TETRAHYDROBIOPTERIN AND DYSFUNCTION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE IN CORONARY-ARTERIES
TETRAHYDROBIOPTERIN AND DYSFUNCTION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE IN CORONARY-ARTERIES
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DOI：
10.1161/01.cir.91.1.139
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发表时间：
1995-01-01
期刊：
影响因子：
37.8
通讯作者：
KATUSIC, ZS
中科院分区：
文献类型：
--
作者：
COSENTINO, F;KATUSIC, ZS
背景L-精氨酸/一氧化氮途径在动脉张力调节中起关键作用。一氧化氮的生物合成需要在四氢生物蝶呤作为辅因子的存在下激活一氧化氮合酶。生物化学研究表明，纯化的一氧化氮合酶在次优浓度的四氢生物蝶呤的激活导致过氧化氢的产生。本实验旨在确定四氢生物蝶呤合成抑制剂2，4-二氨基-6-羟基-嘧啶（2，4-diamino-6-hydroxy-pyrimidine，2，4-diamino-6-hydroxy-6-hydroxy-pyrimidine，2，4-diamino-6-（DAHP; 10（-2）mol/L）。悬挂动脉环用于等长张力记录。用放射免疫法测定cGMP的产生。实验在吲哚美辛（10（-5）mol/L）存在下进行。在血栓素A（2）/前列腺素H-2受体激动剂U46619（10（-7）mol/L）引起的收缩过程中，钙离子载体A23187（10（-9）~ 10（-6）mol/L）引起内皮依赖性舒张。一氧化氮合酶抑制剂N-G-硝基-L-精氨酸甲酯（3 × 10 ~（-4）mol/L）可明显抑制这种舒张作用。在DAHP处理的动脉中，在过氧化氢酶（1200 U/mL）的存在下，对A23187的松弛及其对cGMP产生的刺激作用显著降低。相比之下，过氧化氢酶在没有DAHP的情况下孵育的环中没有发挥任何作用。在DAHP和脂溶性四氢生物蝶呤类似物6-甲基四氢蝶呤（10（-4）mol/L）共同孵育的冠状动脉中，过氧化氢酶对A23187诱导的舒张反应的抑制作用被消除。这种由一氧化氮合酶功能障碍引发的最初代偿反应可能是氧化性血管损伤的重要机制。
Background The L-arginine/nitric oxide pathway plays a key role in the regulation of arterial tone. Biosynthesis of nitric oxide requires activation of nitric oxide synthase in the presence of tetrahydrobiopterin as a cofactor. Biochemical studies demonstrated that activation of purified nitric oxide synthase at suboptimal concentrations of tetrahydrobiopterin leads to production of hydrogen peroxide. The present experiments were designed to determine whether in coronary arteries inhibition of tetrahydrobiopterin synthesis may favor nitric oxide synthase-catalyzed production of hydrogen peroxide.Methods and Results Primary branches of canine left anterior descending artery were incubated for 6 hours in minimum essential medium in the presence or in the absence of the tetrahydrobiopterin synthesis inhibitor 2,4-diamino-6-hydroxy-pyrimidine (DAHP; 10(-2) mol/L). Arterial rings were suspended for isometric tension recording. Production of cGMP was measured by radioimmunoassay. Experiments were performed in the presence of indomethacin (10(-5) mol/L). During contractions to the thromboxane A(2)/prostaglandin H-2 receptor agonist U46619 (10(-7) mol/L), calcium ionophore A23187 (10(-9) to 10(-6) mol/L) caused endothelium-dependent relaxations. A nitric oxide synthase inhibitor, N-G-nitro-L-arginine methyl eater (3x10(-4) mol/L), significantly inhibited these relaxations. In DAHP-treated arteries, relaxations to A23187 and its stimulating effect on cGMP production were significantly reduced in the presence of catalase (1200 U/mL). By contrast, catalase did hot exert any effect in rings incubated in the absence of DAHP. Furthermore, the inhibitory effect of catalase on A23187-induced relaxations was abolished when coronary arteries were incubated in the presence of DAHP plus a liposoluble analogue of tetrahydrobiopterin, 6-methyltetrahydropterin (10(-4) mol/L).Conclusions The present study suggests that hydrogen peroxide may be a mediator of endothelium-dependent relaxations in coronary arteries depleted of tetrahydrobiopterin. This initially compensatory response, triggered by a dysfunctional nitric oxide synthase, may represent an important mechanism underlying oxidative vascular injury.