Rahimian R, Laher I, Dube G, van Breemen C
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
J Pharmacol Exp Ther. 1997 Oct;283(1):116-22.
We report on the modulatory effects of chronic subcutaneous or oral estrogen and LY117018, a selective estrogen receptor modulator, on the release of nitric oxide in rings of rat aorta studied under isometric conditions. Dilator responses to acetylcholine (ACh; 10[8] to 10[-5] M) were obtained in phenylephrine (PE; 2 microM)-contracted aorta, and constrictor dose-response curves to PE (10[-8] to 10[-5] M) were generated before and after pretreatment with N omega-nitro-L-arginine methyl ester (L-NAME; 200 microM), an inhibitor of nitric oxide synthase. Tissue segments were obtained from five groups of rats implanted with a subcutaneous pellet delivery system for 21 days: (1) male, (2) sham-operated placebo-treated female, (3) ovariectomized placebo-treated, (4) ovariectomized, 17beta-estradiol treated (0.5 mg/pellet) and (5) ovariectomized, progesterone (15 mg/pellet) and 17beta-estradiol (0.5 mg/pellet)-treated. Aortic rings from sham rats and ovariectomized rats receiving estrogen relaxed more to ACh (10[-6] to 10[-5] M) than did the rings from ovariectomized, progesterone plus estrogen-treated and male rats (P < .05). They were also characterized by a greater potentiation of the PE responses after L-NAME compared with male, progesterone plus estrogen-treated and ovariectomized rats (P < .05) and a similar sensitivity to PE. In addition, ACh-induced relaxation and L-NAME-induced potentiation of PE contractions in aortic rings from rats dosed orally with LY117018 were similar to responses of aortic rings from rats dosed orally with estrogen. These results demonstrate that chronically administered estrogen and LY117018 enhance the release of nitric oxide from endothelium in rat aortic rings.
我们报告了慢性皮下或口服雌激素以及选择性雌激素受体调节剂LY117018对等长条件下研究的大鼠主动脉环中一氧化氮释放的调节作用。在苯肾上腺素（PE；2μM）收缩的主动脉中获得对乙酰胆碱（ACh；10⁻⁸至10⁻⁵M）的舒张反应，并在用一氧化氮合酶抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME；200μM）预处理前后生成对PE（10⁻⁸至10⁻⁵M）的收缩剂量反应曲线。组织段取自五组皮下植入微丸给药系统21天的大鼠：（1）雄性，（2）假手术安慰剂处理的雌性，（3）卵巢切除安慰剂处理的，（4）卵巢切除，17β-雌二醇处理（0.5mg/微丸）和（5）卵巢切除，孕酮（15mg/微丸）和17β-雌二醇（0.5mg/微丸）处理。与卵巢切除、孕酮加雌激素处理的大鼠和雄性大鼠相比，接受雌激素的假手术大鼠和卵巢切除大鼠的主动脉环对ACh（10⁻⁶至10⁻⁵M）的舒张反应更强（P <.05）。与雄性、孕酮加雌激素处理的大鼠和卵巢切除的大鼠相比，它们还具有L-NAME处理后对PE反应更大的增强作用（P <.05）以及对PE的相似敏感性。此外，口服LY117018的大鼠主动脉环中ACh诱导的舒张和L-NAME诱导的PE收缩增强与口服雌激素的大鼠主动脉环的反应相似。这些结果表明，长期给予雌激素和LY117018可增强大鼠主动脉环内皮细胞一氧化氮的释放。
