Baldus Stephan, Köster Ralf, Chumley Phillip, Heitzer Thomas, Rudolph Volker, Ostad Mir Abolfazl, Warnholtz Ascan, Staude Hans-Jürgen, Thuneke Felix, Koss Klaus, Berger Jürgen, Meinertz Thomas, Freeman Bruce A, Münzel Thomas
Department of Cardiology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Free Radic Biol Med. 2005 Nov 1;39(9):1184-90. doi: 10.1016/j.freeradbiomed.2005.06.004. Epub 2005 Aug 10.
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.
冠状动脉内皮功能障碍是冠心病（CAD）患者的一个重要预后标志物，它与一氧化氮（NO）依赖性血管细胞信号的氧化抑制密切相关。黄嘌呤氧化酶（XO）可与内皮细胞结合并在内皮细胞中表达，在嘌呤氧化时产生超氧化物和过氧化氢。然而，黄嘌呤氧化酶活性的抑制是否能改善CAD患者的冠状动脉血管舒缩功能仍不清楚。我们评估了18例（年龄65±8岁，86%为男性）经血管造影证实患有CAD、左心室功能正常且尿酸水平未升高（233±10μM）患者的冠状动脉和外周（肱动脉）内皮功能。患者接受递增剂量的冠状动脉内乙酰胆碱（ACh；10⁻⁷至10⁻⁵μM），并在静脉注射奥昔嘌醇（200mg）前后评估最小管腔直径（MLD）和冠状动脉血流量（CBF）。奥昔嘌醇抑制血浆XO活性63%（0.051±0.001对0.019±0.005mU/mg蛋白；p<0.01）。在因ACh引起冠状动脉收缩而表现出内皮功能障碍的患者（n=13）中，奥昔嘌醇显著减弱ACh诱导的血管收缩（在ACh 10⁻⁵μM时为-23±4对-15±4%，p<0.05）并显著增加CBF（在ACh 10⁻⁵μM时为16±17对62±18%），而在冠状动脉内皮功能正常的患者中，奥昔嘌醇对ACh依赖性的MLD变化（+2.8±4.2对5.2±0.7%，p>0.05）或CBF（135±75对154±61%，p>0.05）无影响。对连续8例患者评估的肱动脉血流介导的扩张，在奥昔嘌醇给药后从5.1±1.5%增加到7.6±1.5%（p<0.05）。奥昔嘌醇对XO的抑制改善了冠状动脉血管内皮功能障碍，这是CAD患者的一个标志。这些观察结果表明，XO衍生的活性氧显著导致CAD患者冠状动脉NO生物利用度受损，并且XO抑制代表了一种针对炎症性血管疾病的额外治疗概念，值得进一步研究。
