Vascular Endothelial σ1-Receptor Stimulation With SA4503 Rescues Aortic Relaxation via Akt/eNOS Signaling in Ovariectomized Rats With Aortic Banding

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概要

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• Background: We previously reported that σ1-receptor (σ1R) 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 σ1R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury in OVX rats with PO. Methods and Results: SA4503 (0.3–1.0mg/kg) and NE-100 (a σ1R antagonist, 1.0mg/kg) were administered orally for 4 weeks (once daily) to OVX-PO rats. 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. SA4503 administration rescued PO-induced σ1R decreases in aortic smooth muscle and endothelial cells. 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. The SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment. Conclusions: σ1R is downregulated following PO-induced endothelial injury in OVX rats. The selective σ1R agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through σ1R stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting σ1R to prevent vascular endothelial injury in vascular diseases.

著者

• Han Feng

  Institute Of Pharmacology & Toxicology And Biochemical Pharmaceutics College Of Pharmaceutical S

• Fukunaga Kohji

  Department Of Pharmacology Graduate School Of Pharmaceutical Sciences Tohoku University

• Zhang Chen

  Department Of Anatomy Showa University School Of Medicine

• Ishida Keiko

  Department Of Bioresources Chemistry Chiba University

• TAGUCHI Kumiko

  Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University

• Matsumoto Takayuki

  Department Of Electronics Information And Communication Engineering Waseda University

• KOBAYASHI TSUNEO

  Department of Natural Sciences (Physics), School of Medicine, Fukushima Medical University

• Han Feng

  Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University

• Tagashira Hideaki

  Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University

• Nemoto Shingo

  Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University

• Zhang Chen

  Department of Pharmacy, College of Pharmaceutical Sciences, Zhejiang University

• KOBAYASHI Tsuneo

  Department of Agricultural Chemistry, Faculty of Agriculture, Tokyo Noko University

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