Segarra Gloria, Cortina Belén, Mauricio María Dolores, Novella Susana, Lluch Paloma, Navarrete-Navarro Javier, Noguera Inmaculada, Medina Pascual
Gloria Segarra, Belén Cortina, María Dolores Mauricio, Susana Novella, Javier Navarrete-Navarro, Inmaculada Noguera, Pascual Medina, Department of Physiology, University of Valencia and Institute of Health Research INCLIVA, Hospital Clínico Universitario Valencia, 46010 Valencia, Spain.
World J Gastroenterol. 2016 Dec 28;22(48):10545-10556. doi: 10.3748/wjg.v22.i48.10545.
To evaluate the effects of asymmetric dimethylarginine (ADMA) in renal arteries from portal hypertensive and cirrhotic rats.
Rat renal arteries from Sham ( = 15), pre-hepatic portal hypertension (PPVL; = 15) and bile duct ligation and excision-induced cirrhosis (BDL; = 15) were precontracted with norepinephrine, and additional contractions were induced with ADMA (10-10 mol/L), an endogenous inhibitor of nitric oxide (NO) synthase. Concentration-response curves to acetylcholine (1 × 10-3 × 10 mol/L) were determined in precontracted renal artery segments with norepinephrine in the absence and in the presence of ADMA. Kidneys were collected to determine the protein expression and activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes ADMA.
In renal arteries precontracted with norepinephrine, ADMA caused endothelium-dependent contractions. The pD values to ADMA were similar in the Sham and PPVL groups (4.20 ± 0.08 and 4.11 ± 0.09, > 0.05, respectively), but were lower than those of the BDL group (4.79 ± 0.16, < 0.05). Acetylcholine-induced endothelium-dependent relaxation that did not differ, in terms of pD and maximal relaxation, among the 3 groups studied. Treatment with ADMA (3 × 10 mol/L) inhibited acetylcholine-induced relaxation in the 3 groups, but the inhibition was higher ( < 0.05) in the BDL group compared with that for the Sham and PPVL groups. The mRNA and protein expression of DDAH-1 were similar in kidneys from the three groups. Conversely, DDAH-2 expression was increased ( < 0.05) in PPVL and further enhanced ( < 0.05) in the BDL group. However, renal DDAH activity was significantly decreased in the BDL group.
Cirrhosis increased the inhibitory effect of ADMA on basal- and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney.
评估不对称二甲基精氨酸（ADMA）对门静脉高压和肝硬化大鼠肾动脉的影响。
将来自假手术组（n = 15）、肝前性门静脉高压组（PPVL；n = 15）和胆管结扎及切除诱导的肝硬化组（BDL；n = 15）的大鼠肾动脉用去甲肾上腺素预收缩，并用ADMA（10⁻¹⁰ mol/L）诱导额外的收缩，ADMA是一氧化氮（NO）合酶的内源性抑制剂。在不存在和存在ADMA的情况下，测定用去甲肾上腺素预收缩的肾动脉段对乙酰胆碱（1×10⁻³×10 mol/L）的浓度 - 反应曲线。收集肾脏以测定二甲基精氨酸二甲胺水解酶（DDAH）的蛋白表达和活性，DDAH是一种分解代谢ADMA的酶。
在用去甲肾上腺素预收缩的肾动脉中，ADMA引起内皮依赖性收缩。假手术组和PPVL组对ADMA的pD值相似（分别为4.20±0.08和4.11±0.09，P>0.05），但低于BDL组（4.79±0.16，P<0.05）。乙酰胆碱诱导的内皮依赖性舒张在研究的3组之间，在pD和最大舒张方面没有差异。用ADMA（3×10⁻⁹ mol/L）处理抑制了3组中乙酰胆碱诱导的舒张，但与假手术组和PPVL组相比，BDL组的抑制作用更高（P<0.05）。三组大鼠肾脏中DDAH - 1的mRNA和蛋白表达相似。相反，DDAH - 2表达在PPVL组中增加（P<0.05），在BDL组中进一步增强（P<0.05）。然而，BDL组肾脏中的DDAH活性显著降低。
肝硬化增加了ADMA对肾动脉中NO基础释放和诱导释放的抑制作用，并降低了肾脏中的DDAH活性。
