title: Impact of elevated uric acid on ventricular remodeling in infarcted rats with experimental hyperuricemia.
abstract: Hyperuricemia is associated with cardiovascular disease, but it is usually considered a marker rather than a risk factor. Previous studies using uric acid-lowering drugs in normouricemic animals are not suitable to answer the effect of hyperuricemia on ventricular remodeling after myocardial infarction. The purpose of this study was to determine whether hyperuricemia adversely affects ventricular remodeling in infarcted rats with elevated uric acid. Male Wistar rats aged 8 wk were randomly assigned into either vehicle, oxonic acid, oxonic acid + allopurinol, oxonic acid + benzbromarone, oxonic acid + ABT-627, or oxonic acid + tempol for 4 wk starting 24 h after ligation. Postinfarction was associated with increased oxidant production, as measured by myocardial superoxide, isoprostane, xanthine oxidase activity, and dihydroethidium staining. Compared with normouricemic infarcted rats, hyperuricemic infarcted rats had a significant increase of superoxide production (1.7×) and endothelin-1 protein (1.2×) and mRNA (1.4×) expression, which was associated with increased left ventricular dysfunction and enhanced myocardial hypertrophy and fibrosis. These changes were all prevented by treatment with allopurinol. For similar levels of urate lowering, the uricosuric agent benzbromarone had no effect on ventricular remodeling. In spite of equivalent hyperuricemia, the ability of both ABT-627 and tempol to attenuate ventricular remodeling suggested involvement of endothelin-1 and redox pathways. Hyperuricemia is associated with unfavorable ventricular remodeling probably through a superoxide and endothelin-1-dependent pathway. Uric acid lowering without inhibition of superoxide and endothelin-1 may not have an effect on remodeling. Chronic administration of allopurinol, ABT-627, and tempol is associated with attenuated ventricular remodeling.
authors.affiliation: Institute of Biomedical Engineering, National Cheng-Kung University, and Divison of Cardiovascular Surgery, Chia-yi Christian Hospital, Chia-yi City, Taiwan.
authors.forename: Chien-Chang
authors.initials: CC
authors.lastname: Chen
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Hsu
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000077868:Atrasentan; D015415:Biomarkers / Q000097:blood; D003497:Cyclic N-Oxides / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D006074:Gout Suppressants / Q000494:pharmacology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D033461:Hyperuricemia / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D028421:Isoprostanes / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D014527:Uric Acid / Q000097:blood*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D003497:Cyclic N-Oxides; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D006074:Gout Suppressants; D028421:Isoprostanes; D011759:Pyrrolidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D013113:Spin Labels; D013481:Superoxides; D014527:Uric Acid; C075750:8-epi-prostaglandin F2alpha; D000493:Allopurinol; D015237:Dinoprost; D014969:Xanthine Oxidase; C001803:tempol; D000077868:Atrasentan