title: Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure.
abstract: OBJECTIVE
  Portal hypertension is a common complication of liver cirrhosis and significantly increases mortality and morbidity. Previous reports have suggested that the compound thalidomide attenuates portal hypertension (PHT). However, the mechanism for this action is not fully elucidated. One hypothesis is that thalidomide destabilizes tumor necrosis factor α (TNFα) mRNA and therefore diminishes TNFα induction of nitric oxide synthase (NOS) and the production of nitric oxide (NO). To examine this hypothesis, we utilized the murine partial portal vein ligation (PVL) PHT model in combination with endothelial or inducible NOS isoform gene knockout mice.
  
  
  METHODS
  Wild type, inducible nitric oxide synthase (iNOS)(-/-) and endothelial nitric oxide synthase (eNOS)(-/-) mice received either PVL or sham surgery and were given either thalidomide or vehicle. Serum nitrate (total nitrate, NOx) was measured daily for 7 d as a surrogate of NO synthesis. Serum TNFα level was quantified by enzyme-linked immunosorbent assay. TNFα mRNA was quantified in liver and aorta tissue by reverse transcription-polymerase chain reaction. PHT was determined by recording splenic pulp pressure (SPP) and abdominal aortic flow after 0-7 d. Response to thalidomide was determined by measurement of SPP and mean arterial pressure (MAP).
  
  
  RESULTS
  SPP, abdominal aortic flow (Qao) and plasma NOx were increased in wild type and iNOS(-/-) PVL mice when compared to sham operated control mice. In contrast, SPP, Qao and plasma NOx were not increased in eNOS(-/-) PVL mice when compared to sham controls. Serum TNFα level in both sham and PVL mice was below the detection limit of the commercial ELISA used. Therefore, the effect of thalidomide on serum TNFα levels was undetermined in wild type, eNOS(-/-) or iNOS(-/-) mice. Thalidomide acutely increased plasma NOx in wild type and eNOS(-/-) mice but not iNOS(-/-) mice. Moreover, thalidomide temporarily (0-90 min) decreased mean arterial pressure, SPP and Qao in wild type, eNOS(-/-) and iNOS(-/-) PVL mice, after which time levels returned to the respective baseline.
  
  
  CONCLUSIONS
  Thalidomide does not reduce portal pressure in the murine PVL model by modulation of NO biosynthesis. Rather, thalidomide reduces PHT by decreasing MAP by an undetermined mechanism.
authors.affiliation: Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Theodorakis
authors.affiliation: Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.
authors.forename: Yining N
authors.initials: YN
authors.lastname: Wang
authors.affiliation: Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.
authors.forename: Vyacheslav A
authors.initials: VA
authors.lastname: Korshunov
authors.affiliation: Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Maluccio
authors.affiliation: Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skill
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects / Q000503:physiopathology; D062186:Arterial Pressure / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D001783:Blood Flow Velocity; D004195:Disease Models, Animal; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017082:Portal Pressure / Q000187:drug effects*; D000067996:RAW 264.7 Cells; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000187:drug effects; D013792:Thalidomide / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000959:Antihypertensive Agents; D015415:Biomarkers; D009566:Nitrates; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013792:Thalidomide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse
keywords: Endothelial nitric oxide synthase; Inducible nitric oxide synthase; Knockout mice; Nitric oxide; Portal hypertension; Thalidomide; Tumor necrosis factor alpha