Ma X L, Gao F, Yao C L, Chen J, Lopez B L, Christopher T A, Disa J, Gu J L, Ohlstein E H, Yue T L
Division of Emergency Medicine, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-5004, USA.
J Pharmacol Exp Ther. 2000 Nov;295(2):786-92.
Estrogen is known to stimulate endothelial nitric oxide production and attenuate endothelial dysfunction after ischemia and reperfusion. However, estrogen therapy increases the risk of breast and endometrial cancer. The present study was designed to determine whether idoxifene, a selective estrogen receptor modulator without adverse effects on reproductive organs, may stimulate nitric oxide release and protect endothelial function. In U-46619 precontracted superior mesenteric arterial (SMA) segments isolated from ovariectomized rats, idoxifene and 17 beta-estradiol resulted in a comparable dose-dependent vasorelaxation (maximal relaxation: 75.3 +/- 4.9 and 71 +/- 4.7%, respectively). Treatment of the rings with N(omega)-nitro-L-arginine methyl ester completely blocked idoxifene- and 17 beta-estradiol-induced vasorelaxation. In vitro incubation of SMA rings with TNF alpha significantly reduced vasorelaxation to an endothelium-dependent vasodilator, acetylcholine (maximal relaxation: 73 +/- 3.7 versus 95 +/- 2.9% pre-TNF alpha, P <.01). Idoxifene, but surprisingly not 17 beta-estradiol, prevented TNF alpha-induced endothelial dysfunction (maximal relaxation: 86 +/- 2.6% in idoxifene-treated rings and 77 +/- 5.1% in 17beta-estrogen-treated rings). In vivo ischemia and reperfusion resulted in significant endothelial dysfunction as evidenced by decreased vasorelaxation to acetylcholine (maximal relaxation: 48 +/- 5.5 versus 92 +/- 3.9% in normal SMA rings), but a normal relaxation response to an endothelium-independent vasodilator, acidified NaNO(2) (95 +/- 3.2%). Treatment with idoxifene at either 1 or 2 mg/kg/day, or 17beta-estrogen at 1 mg/kg/day for 4 days significantly preserved endothelial function (P <.01 versus vehicle). Taken together, these results demonstrate that idoxifene is an endothelium-dependent vasodilator and exerts significant endothelial protective effects against TNF alpha- and ischemia-reperfusion-induced endothelial injury. These results suggest that selective estrogen receptor modulators have therapeutic potential in diseases where endothelial dysfunction plays an important role.
已知雌激素可刺激内皮细胞产生一氧化氮，并减轻缺血再灌注后的内皮功能障碍。然而，雌激素治疗会增加乳腺癌和子宫内膜癌的风险。本研究旨在确定伊多昔芬（一种对生殖器官无不良影响的选择性雌激素受体调节剂）是否能刺激一氧化氮释放并保护内皮功能。在从去卵巢大鼠分离的经U-46619预收缩的肠系膜上动脉（SMA）节段中，伊多昔芬和17β-雌二醇产生了相当的剂量依赖性血管舒张作用（最大舒张率：分别为75.3±4.9%和71±4.7%）。用N（ω）-硝基-L-精氨酸甲酯处理血管环完全阻断了伊多昔芬和17β-雌二醇诱导的血管舒张。用肿瘤坏死因子α（TNFα）对SMA环进行体外孵育显著降低了对内皮依赖性血管舒张剂乙酰胆碱的血管舒张作用（最大舒张率：TNFα处理前为95±2.9%，处理后为73±3.7%，P<.01）。伊多昔芬可预防TNFα诱导的内皮功能障碍（在伊多昔芬处理的血管环中最大舒张率为86±2.6%，在17β-雌激素处理的血管环中为77±5.1%），但令人惊讶的是17β-雌二醇不能。体内缺血再灌注导致显著的内皮功能障碍，表现为对乙酰胆碱的血管舒张作用降低（最大舒张率：正常SMA环中为92±3.9%，缺血再灌注后为48±5.5%），但对内皮非依赖性血管舒张剂酸化亚硝酸钠的舒张反应正常（95±3.2%）。以1或2mg/kg/天的剂量给予伊多昔芬，或以1mg/kg/天的剂量给予17β-雌激素，持续4天，可显著保留内皮功能（与载体相比，P<.01）。综上所述，这些结果表明伊多昔芬是一种内皮依赖性血管舒张剂，对TNFα和缺血再灌注诱导的内皮损伤具有显著的内皮保护作用。这些结果表明，选择性雌激素受体调节剂在内皮功能障碍起重要作用的疾病中具有治疗潜力。
