title: Nobiletin Relaxes Isolated Mesenteric Arteries by Activating the Endothelial Ca2+-eNOS Pathway in Rats.
abstract: OBJECTIVE
  Nobiletin, a natural polymethoxylated flavonoid compound, has various beneficial properties, such as anticancer, anti-inflammatory, and antioxidant effects, and it also improves memory. Therefore, we investigated the effects and mechanisms of nobiletin on rat isolated mesenteric arteries (MAs).
  
  
  METHODS
  We examined vasodilation induced by nobiletin on rat isolated MA rings with a tension study, the expression and activity of endothelial nitric oxide synthase (eNOS) with Western blotting, NO production with DAF- FMDA fluorescence, and intracellular Ca2+ concentration ([Ca2+]i) with Fluo-3AM.
  
  
  CONCLUSIONS
  Our study showed that nobiletin elicited a dose-dependent vasodilation in phenylephrine precontracted MA rings, but it did not elicit the same response in pulmonary artery rings. Vasodilation was related to endothelium and activated partly by eNOS. Vasodilation was inhibited by denudation of the endothelium or inhibition of eNOS activity. Nobiletin increased NO production by promoting the phosphorylation of eNOS at Ser-1177 without changing the level of eNOS expression in rat mesenteric artery endothelial cells (RMAECs). Nobiletin increased the concentration of endothelial [Ca2+]i, which enhances eNOS activity in RMAECs. In summary, vasodilation induced by nobiletin was dependent on the endothelium and partly on eNOS activation, which is mediated by high endothelial [Ca2+]i. Results suggest nobiletin may offer a therapeutic benefit and could potentially be used as a vasodilator for the treatment of hypertension.
authors.affiliation: College of Food Science, Northeast Agricultural University, Harbin, PR China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yang
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Liao
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
authors.forename: Jiali
authors.initials: J
authors.lastname: Li
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zheng
authors.forename: Xiuling
authors.initials: X
authors.lastname: Zhang
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047309:Flavones / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology; D017207:Rats, Sprague-Dawley; D012694:Serine; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D047309:Flavones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D012694:Serine; C008661:nobiletin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D002118:Calcium