title: Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents.
abstract: Sinusoidal vasoconstriction, in which hepatic stellate cells operate as contractile machinery, has been suggested to play a pivotal role in the pathophysiology of portal hypertension. We investigated whether sphingosine 1-phosphate (S1P) stimulates contractility of those cells and enhances portal vein pressure in isolated perfused rat livers with Rho activation by way of S1P receptor 2 (S1P(2) ). Rho and its effector, Rho kinase, reportedly contribute to the pathophysiology of portal hypertension. Thus, a potential effect of S1P(2) antagonism on portal hypertension was examined. Intravenous infusion of the S1P(2) antagonist, JTE-013, at 1 mg/kg body weight reduced portal vein pressure by 24% without affecting mean arterial pressure in cirrhotic rats induced by bile duct ligation at 4 weeks after the operation, whereas the same amount of S1P(2) antagonist did not alter portal vein pressure and mean arterial pressure in control sham-operated rats. Rho kinase activity in the livers was enhanced in bile duct-ligated rats compared to sham-operated rats, and this enhanced Rho kinase activity in bile duct-ligated livers was reduced after infusion of the S1P(2) antagonist. S1P(2) messenger RNA (mRNA) expression, but not S1P(1) or S1P(3) , was increased in bile duct-ligated livers of rats and mice and also in culture-activated rat hepatic stellate cells. S1P(2) expression, determined in S1P 2LacZ/+ mice, was highly increased in hepatic stellate cells of bile duct-ligated livers. Furthermore, the increase of Rho kinase activity in bile duct-ligated livers was observed as early as 7 days after the operation in wildtype mice, but was less in S1P 2-/- mice.
  
  
  CONCLUSIONS
  S1P may play an important role in the pathophysiology of portal hypertension with Rho kinase activation by way of S1P(2) . The S1P(2) antagonist merits consideration as a novel therapeutic agent for portal hypertension.
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kageyama
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Naoko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Masakazu
authors.initials: M
authors.lastname: Nagamine
authors.forename: Yoshika
authors.initials: Y
authors.lastname: Kusumoto
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Yashiro
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Satoh
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.forename: Koji
authors.initials: K
authors.lastname: Shinozaki
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tomiya
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Inoue
authors.forename: Takako
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Natsuko
authors.initials: N
authors.lastname: Ohtomo
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tanoue
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Yokota
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Koyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ishimaru
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takuwa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D002478:Cells, Cultured / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000502:physiology; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008026:Ligation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics; D012016:Reference Values; D012680:Sensitivity and Specificity; D054460:rho-Associated Kinases / Q000187:drug effects / Q000378:metabolism*
chemical_list: C471998:JTE 013; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D054460:rho-Associated Kinases