硝酸酯类药物耐药机制及临床应对策略研究进展

在全球范围内,急性心肌梗死发病率、病死率均很高,硝酸酯类药物作为急性心肌梗死及心绞痛的一线治疗药物,可有效增加血管内皮细胞一氧化氮(NO)含量及心肌血供,扩张冠状动脉,但长期持续使用可导致硝酸酯类药物耐药,进而导致其扩张血管作用减弱或消失、血管内皮细胞功能紊乱、缺血区心肌细胞存活能力降低、心肌梗死面积扩大等,因此硝酸酯类药物耐药受到越来越多学者的关注。本文就硝酸酯类药物耐药机制及临床应对策略进行综述。     

硝酸酯类药物的耐药性分析

硝酸酯类药物的耐药性分析禹城市中医院（２５１２００）刘莹梁建敏硝酸酯类药物目前广泛用于临床急性心肌梗塞、心绞痛、充血性心力衰竭的治疗，并取得满意疗效，但长期应用或用法欠妥亦出现了耐药现象。现分析如下。硝酸酯类药物进入体内平滑肌细胞后，在巯基的参与下，...     

硝酸酯耐药的影响因素及对策

以硝酸甘油 ( NTG)为代表的硝酸酯类药物是心血管疾病传统、重要的治疗药物。然而 ,硝酸酯的耐药问题一直困扰着广大心血管病医师 ,其发生机制至今仍不十分清楚。硝酸酯耐药现象首先由Crandall等 [1]描述 ,当时及随后相当长的时间里该问题并未引起人们的足够重视。直到近几十年来 ,认识到硝酸酯耐药影响了它对缺血性心脏病 ( IHD)及充血性心力衰竭 ( CHF)的治疗作用 ,对其机制的探讨才提到日程上来。目前认为 ,硝酸酯进入体内后 ,由血管内皮及平滑肌细胞摄取 ,经一系列反应生成一氧化氮 ( NO) ,NO激活细胞中的鸟苷酸环化酶 ( SGC) ,…     

硝酸酯类药物耐药问题

硝酸酯类药物连续应用或频繁给药时迅速恨生耐药，其耐药现象有多因素，主要涉及到神经内分泌系统调整和细胞内硝酸甘油代谢障碍两个方面。本文综述近年来此种类药物耐药的可能机制和预防方面的一些问题。     

乙醛脱氢酶2与硝酸酯耐药关系的研究进展

从19世纪后期开始,硝酸酯类药物就应用于稳定型心绞痛、急性心肌梗死及慢性充血性心力衰竭的临床治疗。然而,长期应用时机体血管很快对其产生耐药,影响了该类药物的血流动力学和抗缺血效果。其耐药机制极为复杂,尚不十分清楚。近来研究表明,线粒体内活性氧簇的产生和继发乙醛脱氢酶2的氧化失活,在硝酸酯耐药和交叉耐药产生过程中起重要作用。     

福辛普利和单硝酸异山梨酯缓释剂联合治疗心绞痛的疗效观察

硝酸酯类药物广泛用于治疗冠心病心绞痛〔1〕。但血管对硝酸酯类药物的耐受性使它的长期应用受到了限制。而单硝酸异山梨酯缓释剂与其他硝酸酯类药物相比耐药性较低。既往有使用转换酶抑制剂 (ACEI)与硝酸酯类合用可防止硝酸酯类耐药的报道〔1〕。本研究联合使用新一代ACEI———福辛普利和单硝酸异山梨酯缓释剂治疗冠心病心绞痛 ,并与单用单硝酸异山梨酯缓释剂比较 ,同时探讨福辛普利增强硝酸酯类药物疗效的机制。1　资料和方法1 1　病例选择　 2 0 0 2年 5月～ 2 0 0 3年 12月在我院住院的冠心病心绞痛患者 90例 ,男 5 8例 ,女 3 2例 …     

对硝酸酯类药物耐药的新认识

目前硝酸类药物仍是临床治疗冠心病、心衰的主要药物之一。本文将有关硝酸酯类药物耐药的近期研究作一综述。     

硝酸酯类药物在冠心病中的应用及注意事项

1硝酸酯类药物在冠心病中的应用 硝酸酯类药物是临床常用的抗心绞痛药物之一，其主要作用是松弛血管平滑肌产生血管扩张。该药对静脉的扩张作用明显强于对动脉的扩张作用。周围静脉的扩张可降低心脏前负荷，动脉的扩张可减轻心脏后负荷，从而减少心脏做功和心肌耗氧量。硝酸酯类药物还可直接扩张冠状动脉，增加心肌血流，预防和解除冠状动脉痉挛，     

硝酸酯耐药研究进展

硝酸酯耐药研究进展黄雅乐，戴闺柱硝酸酯耐药系指为患者对某一剂量的硝酸酯的效应下降，或者需要增加剂量才能维持所要求的效应。１硝酸酯耐药表现及特点过去认为，硝酸酯耐药只存在于慢性充血性心力衰竭（ＣＨＦ）治疗中，而现在认为在缺血性心脏病（ＩＨＤ）治疗中同样...     

硝酸酯类药物的合理应用

硝酸酯类药物的合理应用河北医学院附属第二医院内科郝玉明，李星海综述陶桂华审校硝酸酯类药物用于治疗心肌缺血已有１００多年历史，目前仍然是抗心肌缺血的主要药物之一。本文仅就硝酸酯类药物抗心肌缺血作用机制的新认识、硝酸酯类药物的耐药性及如何合理应用做一综述...     

Pharmacokinetics and pharmacodynamics of organic nitrates

The pharmacokinetic and pharmacodynamic aspects of organic nitrates are discussed, with particular emphasis on the 3 major organic nitrates currently in use, nitroglycerin (NTG), isosorbide dinitrate and isosorbide-5-mononitrate. After intravenous administration, both NTG and isosorbide dinitrate exhibit large systemic clearances and both nitrates appear to be extensively distributed in vascular and other peripheral tissues. Two pharmacokinetic features appear particularly notable for NTG: there is a significant arteriovenous extraction of the drug, and its systemic clearance is related to cardiac output. Both of these features, plus other evidence, suggest that organic nitrates may be substantially removed from the systemic circulation by the vasculature itself. During nitrate tolerance, plasma drug concentrations remain elevated, but vascular activity is diminished. This apparent paradox might be explainable by a unifying hypothesis of reduced nitrate metabolism during vascular tolerance; thus, in the tolerant state, reduced systemic clearance of the intact drug brought about elevated plasma concentrations, whereas reduced cellular metabolism at the smooth muscle brought about a decrease in vascular activity. The complex relations among plasma kinetics, vascular metabolism and pharmacologic action of organic nitrates are still poorly understood.     

Effect of in vitro organic nitrate tolerance on relaxation, cyclic GMP accumulation, and guanylate cyclase activation by glyceryl trinitrate and the enantiomers of isoidide dinitrate

Previously, it was shown that the D enantiomer of isoidide dinitrate was 10-fold more potent than the L enantiomer and 10-fold less potent than glyceryl trinitrate for stimulating cyclic GMP accumulation and relaxation of isolated rat aorta. In the present study, these organic nitrates were tested for their ability to induce tolerance to organic nitrate-induced relaxation, cyclic GMP accumulation, and guanylate cyclase activation in rat aorta in vitro. To compensate for the differences in vasodilator potency, tolerance was induced by incubating isolated rat aorta with concentrations of organic nitrates 1,000-fold greater than the EC50 for relaxation. Under these conditions, the EC50 for relaxation was increased significantly for each organic nitrate and to a similar degree on subsequent reexposure. These data suggest that the potential for inducing in vitro tolerance to relaxation was the same for the three organic nitrates tested. When activation of soluble guanylate cyclase by these compounds was assessed, the enantiomers of isoidide dinitrate were equipotent, but less potent than glyceryl trinitrate, suggesting that the site of enantioselectivity is not guanylate cyclase itself. In blood vessels made tolerant to organic nitrates by pretreatment with glyceryl trinitrate, vasodilator activity, cyclic GMP accumulation, and guanylate cyclase activation were attenuated on reexposure to each organic nitrate. In addition, differences in the potency of the three organic nitrates and the enantioselectivity of isoidide dinitrate for relaxation were abolished in tolerant tissue, whereas the potency difference between glyceryl trinitrate and isoidide dinitrate for activation of guanylate cyclase was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of nitrate tolerance

Summary There is now little dispute that clinical tolerance of organic nitrates occurs, particularly when these drugs are used by themselves to treat patients with stable angina pectoris and congestive heart failure. Classical hypotheses of nitrate tolerance suggest the phenomenon to result from vascular depletion of critical sulfhydryl groups, which are necessary to bring about vasorelaxation from nitrates. While this mechanism of nitrate tolerance probably operates when isolated blood vessels are exposed to high concentrations of nitrate in vitro, there is little evidence to suggest that it contributes to clinical nitrate tolerance. Instead, emerging data suggest that nitrates can cause significant shifts in fluid distribution and secretion of neurohormonal factors that can modulate their vasorelaxant effects. use of angiotensin converting enzyme inhibitors and diuretics in conjunction with nitrates may alleviate the development of tolerance, but the experience has not been universally favorable. Other receptor-effector systems that affect cardiovascular function, such as the adrenergic system, may also be affected by nitrate tolerance. The mechanisms of nitrate tolerance are therefore likely to be multifactorial, involving vascular biochemical changes, physiologic compensation, and possibly receptor regulation.     

The role of reactive free radicals in ischemic preconditioning--clinical and evolutionary implications

Ischemic preconditioning is a condition of reduced sensitivity to ischemic damage. This protective state can be induced by exposure to periods of brief, sublethal, ischemia prior to a protracted ischemic event, but, more interestingly, also by administration of specific drugs. Recent studies have emphasized the central role of free radicals (including superoxide anion and nitric oxide) in this process. In line with these observations, studies have demonstrated that also drugs such as organic nitrates, which are able to release nitric oxide (but also the highly oxidant superoxide anion) can induce preconditioning. Starting from our observations made in human experimental models regarding the effects of chronic therapy with organic nitrates, we criticize the hypothesis whereby nitrates might be used to induce a state similar to preconditioning upon chronic exposure. As well, we propose a theory for the evolutionary meaning of ischemic preconditioning based on the hypothesis that, while protective over short periods of time, continuous exposure to oxidant free radicals might be associated with a loss of this protective effect and, in certain cases, with an increased oxidative damage.     

Possible mechanisms of nitrate tolerance.

Prolonged exposure to organic nitrates has been shown to lead to the rapid development of tolerance to the peripheral and coronary vasodilatory effects of these drugs. As a result of this phenomenon, the hemodynamic and anti-ischemic effects of nitrates may be rapidly attenuated in patients with ischemic heart disease, congestive heart failure, or both. This nitrate tolerance appears to be both dose- and time-dependent. Likely mechanisms proposed for its development are multifactorial and include depletion of sulfhydryl groups, a nitrate-mediated increase in blood volume, and neurohormonal stimulation with activation of vasoconstrictive mechanisms.     

Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention

OBJECTIVE: To review the available information about nitrate tolerance, its potential mechanisms, clinical implications, and strategies for prevention. DATA IDENTIFICATION: A survey of the National Library of Medicine MEDLINE database and bibliographies of the reviewed articles. STUDY SELECTION AND DATA EXTRACTION: Studies were selected from the English language literature with an emphasis on recent studies and, when available, randomized placebo-controlled studies. Old studies were selected on the basis of their historical value and originality. A total of 134 retrieved articles were considered relevant and were reviewed in depth. RESULTS: The available information about the experimental as well as the clinical evidence for tolerance to organic nitrates has been summarized. In addition, information related to potential mechanisms, clinical implications, and possible methods for prevention have been reviewed. CONCLUSIONS: Evidence indicates that prolonged in-vitro exposure to organic nitrates, continuous intravenous or topical administration of nitrates, and frequent in-vivo oral dosing result in the rapid development of tolerance to the peripheral as well as to the coronary vasodilatory effects of the drugs. This phenomenon leads to the rapid attenuation of the hemodynamic and anti-ischemic effects of nitrates in patients with ischemic heart disease or congestive heart failure, or both. Tolerance development seems to be dose- and time-dependent, and its main mechanism seems to be a depletion of sulfhydryl groups at the vascular cell. Although the repletion of sulfhydryl groups with the use of sulfhydryl-containing drugs may help to prevent tolerance, the efficacy and safety of this approach requires further evaluation. Intermittent therapy allowing a sufficiently long, daily nitrate-washout interval seems to be the most effective and the most safe strategy currently available for the prevention of nitrate tolerance.     

Nitrates and angina pectoris

This review discusses the mechanisms of action of the organic nitrates, nitrate tolerance, and the effects of nitrates in patients with stable angina pectoris. The nitrates are prodrugs that enter the vascular smooth muscle, where they are denitrated to form the active agent nitric oxide (NO). NO activates guanylate cyclase, which results in cyclic guanosine monophosphate (cGMP) production and vasodilation as a result of reuptake of calcium by the sarcoplasmic reticulum. NO is identical to endothelium-derived relaxing factor (EDRF), which induces vasodilation, inhibits platelet aggregation, reduces endothelium adhesion, and has anticoagulant and fibrinolytic effects. Thus, the nitrates may be more than vasodilators and, in addition to reducing ischemia, may affect the process of atherosclerosis. The vascular effects of nitrates are attenuated during sustained therapy. Although the basis for the phenomenon of nitrate tolerance is not completely understood, sulfhydryl depletion as well as neurohormonal activation and increased plasma volume may be involved. The administration of N-acetylcysteine, angiotensin-converting enzyme (ACE) inhibitors, or diuretics do not consistently prevent nitrate tolerance. At present, intermittent nitrate therapy is the only way to avoid nitrate tolerance. The intermittent administration of nitrates, however, cannot provide continuous therapeutic benefits, and thus monotherapy with nitrates is not suitable for many patients with stable angina pectoris.     

Organic nitrates: New formulations and their clinical advantages

The organic nitrates have been used for more than a century in the management of patients with myocardial ischemia. The most commonly used agents at this time include nitroglycerin, isosorbide dinitrate, and isosorbide-5-mononitrate. These agents all exert their therapeutic effects through biodegradation to nitric oxide, which stimulates guanylate cyclase in vascular smooth muscle cells with the production of cyclic guanosine monophosphate. The latter induces vasodilation by reducing the availability of ionized calcium to the contractile proteins. Tolerance to the organic nitrates occurs when the agents are administered in an attempt to provide therapeutic effects throughout 24 hours each day. There are probably several mechanisms responsible for nitrate tolerance, but there is no evidence at this time that concurrent medications will modify the development of tolerance. The only available method at this time is to give these agents intermittently to provide a period of washout. In so doing, it is possible to provide therapeutic nitrate effects for approximately 12 hours throughout each 24-hour period.     

Nitrate tolerance in angina pectoris

Summary Tolerance to the hemodynamic and antianginal effects of the organic nitrates develops rapidly during therapy. This has been documented with a variety of nitrate preparations and with different routes of administration. Dosing strategies designed to provide therapeutic plasma nitrate concentrations throughout the 24 hours of the day are regularly associated with the development of tolerance. Recent information indicates that dosing schedules providing a nitrate-free period will permit continued efficacy of the organic nitrates without tolerance development. This can be accomplished in serveral ways. With oral preparations of isosorbide dinitrate, medication can be given 3 times daily, omitting the evening dose. Buccal nitroglycerin is usually given 3 times daily after meals, and this has been shown not to be associated with tolerance. Likewise, preliminary studies suggest that removal of the nitroglycerin patches for a period of several hours each day will prevent the development of tolerance. Much needs to be learned about the nitrate-free period. With oral isosorbide dinitrate, it appears that 12 hours is required, but this could be substantially less with nitroglycerin preparations. It is also possible that several short periods with low nitrate levels each day would suffice. Thus, simply increasing the interval between dosing of oral preparations may provide an adequate, low, nitrate-free period.     

Fluvastatin attenuates nitrate tolerance in patients with ischemic heart disease complicating hypercholesterolemia

Background: Long-term administration of nitrates results in the development of tolerance. Nitrate tolerance is considered to occur in association with oxidative stress, although its underlying mechanisms are multi-factorial. Fluvastatin, a newly developed statin, is considered to have not only a cholesterol-lowering effect but also anti-oxidative properties. Methods: In this study, the effect of fluvastatin on nitrate tolerance was investigated in 12 dyslipidemic patients (nine men and three women, aged 63.5±6.7 years), who were complicated with ischemic heart disease and had received organic nitrates for a long period. Results: Four months after fluvastatin therapy, symptoms of angina were significantly reduced. Consumption of sublingual nitrates over 2 weeks significantly decreased (14.4±11.2 to 2.3±2.5 tablets, P<0.01). In exercise stress testing, exercise duration was significantly prolonged (275±73 to 360±86 s, P<0.01) and the blood pressure-heart rate products significantly increased (16 368±2246 to 18 381±1772, P<0.01). Both the percent change in forearm blood flow with reactive hyperemia (232±83 to 282±104%, P<0.05) and that after sublingual nitroglycerine (2.5±4.7 to 5.8±4.7%, P<0.05) were increased. Although the levels of total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol were unchanged, the serum anti-Ox-LDL titer (16.7±6.3 to 13.4±5.4 AcU/ml, P<0.05) and 8-OHdG level (1.11±0.34 to 0.73±0.34 ng/ml, P<0.05) decreased. Conclusions: Fluvastatin attenuated nitrate tolerance in dyslipidemic patients complicated with ischemic heart disease who had been receiving organic nitrates over long period. The anti-oxidative effect of fluvastatin may attenuate nitrate tolerance.