Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, 123 Dabi Rd., Niausung, Kaohsiung 833, Taiwan.
Transl Res. 2012 Feb;159(2):90-8. doi: 10.1016/j.trsl.2011.09.002. Epub 2011 Sep 29.
Hypertension and hypertensive end-organ damage have been associated with decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) both can inhibit NO availability by competition with L-arginine (L-Arg). However, whether a combined analysis of these 3 parameters can serve as an ideal biomarker of hypertension remains unclear. We measured the plasma and renal levels of L-Arg, ADMA, and SDMA in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) control rats at 3 stages: 4 weeks old (prehypertensive), 12 weeks old (hypertensive), and 24 weeks old (end-organ damage). The plasma and renal L-Arg/ADMA ratio (AAR) and the ADMA/SDMA ratio (ASR) were computed for all 3 age stages. Our results revealed an ADMA level increase, and an AAR decrease in plasma and kidneys may develop early on, even before the onset of hypertension in 4-week-old SHRs. The renal ADMA level and AAR were restored in SHRs at 24 weeks of age, which might protect SHRs against kidney injury. We found that the plasma AAR is superior to the levels of L-Arg and ADMA in plasma, and it predicted blood pressure and urinary NOx levels. Renal AAR is a strong independent marker of renal dimethylarginine dimethylaminohydrolase (DDAH) activity. The plasma ASR was correlated strongly to blood pressure. However, renal DDAH activity was related to the renal ASR but not the plasma ASR. In conclusion, the AAR and ASR may serve as better markers for disease activity and progression than each individual parameter. Clinical use of these ratios to elucidate the role of ADMA in hypertension awaits further validation.
高血压和高血压的靶器官损伤与一氧化氮（NO）生物利用度降低有关。不对称二甲基精氨酸（ADMA）和对称二甲基精氨酸（SDMA）均可通过与 L-精氨酸（L-Arg）竞争来抑制 NO 的可用性。然而，这些 3 个参数的联合分析是否可以作为高血压的理想生物标志物仍不清楚。我们在 3 个阶段测量了自发性高血压大鼠（SHRs）和 Wistar-Kyoto（WKY）对照组大鼠的血浆和肾 L-Arg、ADMA 和 SDMA 水平：4 周龄（前期高血压）、12 周龄（高血压）和 24 周龄（靶器官损伤）。计算了所有 3 个年龄阶段的血浆和肾 L-Arg/ADMA 比值（AAR）和 ADMA/SDMA 比值（ASR）。我们的结果表明，ADMA 水平升高，血浆和肾脏中的 AAR 降低可能会提前发生，甚至在 4 周龄 SHR 发生高血压之前就已经发生。24 周龄的 SHR 肾 ADMA 水平和 AAR 恢复正常，这可能保护 SHR 免受肾脏损伤。我们发现，与血浆中的 L-Arg 和 ADMA 水平相比，血浆 AAR 具有更好的预测血压和尿 NOx 水平的能力。肾 AAR 是肾二甲基精氨酸二甲氨基水解酶（DDAH）活性的强独立标志物。血浆 ASR 与血压密切相关。然而，肾 DDAH 活性与肾 ASR 相关，但与血浆 ASR 无关。总之，AAR 和 ASR 可能比单个参数更能作为疾病活动和进展的更好标志物。这些比值在阐明 ADMA 在高血压中的作用方面的临床应用还需要进一步验证。
