Ghanam K, Ea-Kim L, Javellaud J, Oudart N
Laboratoire de Pharmacologie, Faculté de Pharmacie, 2 rue du Dr Marcland, 87025 cédex, Limoges, France.
Atherosclerosis. 2000 Sep;152(1):59-67. doi: 10.1016/s0021-9150(99)00450-5.
The involvement of endothelium-derived hyperpolarizing factor (EDHF) in the protective effect of 17beta-estradiol was investigated on the phenylephrine-precontracted carotid artery from cholesterol fed rabbits. Animals were fed for 8 weeks as follows: control group, standard chow; (control+estradiol) group, standard chow+17beta-estradiol; standard chow+1% cholesterol, cholesterol group; or (cholesterol+estradiol) group, 1% cholesterol chow+17beta-estradiol. Relaxations to acetylcholine (ACh) (3 nM-30 microM) were performed with N(omega) nitro-L-arginine methyl ester (300 microM) and indomethacin (10 microM). Charybdotoxin (50 nM)+apamin (50 nM), glibenclamide (10 microM) or 4-aminopyridine (1 mM) were used to block, respectively, calcium-activated-K(+), adenosine triphosphate (ATP)-sensitive-K(+) and voltage-dependent K(+) channels. In the control group, ACh induced a residual concentration-dependent relaxation. This response was impaired by hypercholesterolemia and restored by 17beta-estradiol. In control and cholesterol groups, 4-aminopyridine or glibenclamide did not affect this relaxation, but in (control+estradiol) and (cholesterol+estradiol) groups, glibenclamide suppressed it. In all groups, this persisting relaxation was completely abolished by charybdotoxin alone or with apamin, by hemoglobin (10 microM), a nitric oxide scavenger, or by LY83183 (10 microM), a guanylate cyclase inhibitor. Thus, in the rabbit carotid artery, the protective effect of 17beta-estradiol against hypercholesterolemia is probably mediated by a nitric oxide/cyclic GMP pathway which activates calcium-targeted and ATP-dependent K(+) channels.
研究了内皮衍生超极化因子（EDHF）在17β-雌二醇对高胆固醇喂养兔苯肾上腺素预收缩颈动脉的保护作用中的参与情况。动物按以下方式喂养8周：对照组，标准饲料；（对照+雌二醇）组，标准饲料+17β-雌二醇；标准饲料+1%胆固醇，胆固醇组；或（胆固醇+雌二醇）组，1%胆固醇饲料+17β-雌二醇。用N（ω）-硝基-L-精氨酸甲酯（300μM）和吲哚美辛（10μM）进行对乙酰胆碱（ACh）（3 nM - 30μM）的舒张实验。分别使用大蝎毒素（50 nM）+蜂毒明肽（50 nM）、格列本脲（10μM）或4-氨基吡啶（1 mM）来阻断钙激活钾通道、三磷酸腺苷（ATP）敏感性钾通道和电压依赖性钾通道。在对照组中，ACh诱导出残余的浓度依赖性舒张。这种反应因高胆固醇血症而受损，并被17β-雌二醇恢复。在对照组和胆固醇组中，4-氨基吡啶或格列本脲不影响这种舒张，但在（对照+雌二醇）组和（胆固醇+雌二醇）组中，格列本脲抑制了它。在所有组中，这种持续的舒张被单独的大蝎毒素或与蜂毒明肽一起、一氧化氮清除剂血红蛋白（10μM）或鸟苷酸环化酶抑制剂LY83183（10μM）完全消除。因此，在兔颈动脉中，17β-雌二醇对高胆固醇血症的保护作用可能是由激活钙靶向和ATP依赖性钾通道的一氧化氮/环鸟苷酸途径介导的。
