Sphingosine 1-phosphate enhances portal pressure in isolated perfused liver via S1P2 with Rho activation.
Although structural changes are most important to determine vascular resistance in portal hypertension, vasoactive mediators also contribute to its regulation. Hepatic stellate cells (HSCs) are assumed to play a role in modulating intrahepatic vascular resistance based on their residence in the space of Disse and capacity to contract. Because sphingosine 1-phosphate (S1P) has been shown to stimulate HSC contractility, we wondered if S1P could regulate portal pressure. S1P at 0.5-5 microM increased portal pressure in isolated rat perfused liver. This effect was abrogated in the presence of a binding antagonist for S1P2, JTE-013. Perfusion of isolated rat liver with 5 microM S1P increased Rho activity in the liver, and co-perfusion with JTE-013 cancelled S1P-induced Rho activation. Because S1P is present in human plasma at approximately 0.2 microM, S1P might readily regulate portal vascular tone in physiological and pathological status. The antagonist for S1P2 merits consideration for treatment of portal hypertension.
Ikeda
Hitoshi
H
Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. ikeda-1im@h.u-tokyo.ac.jp
Nagashima
Kayo
K
Yanase
Mikio
M
Tomiya
Tomoaki
T
Arai
Masahiro
M
Inoue
Yukiko
Y
Tejima
Kazuaki
K
Nishikawa
Takako
T
Watanabe
Naoko
N
Omata
Masao
M
Fujiwara
Kenji
K
D000818:Animals; D002478:Cells, Cultured; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D017082:Portal Pressure / Q000187:drug effects* / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000081025:Sphingosine-1-Phosphate Receptors; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
C471998:JTE 013; D008246:Lysophospholipids; D011720:Pyrazoles; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D020741:rho GTP-Binding Proteins; D013110:Sphingosine