Joly G A, Ayres M, Chelly F, Kilbourn R G
Department of Genitourinary Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Biochem Biophys Res Commun. 1994 Feb 28;199(1):147-54. doi: 10.1006/bbrc.1994.1207.
A new selective inhibitor of the inducible nitric oxide synthase in the treatment of pathogenesis characterized by overproduction of nitric oxide may be useful. Therefore, we have examined the effects of two L-arginine analogues, NG-methyl-L-arginine (L-NMA) and NG-nitro-L-arginine (L-NNA), and aminoguanidine (AG) on the constitutive and inducible nitric oxide synthase in rat aorta. L-NNA induced greater contractions to phenylephrine than L-NMA whereas AG had no effect on dose-response curves to this alpha 1-agonist in rat aorta with endothelium. Relaxations to acetylcholine, adenosine triphosphate, and A 23187 were fully abolished by L-NNA, while L-NMA partially inhibited and AG did not affect the relaxations to these three vasodilators. L-NNA, L-NMA, and AG were equipotent in inhibiting the vascular hyporeactivity to phenylephrine induced by endotoxin in rat aortic rings with endothelium; however, the rate of onset of the maximum inhibitory effects of AG was slower than that obtained with L-NNA and L-NMA. L-arginine completely abolished the effects of AG, but only partially reversed the effects of L-NNA and L-NMA in LPS-treated rings. These results suggest that AG selectively inhibits inducible nitric oxide synthase, whereas L-NNA and L-NMA exert their effects on both the constitutive and inducible nitric oxide synthase.
一种新型诱导型一氧化氮合酶选择性抑制剂在治疗以一氧化氮产生过多为特征的发病机制中可能有用。因此，我们研究了两种L-精氨酸类似物，NG-甲基-L-精氨酸（L-NMA）和NG-硝基-L-精氨酸（L-NNA），以及氨基胍（AG）对大鼠主动脉中组成型和诱导型一氧化氮合酶的影响。与L-NMA相比，L-NNA对去氧肾上腺素诱导的收缩作用更强，而AG对大鼠有内皮主动脉中该α1激动剂的剂量反应曲线没有影响。L-NNA完全消除了对乙酰胆碱、三磷酸腺苷和A23187的舒张反应，而L-NMA部分抑制了对这三种血管舒张剂的舒张反应，AG则不影响。L-NNA、L-NMA和AG在抑制内皮完整的大鼠主动脉环中由内毒素诱导的对去氧肾上腺素的血管反应性降低方面具有同等效力；然而，AG最大抑制作用的起效速度比L-NNA和L-NMA慢。L-精氨酸完全消除了AG的作用，但仅部分逆转了L-NNA和L-NMA在脂多糖处理环中的作用。这些结果表明，AG选择性抑制诱导型一氧化氮合酶，而L-NNA和L-NMA对组成型和诱导型一氧化氮合酶均有作用。
