De Gennaro Colonna Vito, Bonomo Sara, Ferrario Paolo, Bianchi Mauro, Berti Marco, Guazzi Marco, Manfredi Barbara, Muller Eugenio E, Berti Ferruccio, Rossoni Giuseppe
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Via Vanvitelli 32, Italy.
Eur J Pharmacol. 2007 Feb 28;557(2-3):178-85. doi: 10.1016/j.ejphar.2006.11.034. Epub 2006 Nov 22.
Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor recognized as an independent risk factor for endothelial dysfunction and coronary heart diseases. This study investigated whether ADMA (10 mg/kg day for 14 days) affected endothelial function and aggravated post-ischemic ventricular dysfunction in the perfused rat heart. Systolic blood pressure and heart rate, plasma levels of ADMA and nitrite/nitrate were measured in vehicle- and ADMA-treated rats. Perfused hearts were submitted to global ischemia-reperfusion and vascular endothelial dysfunction was examined with angiotensin II in coronary vessels and aortic rings. Endothelial NO synthase (eNOS) and angiotensin-converting enzyme (ACE) mRNA expression in aortic and cardiac tissues were measured. ADMA-treated rats had higher systolic blood pressure (1.3-fold, P<0.01) and slower heart rate (16%, P<0.05) than controls. Plasma ADMA rose (1.9-fold, P<0.01) and nitrite/nitrate concentration decreased 59% (P<0.001). Ventricular contraction (stiffness) increased significantly, with worsening of post-ischemic ventricular dysfunction. In preparations from ADMA-treated rats the coronary vasculature's response to angiotensin II was almost doubled (P<0.01) and the maximal vasorelaxant effect of acetylcholine in aortic rings was significantly lower than in preparations from vehicle-treated rats. In cardiac and aortic tissues eNOS mRNA and ACE mRNA levels were similar in controls and ADMA-treated rats. The increased plasma levels of ADMA presumably cause endothelial dysfunction because of a deficiency in NO production, which also appears involved in the aggravation of myocardial ischemia-reperfusion injury.
不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮（NO）抑制剂，被认为是内皮功能障碍和冠心病的独立危险因素。本研究调查了ADMA（10mg/kg·天，共14天）是否会影响灌注大鼠心脏的内皮功能并加重缺血后心室功能障碍。在给予溶剂和ADMA处理的大鼠中测量收缩压、心率、血浆ADMA水平以及亚硝酸盐/硝酸盐水平。对灌注心脏进行整体缺血再灌注处理，并在冠状动脉和主动脉环中用血管紧张素II检测血管内皮功能障碍。测量主动脉和心脏组织中内皮型一氧化氮合酶（eNOS）和血管紧张素转换酶（ACE）的mRNA表达。与对照组相比，ADMA处理的大鼠收缩压更高（1.3倍，P<0.01），心率更慢（16%，P<0.05）。血浆ADMA升高（1.9倍，P<0.01），亚硝酸盐/硝酸盐浓度降低59%（P<0.001）。心室收缩（僵硬度）显著增加，缺血后心室功能障碍加重。在ADMA处理大鼠的标本中，冠状动脉血管对血管紧张素II的反应几乎增加了一倍（P<0.01），乙酰胆碱在主动脉环中的最大血管舒张作用明显低于溶剂处理大鼠的标本。在对照组和ADMA处理的大鼠中，心脏和主动脉组织中的eNOS mRNA和ACE mRNA水平相似。血浆ADMA水平升高可能由于NO生成不足导致内皮功能障碍，这似乎也参与了心肌缺血再灌注损伤的加重。
