Empagliflozin Reduces Arrhythmic Events and Improves Ca²⁺ Transient in Hypoxia‐induced Injury Rat Cardiomyocytes

Abstract

Sodium glucose cotransporter 2 inhibitors (SGLT2i) emerged as promising antidiabetic drugs that decreasing glucose reabsorption as well as effectively reduce heart failure hospitalization and cardiovascular death in type 2 diabetes patients. Recently, it has been shown that the SGLT2i also exert beneficial cardiovascular effects in non‐diabetic heart failure patients. However, the cardioprotective mechanisms of these drugs remain unknow. The present study aimed to test the hypothesis that the cardioprotective effects of SGLT2i empagliflozin (EMPA) may be associated with changes of cardiac electrical activity and Ca2+ homeostasis in hypoxia‐induced injury ventricular myocytes. Cardiomyocytes isolated from neonatal rats submitted to chemical hypoxia (200 μM CoCl2) or normoxia were incubated with EMPA (1 μM) or vehicle during 24 hours. Electrophysiological recordings were obtained using multielectrode array (MEA) system and intracellular microelectrode. Cytoplasmic calcium transients were investigated via fura‐2 fluorescence. Compared with vehicle, MEA analysis showed a significant decrease in field potential duration in EMPA‐group in both conditions [hypoxia: 83 ± 4 (N=19) vs. 37 ± 3 (N=44); normoxia: 213 ± 5 (N=53) vs. 62 ± 4 (N=36) ms, p<0.001]. EMPA reduced action potential duration at 30%, 50% and 90% repolarization (APD30, APD50 and APD90, respectively) in hypoxia [APD30: 109 ± 2 (N=41) vs. 98 ± 1 (N=30); APD50: 150 ± 3 (N=41) vs. 134 ± 1 (N=30); APD90: 292 ± 4 (N=41) vs. 271 ± 5 (N=30) ms, p<0.05] and normoxia [APD30: 94 ± 2 (N=30) vs. 81 ± 1 (N=39); APD50: 129 ± 2 (N=30) vs. 111 ± 1 (N=39); APD90: 259 ± 4 (N=30) vs. 244 ± 4 (N=39) ms, p<0.05]. No differences were observed in amplitude and resting membrane potential. Action potential recordings also revealed that the percentage of arrhythmic cells was lower in EMPA‐group in both conditions [hypoxia: 19 (N=41) vs. 10 (N=30) %; normoxia: 7 (N=30) vs. 3 (N=39) %]. In addition, EMPA significantly increased in Ca2+ transient amplitude in hypoxia [F/F0: 0.16 ± 0.01 (N=21) vs. 0.21 ± 0.01 (N=19), p<0.01] and normoxia [F/F0: 0.17 ± 0.01 (N=19) vs. 0.23 ± 0.01 (N=20) μM, p<0.01]. These results suggest that EMPA modulates electrical activity, reduces arrhythmic events and improves Ca2+ transient, which may contribute to cardioprotective effects of SGLT2i. Support or Funding Information FAPESP and CNPq