Heymes C, Habib A, Yang D, Mathieu E, Marotte F, Samuel J, Boulanger C M
INSERM U-127, Institut Fédératif de Recherche IFR Circulation and University Paris VII, Hôpital Lariboisière, F-75475 Paris cedex 10, France.
Br J Pharmacol. 2000 Oct;131(4):804-10. doi: 10.1038/sj.bjp.0703632.
Experiments were designed to investigate the role of cyclo-oxygenase isoforms in endothelial dysfunction in ageing. Aortic rings with endothelium of aged and young (24 vs 4 month-old) Wistar rats, were mounted in organ chambers for the recording of changes in isometric tension. In young rats, acetylcholine (ACh) caused a complete relaxation which was not affected by indomethacin (0.3 microM), NS-398 (a preferential COX-2 inhibitor; 1 microM), SQ-29548 (a thromboxane-receptor antagonist; 1 microM), nor valeryl-salicylate (VAS, a preferential inhibitor of COX-1; 3 mM). In aged rats, ACh caused a biphasic response characterized by a first phase of relaxation (0.01 - 1 microM ACh), followed by a contraction (3 - 100 microM ACh). Indomethacin, NS-398 and SQ-29548, but not VAS, augmented the first phase. Indomethacin, VAS, NS-398 and SQ-29548 decreased the contractions to high ACh concentrations. Then, the sensitivity to thromboxane receptor activation was investigated with U-46619. The results show comparable EC(50) values in young and aged rats. In aged rats, the ACh-stimulated release of prostacyclin, prostaglandin F(2alpha) and thromboxane A(2) was decreased by either indomethacin, NS-398, VAS or endothelium removal. However, in young animals, the ACh-stimulated release of prostacyclin and prostaglandin F(2alpha) were smaller than in older animals and remained unaffected by NS-398. Aortic endothelial cells from aged - but not young - rats express COX-2 isoform, while COX-1 labelling was observed in endothelial cells from both young and aged rats. These data demonstrate the active contribution of COX-1 and -2 in endothelial dysfunction associated with ageing.
设计实验以研究环氧化酶同工型在衰老过程中内皮功能障碍中的作用。将老年（24月龄）和年轻（4月龄）Wistar大鼠的带内皮主动脉环安装在器官浴槽中，记录等长张力变化。在年轻大鼠中，乙酰胆碱（ACh）引起完全舒张，吲哚美辛（0.3微摩尔）、NS-398（一种选择性COX-2抑制剂；1微摩尔）、SQ-29548（一种血栓素受体拮抗剂；1微摩尔）和戊酰水杨酸（VAS，一种选择性COX-1抑制剂；3毫摩尔）对此均无影响。在老年大鼠中，ACh引起双相反应，其特征为第一阶段舒张（0.01 - 1微摩尔ACh），随后是收缩（3 - 100微摩尔ACh）。吲哚美辛、NS-398和SQ-29548（而非VAS）增强了第一阶段反应。吲哚美辛、VAS、NS-398和SQ-29548均降低了对高浓度ACh的收缩反应。然后，用U-46619研究对血栓素受体激活的敏感性。结果显示年轻和老年大鼠的半数有效浓度（EC50）值相当。在老年大鼠中，吲哚美辛、NS-398、VAS或去除内皮均可降低ACh刺激的前列环素、前列腺素F2α和血栓素A2的释放。然而，在年轻动物中，ACh刺激的前列环素和前列腺素F2α的释放量小于老年动物，且不受NS-398影响。老年大鼠而非年轻大鼠的主动脉内皮细胞表达COX-2同工型，而在年轻和老年大鼠的内皮细胞中均观察到COX-1标记。这些数据证明了COX-1和COX-2在与衰老相关的内皮功能障碍中的积极作用。
