Münzel T, Heitzer T, Kurz S, Harrison D G, Luhman C, Pape L, Olschewski M, Just H
Medizinische Klinik III, Division of Cardiology, University of Freiburg, Germany.
J Am Coll Cardiol. 1996 Feb;27(2):297-303. doi: 10.1016/0735-1097(95)00475-0.
We sought to examine whether long-term nitroglycerin treatment causes tolerance in large coronary arteries and whether the loss of vascular effects parallels neurohormonal adjustments.
Nitroglycerin therapy is associated with increased plasma renin activity and aldosterone levels and a decrease in hematocrit. It is assumed that nitroglycerin tolerance results in part from these neurohormonal adjustments and intravascular volume expansion.
Three groups were studied: group I (n = 10), no prior nitroglycerin therapy; and group II (n = 10) and group III (n = 8), 24- and 72-h long-term nitroglycerin infusion (0.5 micrograms/kg body weight per min), respectively. Coronary artery dimensions were assessed using quantitative angiography. Plasma renin activity, plasma aldosterone and vasopressin levels and hematocrit were monitored before and during nitroglycerin infusions.
In group I, increasing intravenous concentrations of nitroglycerin caused a dose-dependent increase of the midportion of the left anterior descending coronary artery (baseline diameter 2.13 +/- 0.07 mm [mean +/- SEM], maximally by 22 +/- 2%) and left circumflex coronary artery (baseline diameter 2.08 +/- 0.07) mm, maximally by 22 +/- 3%). An intracoronary nitroglycerin bolus (0.2 mg) caused no further significant increase in diameter, indicating maximal dilation. In group II (n = 10), the baseline large coronary artery diameter under ongoing nitroglycerin was significantly larger than that in group I (left anterior descending artery 2.61 +/- 0.08 mm, left circumflex artery 2.57 +/- 0.08 mm). Additional intravenous and intracoronary nitroglycerin challenges did not cause further dilation, indicating maximally dilated vessels. At the same time, plasma renin activity, plasma aldosterone and vasopressin levels were significantly increased, and hematocrit significantly decreased. In group III patients, the baseline diameter of the left anterior descending artery and the left circumflex artery did not differ from that in patients without nitroglycerin pretreatment, indicating a complete loss of nitroglycerin coronary vasodilative effects. These patients showed no significant increase in circulating neurohormonal levels but a significant decrease in hematocrit.
Within 24 h of continuous nitroglycerin treatment, the coronary arteries were maximally dilated despite neurohormonal adjustments and signs of intravascular volume expansion. Within 3 days of nitroglycerin infusion, tolerance developed in the absence of neurohormonal activation. The dissociation of neurohormonal adjustments and tolerance in large coronary arteries indicates that after long-term nitroglycerin treatment, true vascular tolerance, perhaps from an intracellular tolerance step, may have developed.
我们试图研究长期硝酸甘油治疗是否会导致大冠状动脉产生耐受性，以及血管效应的丧失是否与神经激素调节平行。
硝酸甘油治疗与血浆肾素活性增加、醛固酮水平升高以及血细胞比容降低有关。据推测，硝酸甘油耐受性部分源于这些神经激素调节和血管内容量扩张。
研究分为三组：第一组（n = 10），未接受过硝酸甘油治疗；第二组（n = 10）和第三组（n = 8），分别进行24小时和72小时的硝酸甘油持续输注（0.5微克/千克体重/分钟）。使用定量血管造影评估冠状动脉尺寸。在硝酸甘油输注前和输注期间监测血浆肾素活性、血浆醛固酮和血管加压素水平以及血细胞比容。
在第一组中，静脉内硝酸甘油浓度增加导致左前降支冠状动脉中段（基线直径2.13±0.07毫米[平均值±标准误]，最大增加22±2%）和左旋支冠状动脉（基线直径2.08±0.07毫米，最大增加22±3%）呈剂量依赖性增加。冠状动脉内注射硝酸甘油推注（0.2毫克）未导致直径进一步显著增加，表明达到最大扩张。在第二组（n = 10）中，持续输注硝酸甘油时的基线大冠状动脉直径显著大于第一组（左前降支动脉2.61±0.08毫米，左旋支动脉2.57±0.08毫米）。额外的静脉内和冠状动脉内硝酸甘油激发试验未导致进一步扩张，表明血管已达到最大扩张。同时，血浆肾素活性、血浆醛固酮和血管加压素水平显著升高，血细胞比容显著降低。在第三组患者中，左前降支动脉和左旋支动脉的基线直径与未接受硝酸甘油预处理的患者无差异，表明硝酸甘油的冠状动脉血管舒张作用完全丧失。这些患者循环神经激素水平无显著升高，但血细胞比容显著降低。
在连续硝酸甘油治疗24小时内，尽管存在神经激素调节和血管内容量扩张的迹象，但冠状动脉已达到最大扩张。在硝酸甘油输注3天内，在无神经激素激活的情况下出现了耐受性。大冠状动脉中神经激素调节与耐受性的分离表明，长期硝酸甘油治疗后，可能从细胞内耐受步骤开始，真正的血管耐受性可能已经形成。
