Quyyumi A A, Dakak N, Mulcahy D, Andrews N P, Husain S, Panza J A, Cannon R O
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1650, USA.
J Am Coll Cardiol. 1997 Feb;29(2):308-17. doi: 10.1016/s0735-1097(96)00472-x.
We determined the activity of nitric oxide at rest and after acetylcholine in the atherosclerotic human coronary circulation.
Although responses to acetylcholine, an endothelium-dependent vasodilator, are abnormal in patients with coronary atherosclerosis, whether this reflects abnormal nitric oxide activity in humans in vivo has not been investigated previously.
We investigated the effects of intracoronary L-NG-monomethyl arginine (L-NMMA), a specific antagonist of nitric oxide synthesis, on coronary vascular resistance and epicardial coronary artery diameter at rest and after acetylcholine in 24 patients with coronary artery disease and in 12 subjects with angiographically normal coronary arteries who were free from atherosclerotic risk factors.
With L-NMMA, the 13 +/- 4% (mean +/- SEM) increase in coronary vascular resistance and the 4 +/- 1% lumen diameter narrowing in atherosclerotic patients were lower than the 38 +/- 9% increase in resistance and the 15 +/- 2% decrease in diameter (both p < 0.01) observed in normal control subjects, indicating reduced basal nitric oxide activity in atherosclerosis. The degree of angiographic atherosclerotic narrowing did not correlate with the magnitude of diameter reduction. Acetylcholine-induced coronary epicardial and microvascular dilation was also depressed in atherosclerotic patients (32.2 +/- 9% reduction in coronary vascular resistance with 10(-6) mol/liter acetylcholine) compared with normal control subjects (65.5 +/- 2% decrease, p < 0.01). L-NMMA inhibited acetylcholine-induced epicardial and microvascular vasodilation in both patient groups, but the inhibition was greater in normal control subjects than in atherosclerotic patients, indicating that stimulation of nitric oxide activity by acetylcholine is reduced in atherosclerotic patients compared with normal control subjects. Coronary vascular dilation with sodium nitroprusside was similar in both groups and was not suppressed by L-NMMA. Furthermore, L-arginine reversed the constrictor effects of L-NMMA, indicating that the action of L-NMMA is specifically caused by inhibition of nitric oxide production from L-arginine.
These findings indicate that 1) there is a reduced basal activity of nitric oxide in the human atherosclerotic epicardial and microvascular coronary circulation; and 2) acetylcholine-induced coronary vascular dilation is at least partly due to stimulation of the activity of nitric oxide, and the reduced response to acetylcholine is due to attenuation in the stimulated activity of nitric oxide in patients with atherosclerosis.
我们测定了人类动脉粥样硬化性冠状动脉循环在静息状态下以及乙酰胆碱作用后的一氧化氮活性。
尽管冠状动脉粥样硬化患者对内皮依赖性血管扩张剂乙酰胆碱的反应异常，但此前尚未研究这是否反映了人类体内一氧化氮活性异常。
我们研究了一氧化氮合成的特异性拮抗剂冠状动脉内注射L-NG-单甲基精氨酸（L-NMMA）对24例冠心病患者以及12例冠状动脉造影正常且无动脉粥样硬化危险因素受试者静息状态下以及乙酰胆碱作用后的冠状动脉血管阻力和心外膜冠状动脉直径的影响。
使用L-NMMA时，动脉粥样硬化患者冠状动脉血管阻力增加13±4%（均值±标准误）以及管腔直径缩小4±1%，低于正常对照受试者观察到的阻力增加38±9%以及直径减小15±2%（均p<0.01），表明动脉粥样硬化时基础一氧化氮活性降低。血管造影显示的动脉粥样硬化狭窄程度与直径减小幅度无关。与正常对照受试者相比，动脉粥样硬化患者乙酰胆碱诱导的心外膜和微血管扩张也受到抑制（10⁻⁶mol/L乙酰胆碱作用下冠状动脉血管阻力降低32.2±9%）（正常对照受试者为65.5±2%降低，p<0.01）。L-NMMA抑制了两组患者乙酰胆碱诱导的心外膜和微血管血管扩张，但正常对照受试者中的抑制作用大于动脉粥样硬化患者，表明与正常对照受试者相比，动脉粥样硬化患者中乙酰胆碱对一氧化氮活性的刺激作用降低。两组中硝普钠引起的冠状动脉血管扩张相似且未被L-NMMA抑制。此外，L-精氨酸逆转了L-NMMA的收缩作用，表明L-NMMA的作用是由抑制L-精氨酸生成一氧化氮特异性引起的。
这些发现表明：1）人类动脉粥样硬化的心外膜和微血管冠状动脉循环中一氧化氮的基础活性降低；2）乙酰胆碱诱导的冠状动脉血管扩张至少部分归因于一氧化氮活性的刺激，而动脉粥样硬化患者对乙酰胆碱反应降低是由于一氧化氮刺激活性减弱。
