title: Vascular endothelial σ1-receptor stimulation with SA4503 rescues aortic relaxation via Akt/eNOS signaling in ovariectomized rats with aortic banding.
abstract: 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.
  
  
  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.
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University.
authors: Hideaki
authors: H
authors: Tagashira
authors: Takayuki
authors: T
authors: Matsumoto
authors: Kumiko
authors: K
authors: Taguchi
authors: Chen
authors: C
authors: Zhang
authors: Feng
authors: F
authors: Han
authors: Keiko
authors: K
authors: Ishida
authors: Shingo
authors: S
authors: Nemoto
authors: Tsuneo
authors: T
authors: Kobayashi
authors: Kohji
authors: K
authors: Fukunaga
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D001012:Aorta, Abdominal / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000378:metabolism / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D005260:Female; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018697:Nootropic Agents / Q000494:pharmacology*; D010052:Ovariectomy; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D000097605:Sigma-1 Receptor
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000840:Anisoles; D014150:Antipsychotic Agents; D006152:Cyclic GMP; D019332:Endothelin-1; D052250:Nitric Oxide Synthase Type III; D018697:Nootropic Agents; D010656:Phenylephrine; D010879:Piperazines; D011437:Propylamines; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C101789:SA 4503; C496316:Nos3 protein, rat