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 cases, clinically unnoticeable. Here, we investigated whether a therapeutic regimen of dexamethasone affects cardiac arrhythmogenesis, focusing on the contribution of Nox-derived 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, reactive oxygen species (ROS) generation, Nox protein expression, superoxide dismutase (SOD) and catalase activities, and arrhythmias incidence 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 ROS generation was observed, whereas the enhanced SOD activity did not prevent the higher levels of lipid peroxidation in the dexamethasone group. On the other hand, increased cardiac Nox 4 expression and hydrogen peroxide decomposition rate was observed in dexamethasone-treated rats, while Nox 2 remained unchanged. Interestingly, although preserved ventricular contractility and β-adrenergic responsiveness, we found that dexamethasone-treated rats displayed greater interstitial and perivascular fibrosis than control. Surprisingly, 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. Together, our results reveal that hearts become arrhythmogenic during dexamethasone treatment, uncovering the pivotal role of ROS-generating NADPH oxidases for arrhythmias vulnerability.

中文翻译：

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NOX依赖性活性氧的产生是地塞米松治疗大鼠心律失常易感性的基础。

地塞米松是临床上使用最广泛的糖皮质激素，在治疗各种炎症相关疾病中起着确定的作用。尽管治疗作用是众所周知的，但地塞米松治疗会引起许多心血管副作用，这些副作用复杂，频繁，在某些情况下在临床上不明显。在这里，我们研究了地塞米松的治疗方案是否会影响心律失常的发生，重点是Nox衍生的活性氧（ROS）的贡献。用地塞米松（2 mg / kg，腹膜内）治疗雄性Wistar大鼠7天。之后，进行血流动力学测量，自主神经调节，左心室功能，心脏纤维化，活性氧（ROS）生成，Nox蛋白表达，超氧化物歧化酶（SOD）和过氧化氢酶活性，评估心律失常的发生率。在这里，我们显示地塞米松可以增加血压，并增强心脏和血管的交感神经调节作用。此外，观察到心脏ROS产生显着增加，而SOD活性增强并未阻止地塞米松组中较高的脂质过氧化水平。另一方面，在地塞米松治疗的大鼠中观察到心脏Nox 4表达增加和过氧化氢分解速率增加，而Nox 2保持不变。有趣的是，尽管保留了心室收缩力和β-肾上腺素反应性，我们发现地塞米松治疗的大鼠显示出比对照组更大的间质和血管周纤维化。令人惊讶的是，尽管在基础条件下不存在心律不齐，但我们通过体内和离体方法证实了：地塞米松治疗的大鼠在受到药理学药物或突然起搏引起的心律不齐的挑战时，更容易发展为有害的室性心律失常。值得注意的是，同时使用NADPH氧化酶抑制剂Apocynin进行治疗，可以预防这些异位性心室事件。总之，我们的结果表明，在地塞米松治疗期间，心脏变得有心律失常作用，从而揭示了产生ROS的NADPH氧化酶在心律失常易感性中的关键作用。