Mechanism of impairment of NO production by aging and trials for the amelioration of endothelial function

血管内皮细胞的功能因衰老而受损。红酒多酚化合物(RWPC)被认为是通过清除氧自由基而具有抗动脉粥样硬化的作用。为了阐明RWPC的急性效应，我们研究了RWPC对Langendorff灌流的大鼠心脏冠脉流量和主动脉平滑肌的反应。我们已经证明RWPC在体外增加了老年大鼠和幼年大鼠的冠脉流量。在苯肾上腺素预收缩的血管制剂中，RWPC对年轻和老年大鼠的主动脉血管具有浓度依赖性的松弛作用。幼年大鼠血管舒缩作用由NO、PGI2和EDHF介导，老年大鼠仅由EDHF介导。接下来，我们研究了长期(长达3个月)口服RWPC对心血管的影响。将大鼠分为三组。各组分别给予正常饮食、高胆固醇饮食、高胆固醇+RWPC饮食。3个月后检测血管反应性、血小板凝固性和冠脉血流反应。长期应用RWPC可改善心血管功能。在高脂饮食组，ADP诱导的血小板凝集功能明显增强，但在高脂饮食中添加RWPC可改善血小板功能障碍。RWPC组血管内皮细胞释放一氧化氮的功能也优于胆固醇组。精氨酸转运体将精氨酸作为一氧化氮的底物输送到内皮细胞，其重要性将在我们未来的研究中进行研究，以了解年龄相关性心血管疾病的机制。

The endothelial function is impaired by aging. Red wine polyphenol compounds (RWPCs) are suggested to have anti-atherosclerotic effect by scavenging oxygen-derived free radicals. In order to elucidate the acute effect of RWPCs, we examined the response of coronary flow in Langendorff-perfused rat heart and of aortic smooth muscle to RWPCs. We have shown that RWPCs increased coronary flow in vitro in aged rat as well as young rat. RWPCs relaxed the aortic vessels concentration-dependently in phenylephrine-precontracted smooth muscle preparations, both in young and aged rats. The vasorelaxant effecs were mediated by NO, PGI2 and EDHF in young rats, while by EDHF alone in aged rats. Next, we examined the cardiovascular effect of the RWPCs orally administered for a long term (up to 3 months). Rats were divided to three groups. Normal diet, high cholesterol diet, and high cholesterol plus RWPCs diet were given to each group, respectively. After 3 months, the vascular reactivity, platelet coagulability, and response of coronary flow were examined. The long term administration of RWPCs ameliorated the cardiovascular function. In cholesterol diet group, the platelet coagulation in response to ADP was dramatically increased, but the platelet dysfunction was improved by the addition of RWPCs into cholesterol diet. The endothelila function to release nitric oxide also tended to be better in the RWPCs group than that in cholesterol group. The importance of the arginine transporters which deliver arginine as a substrate of nitric oxide into endothelilal cells will be investigated in our future study to understand the mechanism of age-related cardiovascular disorders.