Rapún, JosuPérez Martín, SaraCámara Checa, AnabelSan José, GorkaNúñez Fernández, RobertoCrespo García, María TeresaHoban, AdamRubio Alarcón, MarcosMartínez Blanco, ElenaTamargo Menéndez, JuanDíez Guerra, F. JavierLópez, BegoñaGómez García, RicardoGonzález, ArantxaDelpón Mosquera, María EvaCaballero Collado, Ricardo2025-04-292025-04-292025-05Rapún J, Pérez-Martín S, Cámara-Checa A, San José G, Núñez-Fernández R, Crespo-García T, et al. Two concurrent mechanisms are responsible for the INa increase produced by dapagliflozin and empagliflozin in healthy and heart failure cardiomyocytes. Biomedicine & Pharmacotherapy 2025;186:117984. https://doi.org/10.1016/j.biopha.2025.117984.10.1016/j.biopha.2025.117984https://hdl.handle.net/20.500.14352/119732Abstract Dapagliflozin and empagliflozin exert many cardiovascular protective actions in heart failure (HF) patients. HF-induced electrical remodelling decreases the expression of Nav1.5 channels (encoded by SCN5A) that generate the cardiac Na+ current (INa) impairing excitability and promoting arrhythmias. We aimed to mechanistically decipher the peak INa increase produced by dapagliflozin and empagliflozin in healthy and HF cardiomyocytes. We recorded macroscopic and single-channel currents and action potentials (AP) using the patch-clamp technique and generated a mouse model of HF with reduced ejection fraction by transverse aortic constriction (TAC). Single-channel recordings showed that dapagliflozin and empagliflozin (1 μM) increased the open probability (Po) of Nav1.5 channels by augmenting channel re-openings and the number of traces with openings and by doubling the open time constant, respectively. Both drugs increased SCN5A mRNA levels and the membrane expression of Nav1.5 channels. Empagliflozin also enhanced the cytoplasmic mobility of Nav1.5 channels. Molecular modelling and site-directed mutagenesis analysis demonstrated that both drugs bind to a previously unknown site at the Nav1.5 DIII-DIV fenestration. Dapagliflozin and empagliflozin hyperpolarized the resting membrane potential and increased the action potential amplitude in human cardiomyocytes derived from induced pluripotent stem cells. Importantly, in TAC cardiomyocytes dapagliflozin and empagliflozin restored the HF-reduced peak INa to control levels. Dapagliflozin and empagliflozin bind to a novel site within cardiac Nav1.5 increasing INa by augmenting the Po and the membrane expression of the channels. We hypothesized that this unique effects could be of interest for the treatment of arrhythmias associated with decreased Nav1.5 channel expression.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://doi.org/10.1016/j.biopha.2025.11798440101587https://www.sciencedirect.com/science/article/pii/S0753332225001787?via%3Dihubopen access615.9DapagliflozinEmpagliflozinNa+ currentPatch-clampCardiacFarmacología (Medicina)3209 Farmacología