Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats
Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats
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DOI：
10.1172/jci650
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发表时间：
1998-04-01
影响因子：
15.9
通讯作者：
Lüscher, TF
中科院分区：
文献类型：
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作者：
Cosentino, F;Patton, S;Lüscher, TF
辅因子 (6R)-5,6,7,8-四氢生物蝶呤 (H(4)B) 不足的组成型一氧化氮合酶 (cNOS) 可能会产生破坏性超氧化物 (O(2)(-))。本研究旨在确定自发性高血压大鼠 (SHR) 在高血压发作前、4 周龄 SHR 的主动脉和使用 Wistar-Kyoto 大鼠。用钙离子载体A23187刺激cNOS，用电化学传感器原位测量一氧化氮和过氧化氢，用化学发光法原位测量O(2)(-)的产生，连续记录等长张力，用高效液相色谱法测定H(4)B，并在均质组织中测定[(3)H]瓜氨酸测定，A23187刺激的O(2)(-)及其超氧化物歧化酶产物的产生SHR 主动脉中过氧化氢显着升高，而一氧化氮释放减少，外源 H(4)B 存在时结果相反。此外，N(G)-单甲基-L-精氨酸可抑制 cNOS 依赖性 O(2)(-) 的生成，抑制率约为 70%。两种菌株的天然 H(4)B 水平相似；然而，等价。 cNOS 活性需要 SHR 中额外的 H(4)B。仅在 SHR 中，A23187 的内皮依赖性松弛被过氧化氢酶显着抑制，并被超氧化物歧化酶增强。然而，这些酶在 H(4)B 存在的情况下没有作用。因此，功能失调的cNOS可能是高血压前期SHR中O(2)(-)的来源，并导致高血压及其血管并发症的发生。
Constitutive nitric oxide synthase (cNOS) with insufficient cofactor (6R)-5,6,7,8-tetrahydrobiopterin (H(4)B) may generate damaging superoxide (O(2)(-)), This study was designed to determine whether cNOS-dependent generation of O(2)(-) occurs in spontaneously hypertensive rats (SHR) before the onset of hypertension, Aortas from 4-wk-old SHR and Wistar-Kyoto rats were used. cNOS was stimulated by calcium ionophore A23187, In situ measurements of nitric oxide and hydrogen peroxide by electrochemical sensors and O(2)(-) production by chemiluminescence method were performed, Isometric tension was continuously recorded, H(4)B by high performance liquid chromatography and [(3)H]citrulline assay were determined in homogenized tissue, The A23187-stimulated production of O(2)(-) and its superoxide dismutase product hydrogen peroxide were significantly higher, whereas nitric oxide release was reduced in SHR aortas, with opposite results in the presence of exogenous H(4)B. Furthermore, N(G)-monomethyl-L-arginine inhibited the generation of cNOS-dependent O(2)(-) by similar to 70%. Natural H(4)B levels were similar in both strains; however, equivalent. cNOS activity required additional H(4)B in SHR. The endothelium-dependent relaxations to A23187 were significantly inhibited by catalase, and enhanced by superoxide dismutase, only in SHR; however, these enzymes had no effect in the presence of H(4)B. Thus, dysfunctional cNOS may be a source of O(2)(-) in prehypertensive SHR and contribute to the development of hypertension and its vascular complications.