title: A combination of ischemic preconditioning and allopurinol protects against ischemic injury through a nitric oxide-dependent mechanism.
abstract: This study examined the cytoprotective mechanisms of a combination of ischemic preconditioning (IPC) and allopurinol against liver injury caused by ischemia/reperfusion (I/R). Allopurinol (50mg/kg) was intraperitoneally administered 18 and 1h before sustained ischemia. A rat liver was preconditioned by 10 min of ischemia, followed by 10 min of reperfusion, and then subjected to 90 min of ischemia, followed by 5h of reperfusion. Rats were pretreated with adenosine deaminase (ADA), 3,7-dimethyl-1-[2-propargyl]-xanthine (DMPX), and N-nitro-l-arginine methyl ester (l-NAME) before IPC. Hepatic nitrite and nitrate and eNOS protein expression levels were increased by the combination of IPC and allopurinol. This increase was attenuated by ADA, DMPX, and l-NAME. I/R induced an increase in alanine aminotransferase activity, whereas it decreased the hepatic glutathione level. A combination of IPC and allopurinol attenuated these changes, which were abolished by ADA, DMPX, and l-NAME. The increase in the liver wet weight-to-dry weight ratio after I/R was attenuated by the combination of IPC and allopurinol. In contrast, hepatic bile flow was decreased after I/R, which was attenuated by the combination of IPC and allopurinol. These changes were restored by l-NAME. I/R induced a decrease in the level of mitochondrial dehydrogenase, whereas it increased mitochondrial swelling. A combination of IPC and allopurinol attenuated these changes, which were restored by ADA, DMPX, and l-NAME. Our findings suggest that a combination of IPC and allopurinol reduces post-ischemic hepatic injury by enhancing NO generation.
authors: School of Pharmacy, Sungkyunkwan University, Republic of Korea.
authors: Woo-Yong
authors: WY
authors: Lee
authors: Eun-Ji
authors: EJ
authors: Koh
authors: Sun-Mee
authors: SM
authors: Lee
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism / Q000494:pharmacology; D000410:Alanine Transaminase / Q000097:blood; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C026512:arginine methyl ester; D009569:Nitric Oxide; C057837:3,7-dimethyl-1-propargylxanthine; D000493:Allopurinol; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D000410:Alanine Transaminase; D000243:Adenosine Deaminase; D005978:Glutathione; D006152:Cyclic GMP; D013805:Theobromine