title: Induction of endothelium-dependent constriction of mesenteric arteries in endotoxemic hypotensive shock.
abstract: OBJECTIVE
  Effective management of hypotension refractory to vasoconstrictors in severe sepsis is limited. A new strategy to ameliorate endotoxemic hypotension by inducing endothelium-dependent constriction of large arteries was assessed.
  
  
  METHODS
  Endotoxemia in rats was induced by injection of LPS (10 mg·kg(-1), i.v.). Haemodynamics were measured in vivo, reactivity of isolated mesenteric arteries by myography and expression of proteins and enzyme activities by immunohistochemistry, biochemistry and molecular biology.
  
  
  RESULTS
  Six hours after LPS, the hypotension was promptly reversed following injection (i.v. or i.p.) of oroxylin-A (OroA) . In isolated LPS-treated but not normal mesenteric arteries, OroA (1-10 μM) induced endothelium-dependent, sustained constriction, blocked by endothelin-1 (ET-1) receptor antagonists. OroA further enhanced LPS-induced expression of endothelin-converting enzyme, ET-1 mRNA and proteins and ET-1 release, OroA also enhanced phosphorylation of Rho-associated protein kinase (ROCK) and reversed LPS-induced suppression of RhoA activities in smooth muscle of arteries with endothelium. Activated- phosphorylation of smooth muscle ROCK was blocked by ET-1-receptor antagonists and ROCK inhibitors. Moreover, OroA post-treatment suppressed, via inhibiting NF-κB activation, inducible NOS expression and circulating NO.
  
  
  CONCLUSIONS
  Reversal of endotoxemic hypotensive by OroA was due to release of endothelial ET-1, upregulated by LPS, from mesenteric arteries, inducing prompt and sustained vasoconstriction via activation of vascular smooth muscle RhoA/ROCK-pathway. In late endotoxemia, OroA-induced vasoconstriction was partly due to decreased circulating NO. Activation of endothelium-dependent constriction in large resistance arteries and suppression of systemic inflammation offer new strategies for acute management of endotoxemic hypotensive shock.
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.|Institutes of Medical Sciences and Pharmacology & Toxicology, Hualien, Taiwan.|Department of Life Sciences, Tzu Chi Center of Vascular Medicine, College of Life Sciences, Hualien, Taiwan.
authors.forename: Tzu-Ling
authors.initials: TL
authors.lastname: Tseng
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.|Department of Life Sciences, Tzu Chi Center of Vascular Medicine, College of Life Sciences, Hualien, Taiwan.|Tzu Chi College of Technology, Hualien, Taiwan.
authors.forename: Mei-Fang
authors.initials: MF
authors.lastname: Chen
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.|Institutes of Medical Sciences and Pharmacology & Toxicology, Hualien, Taiwan.|Department of Life Sciences, Tzu Chi Center of Vascular Medicine, College of Life Sciences, Hualien, Taiwan.
authors.forename: Chin-Hung
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.|Institutes of Medical Sciences and Pharmacology & Toxicology, Hualien, Taiwan.
authors.forename: Cheng-Yoong
authors.initials: CY
authors.lastname: Pang
authors.affiliation: Institutes of Medical Sciences and Pharmacology & Toxicology, Hualien, Taiwan.|Department of Pathology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.|Institutes of Medical Sciences and Pharmacology & Toxicology, Hualien, Taiwan.|Department of Life Sciences, Tzu Chi Center of Vascular Medicine, College of Life Sciences, Hualien, Taiwan.|Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA.
authors.forename: Tony J F
authors.initials: TJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D065130:Endothelin A Receptor Antagonists / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology; D005419:Flavonoids / Q000627:therapeutic use*; D007022:Hypotension / Q000188:drug therapy* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000503:physiopathology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy* / Q000503:physiopathology; D014661:Vasoconstriction; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D005419:Flavonoids; D008070:Lipopolysaccharides; D009569:Nitric Oxide; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D052247:Nitric Oxide Synthase Type II; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein