β受体阻断剂对实验性动脉粥样硬化内皮型一氧化氮合酶活性和基因表达的影响

Effects of β-Blockers on the Activity and Gene Expression of Endothelial Nitric Oxide Synthase in the Vascular Wall of Atherosclerotic Rabbits

目的比较三种β受体阻断剂卡维地洛、普萘洛尔和阿替洛尔对动脉粥样硬化家兔血管壁内皮型一氧化氮合酶的影响。方法24只雄兔随机分为高脂组、高脂+卡维地洛组[10 mg/(kg.d)]、高脂+普萘洛尔组[10 mg/(kg.d)]和高脂+阿替洛尔组[20 mg/(kg.d)]。各组给予相应处理1周后,行腹主动脉球囊损伤术,并继续相应处理10周。6只家兔给予正常饮食并施以假手术作为正常对照。实验结束时,测定血脂、脂质过氧化物及一氧化氮水平,取动脉组织检测血管内皮型一氧化氮合酶活性,用原位杂交法检测主动脉内皮型一氧化氮合酶基因表达量及分布规律。结果与正常组相比,高脂组内皮型一氧化氮合酶活性及基因表达均明显降低(P<0.01);与高脂组相比,三种β受体阻断剂在所用剂量内均未对血脂产生显著性影响;卡维地洛明显增强内皮型一氧化氮合酶活性,而普萘洛尔和阿替洛尔均未对上述指标产生明显影响。原位杂交显示,正常家兔动脉壁内皮型一氧化氮合酶mRNA主要在内皮层呈强阳性表达,高脂组内皮型一氧化氮合酶mRNA在内皮层表达显著降低,三种β受体阻断剂对内皮型一氧化氮合酶mRNA表达均无显著影响。结论与普萘洛尔和阿替洛尔相比,卡维地洛能独特地增强内皮源性内皮型一氧化氮合酶活性。

Aim To investigate the effect of G-blockers on the activity and mRNA expression of endothelial nitric oxide synthase （ eNOS ） in atherosclerotic rabbits. Methods Rabbits were randomized into 4 groups ： hyperlipidemic diet group, hyperlipidemic diet supplemented with propranolol （ 10 mg/（ kg · d） ） group, hyperlipidemic diet supplemented with atenolol （20 mg/（ kg · d） ） group, hyperlipidemic diet supplemented with carvedilol （ 10 mg/（ kg · d } } group. After treated for 1 week, they underwent balloon injury and remained on their respective diets for the further 10 weeks. 6 sham untreated rabbits received normal diet. At the end of the trial, the activity and gene expression of eNOS was studied by NADPH-diaphorase histochemical staining, and gene expression of eNOS was studied by in situ hybridization and RTPCR. Results The results indicated that eNOS activity and mRNA expression in atherosclerotic model group were obviously decreased. Treatment with carvedilol, but not propranolol, or atenolol, markedly increased eNOS staining with NADPH diaphorase （ P 〈 0.05 ）. Serum lipid levels and aortic endothelial eNOS mRNA expression did not change significantly in all of the drug-treated groups. Conclusion It is suggested that carvedilol-treatment might restore eNOS availability and this action are not shared by other β-blockers such as propranolol, or atenolol. The greater effects of carvedilol in preventing development of atherosclerosis and improving endothelial function may be related to restoration of eNOS availability.