苯那普利与坎地沙坦减轻自发性高血压大鼠主动脉内皮氧化应激

Benazepril and Candesartan Attenuate Oxidative Stress in Aorta in Spontaneously Hypertensive Rats

目的观察苯那普利、坎地沙坦治疗对自发性高血压大鼠(SHR)主动脉内皮氧化应激以及内皮型一氧化氮合酶(eNOS)、NAD(P)H 氧化酶重要亚单位 P22^(phox)表达的作用。方法 12周龄 SHR(n=9)连续灌胃给予苯那普利[10 mg/(kg·d),n=9]或(和)坎地沙坦[4 mg/(kg·d),n=9],每2周测定尾动脉压。12周后检测主动脉病理结构、血清超氧化物歧化酶(SOD)活力、一氧化氮(NO)和羟自由基的含量、血浆血管紧张素Ⅱ(AngⅡ)和环鸟苷酸(cGMP)水平、主动脉内膜 eNOS 和 P22^(phox)的表达。结果 SHR 主动脉血管壁明显增厚,尾动脉压、血清羟自由基、血浆 AngⅡ水平及主动脉 P22^(phox)的表达均显著增高,而血清 SOD 活力、NO 含量、cGMP 水平及血管组织 eNOS 的表达均降低。应用苯那普利(Ben)、坎地沙坦(Can)单独治疗均可改善自发性高血压大鼠主动脉结构,增加血清 SOD 活力[Ben:(68.7±2.1),Can:(65.6±4.2)比 SHR:(48.8±3.2)U/mL,P<0.01]、NO 含量[Ben:(60.2±3.5),Can:(58.3±4.4)比 SHR:(42.7±2.9)μmol/L,P<0.01]、血浆 cGMP 含量[Ben:(8.7±1.3),Can:(8.0±1.2)比 SHR:(5.0±1.1)pmol/mL,P<0.01]及主动脉 eNOS 表达[Ben:(1.1±0.3),Can:(1.1±0.2)比 SHR:(1.0±0.2),P<0.01],减少血清羟自由基量[Ben:(422±27),Can:(428±39)比 SHR:(616±50)U/mL,P<0.01和 P<0.05]及主动脉 P22^(phox)的表达[Ben:(1.0±0.2),Can:(1.1±0.2)比SHR:(1.7±0.4),P<0.01];两药联用[苯那普利5 mg/(kg·d)+坎地沙坦2 mg/(kg·d)]能增加 NO 含量及eNOS 表达、降低 P22^(phox)表达,虽然与两药单独使用没有统计学意义,但是在增加 SOD 活力[(71.6±4.2)U/mL]、cGMP 含量[(10.2±1.2)pmol/mL]及减少羟自由基含量[(399±50)U/mL]效果较好(与 Can 组相比,P<0.05)。结论苯那普利和(或)坎地沙坦单用均能够改善 SHR 主动脉结构及氧化应激状态,两者联合应用具有部分协同作用。

Objective To study the anti-oxidative stress effects of benazepril and candesartan. Methods SHRs of 12 weeks old were given benazepril（10 mg/kg · d, n=9）or candesartan（4 mg/kg · d, n=9）or combination（Ben：10 mg/kg · d ＋Can： 4 mg/kg· d） for 12 weeks. The tail arterial pressure was measured every two weeks. At end of study, pathological changes in the thoracic aorta, activity of SOD, serum contents of NO and hydroxy radicals, plasma Ang H and cGMP, eNOS and P22^phox protein expressions in aortic tunica intima were determined. Results The thoracic aorta wall was thickened markedly in SHRs, and blood pressure, hydroxy radical, Ang 11 and P22^phox protein expression were increased significantly, while the serum NO, level of cGMP and eNOS expression were decreased. Benazepril（Ben） or Candesartan（Can） inhibit the thickening of vessel wall, enhance the activity of SOD （Ben= 68.7±2.1, Can： 65.6±4.2 vs SHR： 48.8± 3.2 U/mL, P〈0.01）, serum NO （Ben： 60.2±3.5, Can：58.3±4.4 vs SHR.. 42.7±2.9 /,mol/L, P〈0.01） and plasma cGMP （Ben： 8.7± 1.3, Can= 8.0±1.2 vs SHR： 5.0±1. 1 pmol/mL, P〈0.01）, and the expression of eNOS in aorta （Ben.. 1.1± 0.3, Can： 1.1±0.2 vs SHR.. 1.0±0.2, P〈0.01）. The concentration of hydroxy radical （Ben： 422±-27, Can.. 428±39 vs SHR： 616±50 U/mL, P〈0.01 or P〈0.05） and the expression of P22^phox in aorta （Ben：1. 0±0.2, Can： 1.1±0.2 vs SHR： 1.7±0. 1 U/mL, P〈0.01） were coincidentlydecreased. The effect of combined treatment [benazepril, 5 mg/（kg· d） l-candesartan, 2 mg/（kg · d）] had been shown no significant differences from Can or Ben monotherapy, however, the activity of SOD （71.6±4.2 U/ml.）, level of cGMP （10.24±1.2 pmol/mL） and the concentTation of hydroxy radical （399 ± 50 U/mL） were more significantly increased. Conclusion Candesartan or/and benazepril reduced BP and improved the blood vessel remodeling associated with attenuation in oxidative stress status. Partial synergistically enhancing effects on activity of serum SOD and plasma cGMP bv combined use of them were shown.