Baumhäkel Magnus, Schlimmer Nils, Büyükafsar Kansu, Arikan Onur, Böhm Michael
Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, D-66421 Homburg/Saar, Germany.
J Pharmacol Exp Ther. 2008 Jun;325(3):818-23. doi: 10.1124/jpet.107.135681. Epub 2008 Mar 25.
To determine the effects and underlying mechanisms of treatment with the beta-receptor blockers nebivolol and metoprolol on penile endothelial function in apolipoprotein E (ApoE)-/- mice, wild-type (WT) and ApoE-/- mice were fed with a cholesterol-rich diet for 7 weeks. ApoE-/- mice were treated with nebivolol (10 mg/kg/day) or metoprolol (90 mg/kg/day). Endothelial function of aortic and corpora cavernosal tissue was assessed by pharmacological stimulation with carbachol (endothelium dependent) or glycerol trinitrate (endothelium independent) in organ bath experiments. Atherosclerotic lesion formation was evaluated with oil-red staining, and modulation of reactive oxygen species (ROS) production was determined with lipid peroxidation. Heart rate, but not blood pressure, was decreased in nebivolol- and metoprolol-treated ApoE-/- mice (p < 0.01) compared with controls and WT mice without significant intergroup differences. Atherosclerotic lesion formation in the aortic root was increased in ApoE-/- mice (p < 0.01) with a more significant improvement in nebivolol- (p < 0.01) compared with metoprolol-treated mice (p < 0.05). Endothelium-dependent relaxation of the corpora cavernosa was significantly impaired in ApoE-/- mice (p < 0.05), which improved in nebivolol- versus metoprolol-treated mice. Efficacy of endothelium-dependent relaxation was comparable in aortic and penile tissue. Quantification of ROS production via lipid peroxidation revealed a significant reduction of superoxide anion production in nebivolol-treated (p < 0.05) but not metoprolol-treated mice compared with ApoE-/- controls. Nebivolol improves penile endothelial function as a surrogate of erectile function in ApoE-/- mice. These effects may be related to a reduction of ROS production, which is independent of heart rate reduction, because metoprolol did not increase endothelial function.
为了确定β受体阻滞剂奈必洛尔和美托洛尔对载脂蛋白E（ApoE）基因敲除小鼠阴茎内皮功能的影响及其潜在机制，将野生型（WT）和ApoE基因敲除小鼠喂以富含胆固醇的饮食7周。对ApoE基因敲除小鼠分别给予奈必洛尔（10毫克/千克/天）或美托洛尔（90毫克/千克/天）治疗。在器官浴实验中，通过用卡巴胆碱（内皮依赖性）或硝酸甘油（非内皮依赖性）进行药理刺激来评估主动脉和海绵体组织的内皮功能。用油红染色评估动脉粥样硬化病变形成情况，用脂质过氧化作用测定活性氧（ROS）生成的调节情况。与对照组和WT小鼠相比，奈必洛尔和美托洛尔治疗的ApoE基因敲除小鼠心率降低（p<0.01），血压无明显变化，组间无显著差异。ApoE基因敲除小鼠主动脉根部的动脉粥样硬化病变形成增加（p<0.01），与美托洛尔治疗的小鼠相比（p<0.05），奈必洛尔治疗的小鼠改善更显著（p<0.01）。ApoE基因敲除小鼠海绵体的内皮依赖性舒张功能明显受损（p<0.05），奈必洛尔治疗的小鼠比美托洛尔治疗的小鼠有所改善。内皮依赖性舒张功能在主动脉和阴茎组织中的效果相当。通过脂质过氧化作用对ROS生成进行定量分析显示，与ApoE基因敲除对照组相比，奈必洛尔治疗的小鼠超氧阴离子生成显著减少（p<0.05），而美托洛尔治疗的小鼠则无此现象。在ApoE基因敲除小鼠中，奈必洛尔可改善阴茎内皮功能，作为勃起功能的替代指标。这些作用可能与ROS生成减少有关，且与心率降低无关，因为美托洛尔并未增强内皮功能。
