Dexamethasone is the most clinically used glucocorticoid with an established role in the treatment of a wide spectrum of inflammatory‐related diseases. While the therapeutic actions are well known, dexamethasone treatment causes a number of cardiovascular side effects, which are complex, frequent and, in some particular cases, clinically unnoticeable. Thus, we investigated whether a therapeutic regimen of dexamethasone affects cardiac arrhythmogenesis and/or promote cardiac remodeling, focusing on the contribution of reactive oxygen species (ROS). Male Wistar rats were treated with dexamethasone (2 mg/kg, i.p.) for 7 days. Afterward, hemodynamic measurements, autonomic modulation, left ventricular function, cardiac fibrosis, superoxide (O2·−) generation, superoxide dismutase (SOD) activity, lipid peroxidation (TBARS) and arrhythmias were evaluated. Here, we show that dexamethasone increases blood pressure, associated with enhanced cardiac and vascular sympathetic modulation. Moreover, a marked increase in the cardiac O2·− generation was observed, whereas the enhanced SOD activity did not prevent the higher levels of lipid peroxidation in dexamethasone group. Although preserved ventricular contractility and β‐adrenergic responsiveness, we found that dexamethasone‐treated rats display greater interstitial and perivascular fibrosis than control. Besides that, despite the absence of arrhythmias at basal condition, we demonstrated by in vivo and ex vivo approaches that dexamethasone‐treated rats are more susceptible to develop harmful forms of ventricular arrhythmias, when challenged with pharmacological drugs or burst pacing‐induced arrhythmias. Notably, concomitant treatment with apocynin, an inhibitor of NADPH oxidase, prevented these ectopic ventricular events. Taken together, our data revealed that the dexamethasone treated rats were hypertensive and their hearts become arrthymogenic, in addition, our results uncover the pivotal role of ROS‐generating NADPH oxidases in the arrhythmias vulnerability.Support or Funding InformationFapitec/SE ; CAPES ; CNPq and Estácio UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.