Farhat M Y, Ramwell P W, Thomas G
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, District of Columbia.
J Pharmacol Exp Ther. 1990 Nov;255(2):473-7.
Endothelium-derived relaxing factor (EDRF) has been suggested to be derived from the metabolism of arginine or an arginine-containing moiety. We have compared the vascular effects of arginine and some of its N-substituted derivatives on the perfusion pressure (Pp) of the isolated rat kidney preparation preconstricted with phenylephrine. Irrespective of the stereochemistry, high doses (10(-4) mol) of L- and D-arginine HCl produced a slight vasodilation. In contrast L- and D-arginine free base, at similar doses, further increased renal Pp. N-substituted L-arginine compounds, however, decreased Pp dose-dependently. Their order of potency (ED50) was as follows: N-alpha-benzoyl-L-arginine ethyl ester (BAEE, 3.8 x 10hm6 mol) greater than N-alpha-benzoyl-L-arginine methyl ester (2.5 x 10(-5) mol) greater than L-arginine ethyl ester (2.7 x 10(-5) mol) greater than L-arginine HCl (10(-4) mol). Methylene blue (10(-5) M), hemoglobin (10(-5) M) and NG-mono-methyl-L-arginine (5 mumol) antagonized the vasodilation elicited by infusion of BAEE. Similarly, injection of xanthine oxidase/xanthine (100 mU) reversed BAEE-induced renal vasodilation, but had no effect on dilation elicited by infusion of atrial natriuretic peptide. These data demonstrate that substituted arginine compounds are more potent renal vasodilators than L-arginine and their potency depends on the nature of the substitution. These compounds exert their effect, at least in part, via an endothelium-dependent mechanism. We conclude that exogenous L-arginine is a poor substrate for EDRF generation in the kidney, and that it may cause release of EDRF by another mechanism, possibly related to a change in the pH of the medium.
内皮源性舒张因子（EDRF）被认为来源于精氨酸或含精氨酸部分的代谢产物。我们比较了精氨酸及其一些N-取代衍生物对用去氧肾上腺素预收缩的离体大鼠肾脏标本灌注压（Pp）的血管效应。无论立体化学如何，高剂量（10⁻⁴mol）的L-和D-精氨酸盐酸盐都会产生轻微的血管舒张。相比之下，相同剂量的L-和D-精氨酸游离碱会进一步升高肾脏灌注压。然而，N-取代的L-精氨酸化合物会剂量依赖性地降低灌注压。它们的效价顺序（ED50）如下：N-α-苯甲酰-L-精氨酸乙酯（BAEE，3.8×10⁻⁶mol）＞N-α-苯甲酰-L-精氨酸甲酯（2.5×10⁻⁵mol）＞L-精氨酸乙酯（2.7×10⁻⁵mol）＞L-精氨酸盐酸盐（10⁻⁴mol）。亚甲蓝（10⁻⁵M）、血红蛋白（10⁻⁵M）和NG-单甲基-L-精氨酸（5μmol）可拮抗BAEE输注引起的血管舒张。同样，注射黄嘌呤氧化酶/黄嘌呤（100mU）可逆转BAEE诱导的肾脏血管舒张，但对心房利钠肽输注引起的舒张无影响。这些数据表明，取代精氨酸化合物作为肾脏血管舒张剂比L-精氨酸更有效，且它们的效价取决于取代基的性质。这些化合物至少部分地通过内皮依赖性机制发挥作用。我们得出结论，外源性L-精氨酸在肾脏中不是生成EDRF的良好底物，它可能通过另一种机制导致EDRF释放，这可能与介质pH值的变化有关。
