Fasehun O A, Gross S S, Rubin L E, Jaffe E A, Griffith O W, Levi R
Department of Pharmacology, Cornell University Medical College, New York, New York.
J Pharmacol Exp Ther. 1990 Dec;255(3):1348-53.
N alpha-benzoyl-L-arginine ethyl ester (BAEE) is a vasorelaxant which resembles an arginine-containing peptide; its action may be partially endothelium-dependent. Because L-arginine (ARG) has little potency as a vasorelaxant, it has been proposed that an arginine-containing peptide, rather than free ARG, is the immediate precursor of endothelium-derived relaxing factor/nitric oxide (EDRF/NO). In the present study we have characterized pharmacologically the vasorelaxant effect of BAEE and assessed the ability of BAEE to serve as a substrate for EDRF/NO synthesis. BAEE elicited a concentration-dependent vasorelaxation of guinea pig pulmonary artery (EC50 of 0.36 +/- 0.05 mM). This vasorelaxation was neither antagonized by -NG-methyl-L-arginine (100 microM), a competitive inhibitor of EDRF/NO synthesis from ARG, nor potentiated by superoxide dismutase (60 U/ml), a superoxide anion scavenger that prolongs EDRF lifetime. Additionally, compound LY 83583 (1 microM) and methylene blue (10 microM), inhibitors of soluble guanylyl cyclase, failed to block BAEE-induced vasorelaxation. Moreover, endothelium removal potentiated the vasorelaxant effect of BAEE 3-fold. Thus, BAEE-induced vasorelaxation is mediated by a direct action on vascular smooth muscle that is unrelated to EDRF/NO synthesis. Furthermore, ARG, but not BAEE, overcame the inhibition by NG-methyl-L-arginine of the acetylcholine-induced endothelium-dependent cyclic GMP accumulation in guinea pig aortic rings and of A23187-induced nitrite formation by cultured bovine aortic endothelial cells (nitrite is a convenient indicator of NO biosynthesis). Thus, BAEE cannot substitute for ARG as a substrate for EDRF/NO biosynthesis. Collectively, our findings support the notion that free ARG, rather than an arginine-containing peptide related to BAEE, is the immediate biosynthetic precursor of EDRF/NO.
Nα-苯甲酰-L-精氨酸乙酯（BAEE）是一种血管舒张剂，类似于含精氨酸的肽；其作用可能部分依赖于内皮。由于L-精氨酸（ARG）作为血管舒张剂的效力很小，有人提出含精氨酸的肽而非游离的ARG是内皮源性舒张因子/一氧化氮（EDRF/NO）的直接前体。在本研究中，我们对BAEE的血管舒张作用进行了药理学特征分析，并评估了BAEE作为EDRF/NO合成底物的能力。BAEE引起豚鼠肺动脉浓度依赖性血管舒张（EC50为0.36±0.05 mM）。这种血管舒张既不被-NG-甲基-L-精氨酸（100μM，一种从ARG合成EDRF/NO的竞争性抑制剂）拮抗，也不被超氧化物歧化酶（60 U/ml，一种延长EDRF寿命的超氧阴离子清除剂）增强。此外，可溶性鸟苷酸环化酶抑制剂LY 83583（1μM）和亚甲蓝（10μM）未能阻断BAEE诱导的血管舒张。此外，去除内皮使BAEE的血管舒张作用增强了3倍。因此，BAEE诱导的血管舒张是通过对血管平滑肌的直接作用介导的，与EDRF/NO合成无关。此外，ARG而非BAEE克服了NG-甲基-L-精氨酸对豚鼠主动脉环中乙酰胆碱诱导的内皮依赖性环鸟苷酸积累以及对培养的牛主动脉内皮细胞中A23187诱导的亚硝酸盐形成的抑制作用（亚硝酸盐是NO生物合成的便捷指标）。因此，BAEE不能替代ARG作为EDRF/NO生物合成的底物。总的来说，我们的研究结果支持这样一种观点，即游离的ARG而非与BAEE相关的含精氨酸肽是EDRF/NO的直接生物合成前体。
