temperature, Ranolazine attenuated gain-of-function in E1784K by decreasing late INa, hyperpolarizing steady-state fast inactivation, and increasing use-dependent inactivation. Both elevated temperature and cytosolic calcium hampered the capacity of Ranolazine to suppress E1784K late INa. In-silico action potential (AP) simulations were done using a modified O'Hara Rudy (ORd) cardiac model. Simulations showed that Ranolazine failed to shorten AP duration, an effect augmented at febrile temperatures. The drug-channel interaction is clearly af...Continue Reading

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Citations

Feb 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mohamed-Yassine AmarouchHugues Abriel
Aug 28, 2020·Molecular and Cellular Biochemistry·Muhammad Afzal
Oct 27, 2018·Frontiers in Physiology·Wenjia LiAijun Sun
Oct 31, 2020·Basic & Clinical Pharmacology & Toxicology·Samuel S Beserra, Danilo Roman-Campos

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