Stimulation of Sigma-1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunctions in ovariectomized rats

Objective: We previously reported that sigma-1 receptor ( σ 1 R ) expression in the thoracic aorta decreased after pressure overload (PO) induced by abdominal aortic banding in ovariectomized (OVX) rats. Here, we asked whether stimulation of σ 1 R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury in OVX rats with PO. Methods: SA4503 (0.3-1.0 mg kg -1 ) and NE-100 (an σ 1 R antagonist, 1.0 mg kg -1 ) were administered orally for 4 weeks (once daily) to OVX-PO rats, starting from the onset of aortic banding. Vascular functions of isolated descending aorta were measured following phenylephrine (PE)- or endothelin-1 (ET-1)-induced vasoconstriction and acetylcholine (ACh)- or clonidine-induced vasodilation. Results: σ 1 R expression in aortic smooth muscle and endothelial cells decreased significantly 4 weeks after PO in OVX rats (vs. Sham or OVX only group). SA4503 administration rescued PO-induced σ 1 R decreases in the descending aorta. SA4503 treatment also rescued PO-induced impairments in ACh- and clonidine-induced vasodilation without affecting PE- and ET-1-induced vasoconstriction. Ameliorated ACh- and clonidine-induced vasodilation was closely associated with increased Akt activity and in turn endothelial nitric oxide synthase (eNOS) phosphorylation. SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment. Conclusions: σ 1 R is downregulated following PO-induced endothelial injury in OVX rats. The selective σ 1 R agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through σ 1 R stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting σ 1 R to prevent vascular endothelial injury in postmenopausal woman.

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Sigma-1 receptor stimulation with fluvoxamine activates Akt–eNOS signaling in the thoracic aorta of ovariectomized rats with abdominal aortic banding

European Journal of Pharmacology ◽

10.1016/j.ejphar.2010.10.055 ◽

2011 ◽

Vol 650 (2-3) ◽

pp. 621-628 ◽

Cited By ~ 25

Author(s):

Md. Shenuarin Bhuiyan ◽

Hideaki Tagashira ◽

Kohji Fukunaga

Keyword(s):

Thoracic Aorta ◽

Ovariectomized Rats ◽

Aortic Banding ◽

Receptor Stimulation ◽

Sigma 1 Receptor ◽

Abdominal Aortic ◽

Sigma 1

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Chronic stimulation of the sigma-1 receptor ameliorates autonomic nerve dysfunction and atrial fibrillation susceptibility in a rat model of depression

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00607.2017 ◽

2018 ◽

Vol 315 (6) ◽

pp. H1521-H1531 ◽

Cited By ~ 7

Author(s):

Xin Liu ◽

Chuan Qu ◽

Hongjie Yang ◽

Shaobo Shi ◽

Cui Zhang ◽

...

Keyword(s):

Atrial Fibrillation ◽

Sympathetic Activity ◽

Autonomic Nerve ◽

Electrical Remodeling ◽

Intragastric Administration ◽

Chronic Stimulation ◽

Sigma 1 Receptor ◽

Sigma 1 ◽

Nerve Dysfunction ◽

Stimulation Of

The present study aimed to assess the effect of sigma-1 receptor (S1R) stimulation on autonomic nerve dysfunction and susceptibility to atrial fibrillation (AF) in a rat depression model. Male rats were randomly divided into one of the following four treatment groups: saline [control (CTL)]; saline + intragastric administration of SA4503, an agonist of S1R (CTS); chronic unpredictable mild stress (CUMS) to produce depression (MDD); and CUMS + intragastric administration of SA4503 (MDS). Depression-like behaviors, such as reduced sucrose preference, decreased body weight gain, and increased immobility time during forced swimming, improved in the MDS group after 4 wk of SA4503 treatment. Compared with rats in the CTL group, rats in the MDD group showed significantly augmented sympathetic activity, reduced parasympathetic activity, decreased heart rate variability, and lowered S1R expression in the atrium and hippocampus (all P < 0.01). However, rats in the MDS group showed mitigated aforementioned alterations and improved electrical remodeling compared with rats in the MDD group (all P < 0.01). Furthermore, rats in the MDS group showed shortened activation latencies, increased effective refractory periods, and lowered frequency of AF incidence duration and fibrosis compared with rats in the MDD group (all P < 0.01). The results indicate that S1R stimulation reduces sympathetic activity and susceptibility to AF by improving depressive behaviors, modulating cardiac autonomic nerve balance, lightening nerve remodeling, and upregulating S1R and ion channel protein expression. NEW & NOTEWORTHY Chronic stimulation of the sigma-1 receptor (S1R) ameliorates depression-induced autonomic nerve dysfunction by modulating the imbalance between overactivated sympathetic activity and decreased vagal activity. Chronic S1R stimulation alleviates atrial electrical remodeling, fibrosis, and susceptibility to atrial fibrillation (AF). The S1R agonist may target the underlying mechanisms related to AF occurrence. The results indicate that the S1R could be a potential clinical target for atrial arrhythmia, especially when it is combined with major depressive disorders.

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