title: Oxypurinol improves coronary and peripheral endothelial function in patients with coronary artery disease.
abstract: Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65+/-8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and non-elevated uric acid levels (233+/-10 microM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10(-7) to 10(-5) microM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051+/- 0.001 vs 0.019+/- 0.005 microU/mg protein; p<0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh (n=13), oxypurinol markedly attenuated ACh-induced vasoconstriction (-23+/- 4 vs -15+/- 4% at ACh 10(-5) microM, p<0.05) and significantly increased CBF (16+/-17 vs 62+/-18% at ACh 10(-5) microM, p<0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8+/- 4.2 vs 5.2+/- 0.7%, p>0.05) or CBF (135+/-75 vs 154+/-61%, p>0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1+/-1.5 before to 7.6+/-1.5% after oxypurinol administration (p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.
authors.affiliation: Department of Cardiology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. baldus@uke.uni-hamburg.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.forename: Ralf
authors.initials: R
authors.lastname: Köster
authors.forename: Phillip
authors.initials: P
authors.lastname: Chumley
authors.forename: Thomas
authors.initials: T
authors.lastname: Heitzer
authors.forename: Volker
authors.initials: V
authors.lastname: Rudolph
authors.forename: Mir Abolfazl
authors.initials: MA
authors.lastname: Ostad
authors.forename: Ascan
authors.initials: A
authors.lastname: Warnholtz
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Staude
authors.forename: Felix
authors.initials: F
authors.lastname: Thuneke
authors.forename: Klaus
authors.initials: K
authors.lastname: Koss
authors.forename: Jürgen
authors.initials: J
authors.lastname: Berger
authors.forename: Thomas
authors.initials: T
authors.lastname: Meinertz
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
mesh_terms: D000368:Aged; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000503:physiopathology; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010117:Oxypurinol / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000097:blood / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D004791:Enzyme Inhibitors; D011687:Purines; D014969:Xanthine Oxidase; D010117:Oxypurinol