title: Effects of simvastatin on the portal-systemic collateral vascular response to endothelin-1 and shunting degree in portal hypertensive rats.
abstract: OBJECTIVE
  Endothelin-1 (ET-1) exerts vasoconstrictive effect on portal-systemic collateral vascular bed of portal hypertensive rats. Statins are lipid-lowering agents with nitric oxide (NO)-related vasodilatory effects. Considering NO-associated vascular hyporesponsiveness to vasoconstrictors and shunting formation in portal hypertension, this study investigated the effects of simvastatin on 1) the portal-systemic collateral vascular responsiveness to ET-1 and 2) the portal-systemic shunting degree.
  
  
  METHODS
  Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Simvastatin (20 mg/kg/day) or distilled water (control) was randomly administered by oral gavage since 2 days prior to until 7 days after PVL. Systemic and portal hemodynamics were measured on the 8th day. In another series, collateral perfusion with Krebs solution at different flow rates was performed to get flow-pressure curves which serve as an index of shunting degree. To survey the direct vascular effect, PVL rats randomly underwent preincubation with 1) Krebs solution, that is, the control group; or Krebs solution plus 2) simvastatin; 3) simvastatin + N (ω)-nitro-L-arginine (NNA, a NO synthase inhibitor); 4) simvastatin + indomethacin (a cyclooxygenase inhibitor), followed by ET-1 to evaluate the collateral vascular responsiveness.
  
  
  RESULTS
  Chronic simvastatin treatment significantly reduced portal pressure. The flow-pressure curves were similar between two groups. Simvastatin preincubation reduced collateral perfusion pressure changes to ET-1 (p < 0.05), which were partially reversed by NNA (p < 0.05), but not by indomethacin. Conclusions. Chronic simvastatin treatment significantly improved portal hypertension. The effect was at least partially exerted by decreased portal-systemic collateral vascular resistance through NO-mediated vascular hyporesponsiveness. The severity of portal-systemic collaterals was not influenced by simvastatin.
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine , Taipei , Taiwan.
authors.forename: Shao-Jung
authors.initials: SJ
authors.lastname: Hsu
authors.forename: Sang-Sun
authors.initials: SS
authors.lastname: Wang
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Hsin
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Huang
authors.forename: Fa-Yauh
authors.initials: FY
authors.lastname: Lee
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Lee
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.forename: Chiao-Lin
authors.initials: CL
authors.lastname: Chuang
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D000818:Animals; D003097:Collateral Circulation / Q000187:drug effects* / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D016014:Linear Models; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014662:Vasoconstrictor Agents; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D007213:Indomethacin