Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University.
Circ J. 2013;77(11):2831-40. doi: 10.1253/circj.cj-13-0256. Epub 2013 Aug 20.
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.
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.
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.
我们之前报道过，在去卵巢（OVX）大鼠腹部主动脉结扎引起的压力超负荷（PO）后，胸主动脉中的 σ1 受体（σ1R）表达减少。在这里，我们想知道 σ1R 的选择性激动剂 SA4503 是否会刺激 OVX-PO 大鼠的血管损伤后主动脉血管舒张和收缩功能的恢复。
SA4503（0.3-1.0mg/kg）和 NE-100（一种 σ1R 拮抗剂，1.0mg/kg）以口服方式（每天一次）给予 OVX-PO 大鼠 4 周。用苯肾上腺素（PE）或内皮素-1（ET-1）诱导血管收缩，乙酰胆碱（ACh）或可乐定诱导血管舒张来测量分离的降主动脉的血管功能。SA4503 给药可挽救 PO 诱导的主动脉平滑肌和内皮细胞中的 σ1R 减少。SA4503 治疗还挽救了 PO 诱导的 ACh 和可乐定诱导的血管舒张受损，而不影响 PE 和 ET-1 诱导的血管收缩。改善的 ACh 和可乐定诱导的血管舒张与 Akt 活性增加密切相关，进而与内皮型一氧化氮合酶（eNOS）磷酸化相关。SA4503 介导的血管舒张改善被 NE-100 治疗阻断。
在 OVX 大鼠 PO 诱导的内皮损伤后，σ1R 下调。选择性 σ1R 激动剂 SA4503 通过 σ1R 刺激挽救 OVX-PO 大鼠主动脉中受损的内皮依赖性血管舒张，增强血管内皮细胞中的 eNOS-cGMP 信号。这些观察结果鼓励开发针对 σ1R 的新型治疗方法，以防止血管疾病中的血管内皮损伤。
