Nakae Ichiro, Matsumoto Tetsuya, Omura Tomoko, Takashima Hiroyuki, Ohira Naoto, Tarutani Yasuhiro, Yasuda Yo, Matsuo Shinro, Koh Terue, Nakaura Yasuyuki, Kinoshita Masahiko, Horie Minoru
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan.
Life Sci. 2003 Oct 31;73(24):3083-94. doi: 10.1016/j.lfs.2003.04.005.
We investigated the endothelial modulations in nitrate tolerance in isolated rabbit aorta. Nitrate tolerance was induced by a 72-h treatment with transdermal nitroglycerin (NTG, 0.4 mg/h) in conscious rabbits, which was verified by a 20-fold increase in the EC50 values [NTG tolerance (6.1 +/- 0.8) x 10(-7) M vs control (3.0 +/- 0.6) x 10(-8) M]. The relaxations to NTG in tolerant and nontolerant aortic strips were enhanced when their endothelia were denuded [E(-)]. In the presence of endothelium [E(+)], NTG-tolerant vessels were not tolerant to acetylcholine (ACh), which can release endothelial nitric oxide (NO), exogenous NO or 8-bromo (Br)-cGMP. In NTG-tolerant and nontolerant vessels with endothelium, concentration-response curves for NO were the same as those in endothelium-absent tolerant vessels. In both NTG-tolerant and nontolerant vessels, treatment with superoxide dismutase (SOD, 20 units/ml), an O2-. scavenger, unaffected the responses to NTG reduced in the presence of endothelium, but treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), an NO synthase (NOS) inhibitor, reversed these reductions. Thus, our data did not indicate that an increased endothelial superoxide O2-. production contributes to nitrate tolerance. Our study suggested that (i) an impaired biotransformation process from NTG to NO is responsible for the occurrence of nitrate tolerance and (ii) vascular response to NTG enhanced by endothelial removal is related to blocked endothelial NO release.
我们研究了离体兔主动脉中硝酸盐耐受性的内皮调节作用。在清醒兔中，通过经皮给予硝酸甘油（NTG，0.4 mg/h）72小时诱导硝酸盐耐受性，其通过EC50值增加20倍得到证实[NTG耐受性（6.1±0.8）×10⁻⁷ M对比对照组（3.0±0.6）×10⁻⁸ M]。当耐受性和非耐受性主动脉条的内皮被剥脱[E（-）]时，它们对NTG的舒张作用增强。在内皮存在[E（+）]的情况下，NTG耐受性血管对乙酰胆碱（ACh）不耐受，ACh可释放内皮一氧化氮（NO）、外源性NO或8-溴（Br）-环鸟苷酸。在有内皮的NTG耐受性和非耐受性血管中，NO的浓度-反应曲线与无内皮的耐受性血管中的相同。在NTG耐受性和非耐受性血管中，用超氧化物歧化酶（SOD，20单位/ml）（一种O₂⁻清除剂）处理，不影响在内皮存在时对NTG降低的反应，但用NO合酶（NOS）抑制剂NG-硝基-L-精氨酸甲酯（L-NAME，10⁻⁴ M）处理可逆转这些降低。因此，我们的数据并未表明内皮超氧化物O₂⁻产生增加导致硝酸盐耐受性。我们的研究表明：（i）从NTG到NO的生物转化过程受损是硝酸盐耐受性发生的原因；（ii）内皮去除增强的血管对NTG的反应与内皮NO释放受阻有关。
