Huynh N N, Harris E E, Chin-Dusting J F P, Andrews K L
Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Vic., Australia.
Br J Pharmacol. 2009 Jan;156(1):84-93. doi: 10.1111/j.1476-5381.2008.00036.x.
Arginase and nitric oxide (NO) synthase share the common substrate L-arginine, and arginase inhibition is proposed to increase NO production by increasing intracellular levels of L-arginine. Many different inhibitors are used, and here we have examined the effects of these inhibitors on vascular tissue.
Each arginase inhibitor was assessed by its effects on isolated rings of aorta and mesenteric arteries from rats by: (i) their ability to preserve the tolerance to repeated applications of the endothelium-dependent agonist acetylcholine (ACh); and (ii) their direct vasorelaxant effect.
In both vessel types, tolerance (defined as a reduced response upon second application) to ACh was reversed with addition of L-arginine, (S)-(2-boronethyl)-L-cysteine HCl (BEC) or N(G)-Hydroxy-L-arginine (L-NOHA). On the other hand, N(omega)-hydroxy-nor-L-arginine (nor-NOHA) significantly augmented the response to ACh, an effect that was partially reversed with L-arginine. No effect on tolerance to ACh was observed with L-valine, nor-valine or D,L, alpha-difluoromethylornithine (DFMO). BEC, L-NOHA and nor-NOHA elicited endothelium-independent vasorelaxation in both endothelium intact and denuded aorta while L-valine, DFMO and nor-valine did not.
BEC and L-NOHA, but not nor-NOHA, L-valine, DFMO or nor-valine, significantly reversed tolerance to ACh possibly conserving L-arginine levels and therefore increasing NO bioavailability. However, both BEC and L-NOHA caused endothelium-independent vasorelaxation in rat aorta, suggesting that these inhibitors have a role beyond arginase inhibition alone. Our data thus questions the interpretation of many studies using these antagonists as specific arginase inhibitors in the vasculature, without verification with other methods.
精氨酸酶与一氧化氮（NO）合酶共用共同底物L-精氨酸，有人提出抑制精氨酸酶可通过提高细胞内L-精氨酸水平来增加NO生成。人们使用了许多不同的抑制剂，在此我们研究了这些抑制剂对血管组织的作用。
通过以下方式评估每种精氨酸酶抑制剂对大鼠离体主动脉环和肠系膜动脉的作用：（i）它们保留对内皮依赖性激动剂乙酰胆碱（ACh）重复给药耐受性的能力；（ii）它们的直接血管舒张作用。
在两种血管类型中，添加L-精氨酸、（S）-（2-硼乙基）-L-半胱氨酸盐酸盐（BEC）或N（G）-羟基-L-精氨酸（L-NOHA）可逆转对ACh的耐受性（定义为第二次给药时反应减弱）。另一方面，N（ω）-羟基-nor-L-精氨酸（nor-NOHA）显著增强对ACh的反应，L-精氨酸可部分逆转该作用。L-缬氨酸、nor-缬氨酸或D，L，α-二氟甲基鸟氨酸（DFMO）对ACh耐受性无影响。BEC、L-NOHA和nor-NOHA在完整内皮和去内皮的主动脉中均引起非内皮依赖性血管舒张，而L-缬氨酸、DFMO和nor-缬氨酸则无此作用。
BEC和L-NOHA而非nor-NOHA、L-缬氨酸、DFMO或nor-缬氨酸可显著逆转对ACh的耐受性，可能是通过维持L-精氨酸水平从而增加NO生物利用度。然而，BEC和L-NOHA均在大鼠主动脉中引起非内皮依赖性血管舒张，表明这些抑制剂的作用不仅仅是抑制精氨酸酶。因此，我们的数据对许多在血管系统中使用这些拮抗剂作为特异性精氨酸酶抑制剂而未用其他方法验证的研究的解释提出了质疑。
