TEDA International Cardiovascular Hospital, Medical College, Nankai University, Tianjin, China.
J Thorac Cardiovasc Surg. 2012 Sep;144(3):697-703. doi: 10.1016/j.jtcvs.2012.01.020. Epub 2012 Feb 14.
Endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine is a cardiovascular risk factor that is elevated in patients with coronary artery disease. We hypothesized that novel endothelial nitric oxide synthase enhancer AVE3085 might improve the endothelial function altered by asymmetric dimethylarginine in the human internal thoracic artery.
Cumulative concentration-relaxation curves to acetylcholine (-11 to -5 log mol/L) were established in left internal thoracic artery rings (n = 65) from 27 patients undergoing coronary artery bypass grafting in precontraction induced by U46619 (-8 log mol/L) in the absence or presence of asymmetric dimethylarginine (100 μmol/L) or AVE3085 (30 μmol/L). Protein expressions of endothelial nitric oxide synthase and levels of superoxide anion production were detected.
Maximal relaxation induced by acetylcholine was significantly attenuated by asymmetric dimethylarginine (12.7% ± 2.3% vs 35.3% ± 5.0% in control; P < .05) and significantly restored by AVE3085 (23.4% ± 2.8%; P < .05). AVE3085 also markedly restored endothelial nitric oxide synthase expression (0.29 ± 0.008; P = .012) reduced by asymmetric dimethylarginine (0.05 ± 0.04 vs 0.36 ± 0.03 in control; P = .014). Increased superoxide anion production by asymmetric dimethylarginine (2.97 ± 0.25 vs 0.51 ± 0.10 relative light units/[s/mg] in control; P < .05) was inhibited by AVE3805 (0.62 ± 0.104 relative light units/[s/mg]; P < .05).
AVE3085 may restore endothelium-dependent relaxation reduced by asymmetric dimethylarginine through upregulation of endothelial nitric oxide synthase expression and inhibition of production of superoxide anion in human internal thoracic artery. These findings provide new insights into endothelial protection of coronary bypass grafting vessels to improve long-term patency of grafts.
内源性一氧化氮合酶抑制剂对称二甲基精氨酸是一种心血管危险因素，在冠心病患者中升高。我们假设新型内皮型一氧化氮合酶增强剂 AVE3085 可能改善对称二甲基精氨酸引起的人胸廓内动脉内皮功能障碍。
在无或存在对称二甲基精氨酸（100 μmol/L）或 AVE3085（30 μmol/L）的情况下，通过 U46619（-8 log mol/L）预收缩，建立 27 例接受冠状动脉旁路移植术患者的左胸廓内动脉环（n = 65）对乙酰胆碱（-11 至-5 log mol/L）的累积浓度松弛曲线。检测内皮型一氧化氮合酶的蛋白表达和超氧阴离子产生水平。
乙酰胆碱诱导的最大松弛作用被对称二甲基精氨酸显著减弱（12.7%±2.3%比对照组中的 35.3%±5.0%；P<.05），并用 AVE3085 显著恢复（23.4%±2.8%；P<.05）。AVE3085 还明显恢复了被对称二甲基精氨酸降低的内皮型一氧化氮合酶表达（0.29±0.008；P=.012）（0.05±0.04 比对照组中的 0.36±0.03；P=.014）。对称二甲基精氨酸引起的超氧阴离子产生增加（2.97±0.25 比对照组中的 0.51±0.10 相对光单位/[s/mg]；P<.05）被 AVE3805 抑制（0.62±0.104 相对光单位/[s/mg]；P<.05）。
AVE3085 可能通过上调内皮型一氧化氮合酶的表达和抑制超氧阴离子的产生来恢复对称二甲基精氨酸引起的人胸廓内动脉内皮依赖性松弛作用。这些发现为改善移植物通畅率提供了新的见解，以保护冠状动脉旁路移植术血管的内皮。
