关于抗坏血酸盐对充血性心力衰竭患者硝酸盐耐受性预防作用的随机、双盲、安慰剂对照研究。

Randomized, double-blind, placebo-controlled study of ascorbate on the preventive effect of nitrate tolerance in patients with congestive heart failure.

作者信息

Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y

机构信息

Department of Cardiology, KINU Medical Association Hospital, Mitsukaido, Ibaraki, Japan.

出版信息

Circulation. 1998 Mar 10;97(9):886-91. doi: 10.1161/01.cir.97.9.886.

DOI:10.1161/01.cir.97.9.886

PMID:9521337

Abstract

BACKGROUND

Reduced cGMP production caused by increased superoxide has been proposed as a mechanism of nitrate tolerance during continuous nitrate therapy. This study was designed to evaluate the effects of ascorbate, an antioxidant, on the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.

METHODS AND RESULTS

Twenty patients with congestive heart failure were randomized to receive intravenous infusion of nitroglycerin concomitantly with placebo (placebo group, n=10) or intravenous ascorbate (vitamin C group, n=10). After baseline measurements were obtained, dose titration was started by the infusion of nitroglycerin at a rate of 0.5 microg/kg per minute (titration period). Measurements of hemodynamic parameters and blood sampling were performed serially at 0, 6, 12, 18, and 24 hours after the titration period. At baseline, mean pulmonary artery pressure (MPAP, mm Hg), mean pulmonary capillary wedge pressure (PCWP, mm Hg), plasma vitamin E level (micromol/L), and platelet cGMP level (pmol/10[9] platelets) were comparable in the two groups (placebo group: MPAP, 48+/-6; PCWP, 24+/-4; cGMP, 0.76+/-0.12; vitamin E, 18.2+/-1.2; vitamin C: MPAP, 49+/-7; PCWP, 24+/-4; cGMP, 0.71+/-0.16; vitamin E, 18.6+/-1.3). In both groups, at 6 hours after the titration period, MPAP and PCWP were significantly decreased (placebo group: MPAP, 26+/-5; PCWP, 15+/-4; vitamin C: MPAP, 26+/-4; PCWP, 16+/-4), and platelet cGMP was significantly increased (placebo group: 2.42+/-0.24; vitamin C: 2.26+/-0.26). However, at 18 hours after titration, in the placebo group, MPAP (44+/-5) and PCWP (23+/-4) were increased, and platelet cGMP (0.85+/-0.20) and plasma vitamin E levels (12.4+/-1.4) were significantly decreased. In contrast, in the vitamin C group, MPAP (31+/-6), PCWP (17+/-5), platelet cGMP (2.49+/-0.23), and plasma vitamin E levels (17.6+/-1.4) were maintained for 18 hours after the titration period.

CONCLUSIONS

These findings indicate that ascorbate, an antioxidant, may prevent the development of nitrate tolerance during continuous nitrate therapy in patients with congestive heart failure.

摘要

背景

超氧化物增加导致环磷酸鸟苷（cGMP）生成减少被认为是持续硝酸酯治疗期间产生硝酸酯耐受性的一种机制。本研究旨在评估抗氧化剂抗坏血酸对充血性心力衰竭患者持续硝酸酯治疗期间硝酸酯耐受性发展的影响。

方法与结果

20例充血性心力衰竭患者被随机分为两组，一组静脉输注硝酸甘油同时给予安慰剂（安慰剂组，n = 10），另一组静脉输注抗坏血酸（维生素C组，n = 10）。在获得基线测量值后，以每分钟0.5微克/千克的速率输注硝酸甘油开始剂量滴定（滴定期）。在滴定期后的0、6、12、18和24小时连续进行血流动力学参数测量和血液采样。基线时，两组的平均肺动脉压（MPAP，毫米汞柱）、平均肺毛细血管楔压（PCWP，毫米汞柱）、血浆维生素E水平（微摩尔/升）和血小板cGMP水平（皮摩尔/10⁹血小板）相当（安慰剂组：MPAP，48±6；PCWP，24±4；cGMP，0.76±0.12；维生素E，18.2±1.2；维生素C组：MPAP，49±7；PCWP，24±4；cGMP，0.71±0.16；维生素E，18.6±1.3）。在两组中，滴定期后6小时，MPAP和PCWP显著降低（安慰剂组：MPAP，26±5；PCWP，15±4；维生素C组：MPAP，26±4；PCWP，16±4），血小板cGMP显著增加（安慰剂组：2.42±0.24；维生素C组：2.26±0.26）。然而，滴定后18小时，安慰剂组的MPAP（44±5）和PCWP（23±4）升高，血小板cGMP（0.85±0.20）和血浆维生素E水平（12.4±1.4）显著降低。相比之下，维生素C组在滴定期后18小时，MPAP（31±6）、PCWP（17±5）、血小板cGMP（2.49±0.23）和血浆维生素E水平（17.6±1.4）保持稳定。