The purpose of the study was to investigate what effects the sigma-1 receptor (S1R) could exert on the cardiac myocyte ion channels in a rodent model of depression and to explore the underlying mechanisms since depression is an independent risk factor for cardiovascular diseases including ventricular arrhythmias (VAs). To establish the depression model in rats, chronic mild unpredictable stress (CMUS) for 28 days was used. The S1R agonist fluvoxamine was injected intraperitoneally from the second week to the last week for 21 days in total, and the effects were evaluated by patch clamp, western blot analysis, and Masson staining. We demonstrated that depression was improved after treatment with fluvoxamine. In addition, the prolongation of the corrected QT (QTc) interval under CMUS that increased vulnerability to VAs was significantly attenuated by stimulation of S1R due to the decreased amplitude of L-type calcium current (I) and the restoration of reduced transient outward potassium current (I) resulting from CMUS induction. The S1R also decelerated I inactivation and accelerated I recovery by activating Ca/calmodulin-dependent kinase II. Moreover, the stimulation of S1R ameliorated the structural remodeling as the substrate for maintenance of VAs. All these effects were abolished by the administration of S1R antagonist BD1047, which verified the roles for S1R. Activation of S1R could decrease the vulnerability to VAs by inhibiting I and restoring I, in addition to ameliorating the CMUS-induced depressive symptoms and structural remodeling.

中文翻译：

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慢性刺激 sigma-1 受体可改善抑郁症啮齿动物模型的心室离子和结构重塑

本研究的目的是调查 sigma-1 受体 (S1R) 对抑郁症啮齿动物模型中心肌细胞离子通道的影响，并探讨其潜在机制，因为抑郁症是心血管疾病（包括心室疾病）的独立危险因素。心律失常（VA）。采用28天的慢性轻度不可预知应激（CMUS）建立大鼠抑郁模型。第2周至最后一周腹腔注射S1R激动剂氟伏沙明，共21天，通过膜片钳、Western blot分析和Masson染色评价效果。我们证明，氟伏沙明治疗后抑郁症得到改善。此外，CMUS 下校正 QT (QTc) 间期的延长增加了对 VAs 的脆弱性，但由于 L 型钙电流 (I) 幅度降低和瞬时外向钾电流减少的恢复，刺激 S1R 显着减弱(I) 由 CMUS 诱导产生。 S1R 还通过激活 Ca/钙调蛋白依赖性激酶 II 来减缓 I 失活并加速 I 恢复。此外，S1R 的刺激改善了结构重塑，作为维持 VA 的底物。所有这些效应均通过给予S1R拮抗剂BD1047而消除，从而验证了S1R的作用。除了改善 CMUS 引起的抑郁症状和结构重塑之外，S1R 的激活还可以通过抑制 I 和恢复 I 来降低对 VA 的脆弱性。