Jurt U, Gori T, Ravandi A, Babaei S, Zeman P, Parker J D
Division of Cardiology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
J Am Coll Cardiol. 2001 Sep;38(3):854-9. doi: 10.1016/s0735-1097(01)01414-0.
We investigated the development of nitrate tolerance after continuous exposure to nitroglycerin (GTN) as compared with pentaerythritol tetranitrate (PETN) in humans.
Sustained therapy with GTN causes tolerance and has been associated with increased production of free oxygen radicals by the endothelium. Pentaerythritol tetranitrate is an organic nitrate that has been used in the therapy of angina. There have been no investigations concerning the development of tolerance to PETN in humans. Animal investigations suggested that continuous therapy with PETN does not cause increased free radical production or hemodynamic tolerance.
We randomized 30 healthy volunteers to continuous GTN (0.6 mg/h/24 h), long-acting PETN (60 mg orally three times a day) or no treatment (control group) for seven days. We studied systemic blood pressure responses and venous volume responses to GTN with strain-gauge plethysmography. The levels of cytotoxic aldehydes and isoprostanes were measured as markers of free radical-mediated lipid peroxidation.
Tolerance, as demonstrated by blood pressure and forearm plethysmography, developed in the GTN group and was absent in the PETN group (p < 0.05). Therapy with GTN was associated with a significant increase in plasma markers of lipid peroxidation. This response was not observed in those treated with PETN (isoprostanes: control: 38 +/- 5; GTN: 59 +/- 6; PETN: 38 +/- 3 microg/ml; p < 0.005).
Treatment with PETN does not cause tolerance and is not associated with evidence of increased free radical production.
我们研究了人类连续暴露于硝酸甘油（GTN）与季戊四醇四硝酸酯（PETN）后硝酸酯耐受性的发展情况。
GTN持续治疗会导致耐受性，并与内皮细胞产生的游离氧自由基增加有关。季戊四醇四硝酸酯是一种有机硝酸盐，已用于心绞痛治疗。目前尚无关于人类对PETN耐受性发展的研究。动物研究表明，PETN持续治疗不会导致自由基产生增加或血流动力学耐受性增加。
我们将30名健康志愿者随机分为三组，分别接受连续GTN治疗（0.6毫克/小时/24小时）、长效PETN治疗（每日口服60毫克，分三次服用）或不治疗（对照组），为期七天。我们通过应变片体积描记法研究了全身血压反应和对GTN的静脉容量反应。测量细胞毒性醛和异前列腺素的水平作为自由基介导的脂质过氧化的标志物。
GTN组出现了由血压和前臂体积描记法显示的耐受性，而PETN组未出现（p<0.05）。GTN治疗与脂质过氧化血浆标志物的显著增加有关。在接受PETN治疗的患者中未观察到这种反应（异前列腺素：对照组：38±5；GTN组：59±6；PETN组：38±3微克/毫升；p<0.005）。
PETN治疗不会导致耐受性，也与自由基产生增加的证据无关。
