Packer M
Department of Medicine, Mount Sinai School of Medicine, City University of New York, New York.
Eur Heart J. 1989 May;10 Suppl A:20-5. doi: 10.1093/eurheartj/10.suppl_a.20.
Tolerance develops during the prolonged use of organic nitrates in patients with chronic heart failure in a fashion similar to its development in patients with angina pectoris, the magnitude of tolerance development being directly proportional to the frequency of dosing. When nitroglycerin is given continuously or when isosorbide dinitrate is administered frequently throughout the day (e.g., every 4h), haemodynamic tolerance develops completely in most patients within 24-48h. Such tolerance can be avoided, however, when these drugs are given intermittently (e.g., every 8 or 12 h). Unfortunately, most clinical trials with isosorbide dinitrate have attempted to produce continuous haemodynamic effects by administering the drug at frequent intervals; this may explain why these trials have produced equivocal results. Two mechanisms have been proposed to explain the development of tolerance in patients with chronic heart failure. According to the first hypothesis, tolerance develops as a result of the depletion of intracellular sulfhydryl groups that are essential to the ability of nitroglycerin to activate guanylate cyclase--the key enzyme in the action of nitrates on blood vessels. According to the second hypothesis, tolerance develops as a result of the activation of endogenous neurohormonal systems; the resulting vasoconstriction limits the direct effects of the nitrovasodilators. A better understanding of both mechanisms may lead to interventions that will circumvent the development of tolerance and enhance the efficacy of long-term nitrate therapy.
在慢性心力衰竭患者中长期使用有机硝酸盐时会产生耐受性，其产生方式与心绞痛患者相似，耐受性的程度与给药频率成正比。当持续给予硝酸甘油或一天中频繁给予硝酸异山梨酯（如每4小时一次）时，大多数患者在24 - 48小时内会完全产生血流动力学耐受性。然而，当这些药物间歇给药（如每8或12小时一次）时，可以避免这种耐受性。不幸的是，大多数硝酸异山梨酯的临床试验试图通过频繁给药来产生持续的血流动力学效应；这可能解释了为什么这些试验结果不明确。已经提出了两种机制来解释慢性心力衰竭患者耐受性的产生。根据第一种假设，耐受性的产生是由于细胞内巯基的消耗，而巯基是硝酸甘油激活鸟苷酸环化酶（硝酸盐对血管作用的关键酶）能力所必需的。根据第二种假设，耐受性的产生是由于内源性神经激素系统的激活；由此产生的血管收缩限制了硝基血管扩张剂的直接作用。对这两种机制的更好理解可能会带来一些干预措施，从而避免耐受性的产生并提高长期硝酸盐治疗的疗效。
