Lehmann G, Hähnel I, Reiniger G, Lampen M, Beyerle A, Schömig A
Deutsches Herzzentrum München, Klinik an der Technischen Universität, Munich, Germany.
J Cardiovasc Pharmacol. 1998 Feb;31(2):212-20. doi: 10.1097/00005344-199802000-00006.
The use of nitrates for treatment of heart failure is encumbered by tolerance, caused by whatever mechanism, which has been reported only in a few instances with sydnonimines. Accordingly, we compared molsidomine (6 mg/h) and isosorbide-5-mononitrate (3.75 mg/h) with respect to maximal hemodynamic effects, rapidity and extent of attenuation, and underlying mechanisms by means of constant infusions over 24 h each in 15 patients with chronic congestive heart failure (NYHA II-III) with a placebo-controlled, double-blind, randomized, crossover protocol. Hemodynamic measurements and determinations of neurohormones were performed at baseline and at 2, 8, and 24 h after the beginning of infusions. With molsidomine, reductions of diastolic pulmonary artery pressure by 29% (p < 0.001), by 24% (p < 0.01), and by 24% (p < 0.01) versus placebo were found at 2, 8, and 24 h, which amounted to 19% (p < 0.01), 10% (NS), and 14% (NS) with the nitrate. Cardiac output was meaningfully affected only with molsidomine (+5%, NS, at 2 h; +9%, p < 0.05, at 8 h; and +15%, p < 0.05, at 24 h), as was systemic vascular resistance (-13%, p < 0.05; -9%, NS; and -18%, p < 0.01) at the corresponding times. Increases in renin activity amounted to 130% (p < 0.001), 117% (p < 0.001), and 112% (p < 0.001) with molsidomine, and to 14, 16%, and 0 (each NS) with the nitrate at the corresponding times. Hematocrit was reduced by 5% (p < 0.001), 7% (p < 0.001), and 12% (p < 0.01) with molsidomine and by 5% (NS), 5% (p < 0.05), and 5% (NS) with the nitrate. We conclude that neurohumoral counterregulation or fluid shift, which is even more pronounced with molsidomine despite longer-lasting effects, has no essential role in nitrate-tolerance development. With molsidomine, such a role cannot be ruled out, although alternatively, a fluid shift from arterial to the low-pressure arm of circulation during the later course of infusion would be even more likely.
硝酸盐类用于治疗心力衰竭时会受到耐受性的困扰，无论其机制如何，仅在少数与亚胺类药物相关的病例中有所报道。因此，我们采用安慰剂对照、双盲、随机、交叉试验方案，对15例慢性充血性心力衰竭（纽约心脏协会II - III级）患者分别持续输注吗多明（6毫克/小时）和5-单硝酸异山梨酯（3.75毫克/小时）24小时，比较了它们的最大血流动力学效应、效应衰减的速度和程度以及潜在机制。在输注开始时的基线以及输注后2小时、8小时和24小时进行血流动力学测量和神经激素测定。使用吗多明时，与安慰剂相比，在2小时、8小时和24小时时舒张压肺动脉压分别降低29%（p < 0.001）、24%（p < 0.01）和24%（p < 0.01），而使用硝酸盐时分别降低19%（p < 0.01）、10%（无统计学意义）和14%（无统计学意义）。仅吗多明对心输出量有显著影响（2小时时增加5%，无统计学意义；8小时时增加9%，p < 0.05；24小时时增加15%，p < 0.05），相应时间的全身血管阻力也有变化（分别降低 - 13%，p < 0.05； - 9%，无统计学意义； - 18%，p < 0.01）。吗多明在相应时间使肾素活性分别增加130%（p < 0.001）、117%（p < 0.001）和112%（p < 0.001），而硝酸盐分别增加14%、16%和0（均无统计学意义）。吗多明使血细胞比容分别降低5%（p < 0.001）、7%（p < 0.001）和12%（p < 0.01），硝酸盐分别降低5%（无统计学意义）、5%（p < 0.05）和5%（无统计学意义）。我们得出结论，神经体液的反调节或液体转移在硝酸盐耐受性形成中并非起关键作用，尽管吗多明的作用持续时间更长，但其这种作用更明显。对于吗多明，虽然不能排除这种作用，但输注后期从动脉向循环低压部分的液体转移可能更有可能。
