Unger P, Vachiery J L, de Cannière D, Staroukine M, Berkenboom G
Cardiology Department, Erasme Hospital, Free University of Brussels.
Am Heart J. 1994 Sep;128(3):557-63. doi: 10.1016/0002-8703(94)90632-7.
To evaluate the mechanisms involved in nitrate tolerance, we randomized 23 patients with congestive heart failure resulting from coronary artery disease to an isosorbide dinitrate or a molsidomine infusion. The drugs were titrated to decrease pulmonary capillary wedge pressure by > or = 30% or > or = 10 mm Hg. Then isosorbide dinitrate, molsidomine, or placebo was infused in a double-blind randomized manner for 24 hours. In all patients, treatment with enalapril was begun > or = 48 hours before the beginning of the protocol and was continued throughout the study to avoid renin-angiotensin activation. The pulmonary capillary wedge pressure remained significantly decreased at 24 hours during molsidomine infusion only. No significant increase in catecholamines occurred. Because molsidomine differs from organic nitrates by its property of directly stimulating guanylate cyclase without depending on thiol group availability, these results suggest that impaired biotransformation of nitrates is involved in tolerance induced by high doses of isosorbide dinitrate in congestive heart failure.
为评估硝酸酯类耐受性的相关机制，我们将23例因冠状动脉疾病导致充血性心力衰竭的患者随机分为两组，分别接受二硝酸异山梨酯或莫索尼定静脉输注。药物滴定以使肺毛细血管楔压降低≥30%或≥10 mmHg。然后以双盲随机方式输注二硝酸异山梨酯、莫索尼定或安慰剂24小时。在所有患者中，在方案开始前≥48小时开始使用依那普利治疗，并在整个研究过程中持续使用，以避免肾素-血管紧张素激活。仅在输注莫索尼定时，肺毛细血管楔压在24小时时仍显著降低。儿茶酚胺未显著增加。由于莫索尼定与有机硝酸盐不同，其具有直接刺激鸟苷酸环化酶的特性，而不依赖于巯基的可用性，这些结果表明，在充血性心力衰竭中，高剂量二硝酸异山梨酯诱导的耐受性涉及硝酸酯类生物转化受损。
