Sigma-1 receptor ligands improves ventricular repolarization-related ion remodeling in rats with major depression disord

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ORIGINAL INVESTIGATION

Sigma-1 receptor ligands improves ventricular repolarization-related ion remodeling in rats with major depression disorder Yan Guo 1,2,3 & Cui Zhang 1,2,3 & Xiuhuan Chen 1,2,3 & Xin Liu 1,2,3 & Tianxin Ye 1,2,3 & Yuhong Fo 1,2,3 & Shaobo Shi 1,2,3 & Chuan Qu 1,2,3 & Jinjun Liang 1,2,3 & Bo Shen 1,2,3 & Bo Yang 1,2,3 Received: 27 June 2020 / Accepted: 23 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract Rationale It has been reported that patients with major depressive disorder (MDD) are prone to developing ventricular arrhythmias. Moreover, the Sigma-1 receptor not only plays a crucial role in MDD but has also been shown to have antiarrhythmic properties. The Sigma-1 receptor is a common receptor related to depression and ventricular arrhythmias. Objective We analyzed the effects of the Sigma-1 receptor on depression and ventricular repolarization-related ion remodeling in MDD rats. Methods MDD was induced in rats by chronic unpredictable mild stress (CUMS), and 28 days later, the rats were subjected to behavior tests. Protein expression was measured by western blotting, and cardiac morphological changes were observed by Masson staining. Electrophysiological measurement of the myocardium was performed with the whole-cell patch-clamp technique. Results Compared with the control rats, the MDD rats exhibited lower transient outward potassium current (Ito) and L-type calcium current (ICa-L) amplitudes. On the other hand, a trend of depolarization of Ito and hyperpolarization of ICa-L was observed in the MDD rats. Thus, we investigated the effect of fluvoxamine, a Sigma-1 receptor agonist, on Ito and ICa-L. Fluvoxamine enhanced Ito and altered its current kinetics, as shown by acceleration of activation and recovery from inactivation. In contrast, fluvoxamine inhibited the Ca2+ by hyperpolarizing the steady-state activation of ICa-L. All these effects were blocked by BD1047. Conclusion Taken together, our results indicate that Sigma-1 receptor modulates the functions of Ito and ICa-L to possibly exert antiarrhythmic effects. Keywords Sigma-1 receptor . Major depressive disorder . Ventricular arrhythmia . Ionic remodeling

Abbreviations MDD Major depressive disorder CUMS Chronic unpredictable mild stress Yan Guo, Cui Zhang, Bo Shen and Bo Yang contributed equally to this work. * Bo Shen [email protected] * Bo Yang [email protected] 1

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China

2

Cardiovascular Research Institute, Wuhan University, Wuhan, People’s Republic of China

3

Hubei Key Laboratory of Cardiology, Wuhan, People’s Republic of China

CTL Flu BD HP SSRI

Control Fluvoxamine BD1047 Holding potential Selective serotonin reuptake inhibitor

Introduction Recognition of the contribution of mental stress to the development of cardiovascular has increased with a growing understanding of the brain-heart connection. Major depression disorder (MDD) is a devastating disorder that leads to substantial individual suffe