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. 2021 Jun 2;143(22):2188–2204. doi: 10.1161/CIRCULATIONAHA.121.053350

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© 2021 The Authors.

Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

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Figure 4. — Empagliflozin improves cardiomyocyte calcium handling induced by the late component of the cardiac sodium channel current (late-I_Na) activation. A through D, Representative traces showing that empagliflozin reversibly reduces the incidence of spontaneous calcium events induced by the late-I_Na activator veratridine. Representative 50-s sections of calcium transient recordings (1 Hz field stimulation) observed in the same myocyte under (A) control conditions, (B) during the application of 20 nmol/L veratridine, (C) with veratridine and 1 µmol/L empagliflozin, and (D) with veratridine alone after washout of empagliflozin. F through H, Representative traces of calcium transient recordings from myocytes (1 Hz field stimulation) showing that tetrodotoxin (TTX; 5 µmol/L), ranolazine (10 µmol/L) and lidocaine (50 µmol/L) also reduce the incidence of veratridine-induced spontaneous calcium events. E, Box plot of grouped data indicating the number of spontaneous calcium transients observed in 50-s segments in control conditions, during application of veratridine, or during application of veratridine and empagliflozin (n=28 myocytes from 7 heart isolations). I through K, Box plots of grouped data indicating the number of spontaneous calcium events either in control conditions, during application of veratridine alone or veratridine plus TTX (I), ranolazine (J), or lidocaine (K). n=6 or 7 myocytes per group from 5 heart isolations. L, Representative whole-cell patch-clamp recording and grouped data (n=5 cells) showing the lack of reverse-mode NCX1.1 inhibition by empagliflozin (NCX1.1 = sodium/calcium exchanger isoform 1.1). ***P<0.001, **P<0.01, paired t test.