title: Influence of ezetimibe on ADMA-DDAH-NO pathway in rat liver subjected to partial ischemia followed by global reperfusion.
abstract: BACKGROUND
  We evaluated effect of ezetimibe on selected parameters determining NO level in rat liver subjected to ischemia reperfusion (IR).
  
  
  METHODS
  Rats received ezetimibe (5 mg/kg) (groups E0 and EIR) or saline solution (groups C0 and CIR) intragastrically for 21 days. Then, the livers of CIR and EIR underwent ischemia (60 min) and reperfusion (4 h). Blood samples were obtained before surgery to estimate activities of aminotransferases, and just before ischemia and during reperfusion to estimate asymmetric and symmetric dimethylarginine (ADMA, SDMA) and arginine (Arg) levels. After IR, dimethylarginine dimethylaminohydrolase (DDAH) activity and endothelial nitric oxide synthase (eNOS) protein concentration were measured in liver homogenates. DDAH and protein arginine methyltransferase (PRMT) mRNA were quantified by real-time PCR in liver tissue samples.
  
  
  RESULTS
  In CIR, the ADMA level was significantly higher compared to all other groups in 30 min and to E0 group in 120 min of reperfusion. In EIR, ADMA was low, compared to non-ischemic groups. At 30 and 120 min of reperfusion, in non-ischemic groups the level of Arg and Arg/ADMA ratio were significantly higher than in ischemic groups and E0 was the group with the highest levels of those parameters of all. In CIR, eNOS protein concentration was significantly lower than in ezetimibe-treated groups. Activity of DDAH was significantly higher in E0 than in non-treated groups. In ischemic groups, DDAH mRNA expression was significantly higher than in non-ischemic ones and PRMT mRNA expression was significantly higher in C0 than in all other groups.
  
  
  CONCLUSIONS
  Influence of ezetimibe on ADMA/DDAH/NO pathway demonstrated in this work may suggest protective properties of this drug on rat livers injured by IR and, to a lower extent, on livers non-subjected to IR.
authors.affiliation: Department of Pharmacology, Wroclaw Medical University & 4th Military Hospital in Wroclaw, Mikulicza-Radeckiego 2, PL 50-345 Wrocław, Poland. malgorzata.trocha@gmail.com
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Trocha
authors.forename: Anna
authors.initials: A
authors.lastname: Merwid-Ląd
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sozański
authors.forename: Ewa
authors.initials: E
authors.lastname: Ewa Chlebda-Sieragowska
authors.forename: Andrzej
authors.initials: A
authors.lastname: Szuba
authors.forename: Piotr
authors.initials: P
authors.lastname: Dzięgiel
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Pieśniewska
authors.forename: Lidia
authors.initials: L
authors.lastname: Fereniec-Gołębiewska
authors.forename: Joanna
authors.initials: J
authors.lastname: Kwiatkowska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Gomułkiewicz
authors.forename: Łucja
authors.initials: Ł
authors.lastname: Cwynar-Zając
authors.forename: Renata
authors.initials: R
authors.lastname: Brykner
authors.forename: Adam
authors.initials: A
authors.lastname: Szeląg
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D001384:Azetidines / Q000494:pharmacology*; D000069438:Ezetimibe; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D012333:RNA, Messenger; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D000581:Amidohydrolases; C059999:dimethylargininase; D000069438:Ezetimibe