Quyyumi A A, Dakak N, Andrews N P, Gilligan D M, Panza J A, Cannon R O
National Institutes of Health, Cardiology Branch, NHLBI, Bethesda, MD 20892-1650, USA.
Circulation. 1995 Aug 1;92(3):320-6. doi: 10.1161/01.cir.92.3.320.
The vascular endothelium contributes to smooth muscle relaxation by tonic release of nitric oxide. To investigate the contribution of nitric oxide to human coronary epicardial and microvascular dilation during conditions of increasing myocardial oxygen requirements, we studied the effect of inhibiting nitric oxide synthesis with NG-monomethyl-L-arginine (L-NMMA) on the coronary vasodilation during cardiac pacing in patients with angiographically normal coronary arteries with and without multiple risk factors for coronary atherosclerosis.
In 26 patients with angiographically normal or near-normal epicardial coronary arteries, metabolic vasodilation was assessed as a change in coronary vascular resistance and diameter during cardiac pacing (mean heart rate, 141 beats per minute). Endothelium-dependent vasodilation was estimated with intracoronary acetylcholine and endothelium-independent dilation with intracoronary sodium nitroprusside and adenosine. These measurements were repeated after 64 mumol/min intracoronary L-NMMA. At rest, L-NMMA produced a 16 +/- 25% (mean +/- SD) increase in coronary vascular resistance (P < .05) and an 11% reduction in distal epicardial coronary artery diameter (P < .01), indicating tonic basal release of nitric oxide from human coronary epicardial vessels and microvessels. Significant inhibition of pacing-induced metabolic coronary vascular dilation occurred with L-NMMA, coronary vascular resistance was 38 +/- 56% higher (P < .03), and epicardial coronary dilation during control pacing (9 +/- 13%) was converted to constriction after L-NMMA and pacing (-6 +/- 9%, P < .04). L-NMMA specifically inhibited endothelium-dependent vasodilation with acetylcholine (coronary vascular resistance was 72% higher [P < .01]) but did not alter endothelium-independent dilation with sodium nitroprusside and adenosine. Nine patients had no major risk factors for atherosclerosis, defined as serum cholesterol > 240 mg/dL, hypertension, or diabetes. The remaining 17 patients with one or more of these risk factors had depressed microvascular vasodilation during cardiac pacing (coronary vascular resistance decreased by 13% versus 36% in those without risk factors, P < .05). The inhibitory effect of L-NMMA on pacing-induced coronary epicardial and microvascular vasodilation was observed only in patients without risk factors, whereas those with risk factors had an insignificant change, indicating that nitric oxide contributes significantly to pacing-induced coronary vasodilation in patients free of risk factors and without endothelial dysfunction. Patients with risk factors also had reduced vasodilation with acetylcholine (40 +/- 28% versus 68 +/- 8% decrease in coronary vascular resistance, P < .01), but the responses to sodium nitroprusside were similar in both groups.
During metabolic stimulation of the human heart, nitric oxide release contributes significantly to microvascular vasodilation and is almost entirely responsible for the epicardial vasodilation. This contribution of nitric oxide is reduced in patients exposed to risk factors for coronary atherosclerosis and leads to a net reduction in vasodilation during stress. An important implication of these findings is that reduced nitric oxide bioavailability during stress in patients with atherosclerosis or risk factors for atherosclerosis may contribute to myocardial ischemia by limiting epicardial and microvascular coronary vasodilation.
血管内皮通过持续释放一氧化氮促进平滑肌舒张。为研究在心肌需氧量增加的情况下一氧化氮对人冠状动脉心外膜血管和微血管扩张的作用，我们在有或无冠状动脉粥样硬化多种危险因素的冠状动脉造影正常的患者中，研究了用NG-单甲基-L-精氨酸（L-NMMA）抑制一氧化氮合成对心脏起搏期间冠状动脉扩张的影响。
在26例冠状动脉造影正常或接近正常的心外膜冠状动脉患者中，代谢性血管舒张通过心脏起搏期间（平均心率141次/分钟）冠状动脉血管阻力和直径的变化来评估。内皮依赖性血管舒张用冠状动脉内乙酰胆碱评估，内皮非依赖性舒张用冠状动脉内硝普钠和腺苷评估。在冠状动脉内给予64 μmol/min的L-NMMA后重复这些测量。静息时，L-NMMA使冠状动脉血管阻力增加16±25%（平均值±标准差，P<0.05），心外膜冠状动脉远端直径减少11%（P<0.01），表明人冠状动脉心外膜血管和微血管持续基础释放一氧化氮。L-NMMA显著抑制起搏诱导的代谢性冠状动脉血管舒张，冠状动脉血管阻力升高38±56%（P<0.03），对照起搏期间的心外膜冠状动脉扩张（9±13%）在L-NMMA和起搏后转变为收缩（-6±9%，P<0.04）。L-NMMA特异性抑制乙酰胆碱介导的内皮依赖性血管舒张（冠状动脉血管阻力升高72%[P<0.01]），但不改变硝普钠和腺苷介导的内皮非依赖性舒张。9例患者无动脉粥样硬化的主要危险因素，定义为血清胆固醇>240 mg/dL、高血压或糖尿病。其余17例有这些危险因素中一项或多项的患者在心脏起搏期间微血管舒张减弱（冠状动脉血管阻力降低13%，而无危险因素者为36%，P<0.05）。L-NMMA对起搏诱导的冠状动脉心外膜和微血管舒张的抑制作用仅在无危险因素的患者中观察到，但有危险因素的患者变化不显著，表明一氧化氮对无危险因素且无内皮功能障碍患者的起搏诱导冠状动脉舒张有显著作用。有危险因素的患者乙酰胆碱介导的血管舒张也减弱（冠状动脉血管阻力降低40±28%，而无危险因素者为68±8%，P<0.01），但两组对硝普钠的反应相似。
在人心脏的代谢刺激过程中，一氧化氮释放对微血管舒张有显著作用，并且几乎完全负责心外膜血管舒张。在暴露于冠状动脉粥样硬化危险因素的患者中，一氧化氮的这种作用减弱，导致应激期间血管舒张净减少。这些发现的一个重要意义是，动脉粥样硬化患者或有动脉粥样硬化危险因素的患者在应激期间一氧化氮生物利用度降低可能通过限制心外膜和微血管冠状动脉舒张而导致心肌缺血。
