Angulo Javier, Cuevas Pedro, Fernández Argentina, Gabancho Sonia, Allona Antonio, Martín-Morales Antonio, Moncada Ignacio, Sáenz de Tejada Iñigo
Fundación para la Investigación y el Desarrollo en Andrología, Hospital Ramón y Cajal, Madrid, Spain.
Br J Pharmacol. 2003 Jan;138(1):63-70. doi: 10.1038/sj.bjp.0705027.
1 When nitric oxide synthase (NOS) produces NO from N(G)-hydroxy-L-arginine (OH-arginine) instead of L-arginine, the total requirement of molecular oxygen and NADPH to form NO is reduced. The aim of this work was to evaluate the effects of OH-arginine on the contractility of rabbit corpus cavernosum (RCC) and to compare the capacities of L-arginine and OH-arginine to enhance NO-mediated responses under normoxic and hypoxic conditions and in ageing, as models of defective NO production. 2 OH-arginine, but not L-arginine, was able to relax phenylephrine-contracted rabbit trabecular smooth muscle. OH-arginine-induced relaxation was inhibited by the NOS-inhibitor, L-NNA (300 microM), and by the guanylyl cyclase inhibitor, ODQ (20 microM), while it was not affected by the cytochrome P450 oxygenase inhibitor, miconazole (0.1 mM). Administration of OH-arginine, but not L-arginine, produced a significant increment of cGMP accumulation in RCC tissue. 3 Relaxation elicited by OH-arginine (300 microM) was still observed at low oxygen tension. The increase of cGMP levels induced by ACh (30 microM) in RCC was significantly enhanced by addition of OH-arginine (300 microM) in normoxic conditions, as well as under hypoxia, while L-arginine did not alter the effects of ACh on cGMP accumulation. 4 Endothelium-dependent and nitrergic nerve-mediated relaxations were both significantly reduced in RCC from aged animals (>20-months-old) when compared with young adult rabbits (5-months-old). Treatment with OH-arginine (300 microM) significantly potentiated endothelium-dependent and neurogenic relaxation in corpus cavernosum from aged rabbits, while L-arginine (300 microM) did not have significant effects. 5 Results show that OH-arginine promotes NO-mediated relaxation of RCC and potentiates the NO-mediated responses induced by stimulation of endogenous NO generation in hypoxic and aged tissues. We propose that the use of OH-arginine could be of interest in the treatment of erectile dysfunction, at least in those secondary to defective NO production.
1 当一氧化氮合酶（NOS）从N（G）-羟基-L-精氨酸（OH-精氨酸）而非L-精氨酸生成一氧化氮（NO）时，生成NO所需的分子氧和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的总量会减少。本研究的目的是评估OH-精氨酸对兔海绵体（RCC）收缩性的影响，并比较L-精氨酸和OH-精氨酸在常氧和低氧条件下以及在衰老（作为NO生成缺陷的模型）时增强NO介导反应的能力。2 OH-精氨酸而非L-精氨酸能够舒张苯肾上腺素收缩的兔小梁平滑肌。OH-精氨酸诱导的舒张被NOS抑制剂L-硝基精氨酸甲酯（L-NNA，300微摩尔）和鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮（ODQ，20微摩尔）抑制，而不受细胞色素P450加氧酶抑制剂咪康唑（0.1毫摩尔）影响。给予OH-精氨酸而非L-精氨酸可使RCC组织中的环磷酸鸟苷（cGMP）积累显著增加。3 在低氧张力下仍可观察到OH-精氨酸（300微摩尔）引起的舒张。在常氧条件下以及低氧时，加入OH-精氨酸（300微摩尔）可显著增强乙酰胆碱（ACh，30微摩尔）在RCC中诱导的cGMP水平升高，而L-精氨酸不改变ACh对cGMP积累的影响。4 与年轻成年兔（5月龄）相比，老年动物（>20月龄）的RCC中内皮依赖性和氮能神经介导的舒张均显著降低。用OH-精氨酸（300微摩尔）处理可显著增强老年兔海绵体内皮依赖性和神经源性舒张，而L-精氨酸（300微摩尔）无显著作用。5 结果表明，OH-精氨酸可促进RCC的NO介导舒张，并增强低氧和衰老组织中内源性NO生成刺激诱导的NO介导反应。我们提出，使用OH-精氨酸可能对勃起功能障碍的治疗有意义，至少对那些继发于NO生成缺陷的勃起功能障碍有意义。
