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 nonelevated uric acid levels (233 ± 10 μM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10 −7 to 10 −5 μM), 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 μU/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 μM, p < 0.05) and significantly increased CBF (16 ± 17 vs 62 ± 18% at ACh 10 −5 μM, 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.

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call