The Beneficial Effects of P2X7 Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis.
Splanchnic angiogenesis in liver cirrhosis often leads to complications as gastroesophageal variceal hemorrhage and the treatment efficacy is adversely affected by poor portal-systemic collateral vasoresponsiveness related to nitric oxide (NO). Purinergic receptor subtype P2X7 participates in the modulation of inflammation, angiogenesis, fibrogenesis and vasoresponsiveness, but the relevant influence in cirrhosis is unknown. Common bile duct-ligated (CBDL) or sham-operated Spraque-Dawley rats received brilliant blue G (BBG, a P2X7 antagonist and food additive) or vehicle from the 15th to 28th day after operations, then hemodynamics, mesenteric angiogenesis, portal-systemic shunting, liver fibrosis, and protein expressions of angiogenic and fibrogenic factors were evaluated. The influence of oxidized ATP (oATP, another P2X7 receptor antagonist) on the collateral vasoresponsiveness to arginine vasopressin (AVP) was also surveyed. BBG decreased superior mesenteric artery (SMA) flow, portal-systemic shunting, mesenteric vascular density, and mesenteric protein expressions of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), phospho (p)-VEGFR2, platelet-derived growth factor (PDGF), PDGF receptor beta (PDGFRβ), cyclooxygenase (COX)-1, COX-2, and endothelial NO synthase (eNOS) in CBDL rats. BBG also ameliorated liver fibrosis and down-regulated hepatic interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), PDGF, IL-1β, transforming growth factor-beta (TGF-β), p-extracellular-signal-regulated kinases (ERK), and alpha-smooth muscle actin (α-SMA) expressions in CBDL rats. The collateral vasocontractility to AVP was enhanced by oATP. oATP down-regulated eNOS, inducible NOS (iNOS), VEGF, Akt, p-Akt, and nuclear factor-kappa B (NF-κB) expressions in splenorenal shunt, the most prominent intra-abdominal collateral vessel in rodents. P2X7 antagonism alleviates splanchnic hyperemia, severity of portal-systemic shunting, mesenteric angiogenesis, liver fibrosis, and enhances portal-systemic collateral vasoresponsiveness in cirrhotic rats. P2X7 blockade may be a feasible strategy to control cirrhosis and complications.
Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Hung-Chun
HC
Tung
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Fa-Yauh
FY
Lee
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Department of Medical Affair and Planning, Taipei Veterans General Hospital, Taipei, Taiwan.
Sun-Sang
SS
Wang
Division of digestive therapeutic endoscopy, Chang Gung Memorial Hospital, Taipei, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan.
Ming-Hung
MH
Tsai
Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Jing-Yi
JY
Lee
Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Teh-Ia
TI
Huo
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Hui-Chun
HC
Huang
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Chiao-Lin
CL
Chuang
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Han-Chieh
HC
Lin
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan.
Shou-Dong
SD
Lee
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001652:Bile Ducts / Q000187:drug effects / Q000473:pathology*; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D011170:Portasystemic Shunt, Surgical; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D012394:Rosaniline Dyes / Q000494:pharmacology / Q000627:therapeutic use; D051785:Smad Proteins / Q000378:metabolism
D016207:Cytokines; D058920:Purinergic P2X Receptor Antagonists; D012394:Rosaniline Dyes; D051785:Smad Proteins; D001127:Arginine Vasopressin; C017199:2',3'-dialdehyde ATP; D000255:Adenosine Triphosphate; C004692:coomassie Brilliant Blue