单药及两药联用对肾血管性高血压大鼠左心室及肾素血管紧张素醛固酮系统的影响

Effects of either separate or combined use of two antihypertensive drugs on left ventricles and renin-angiotensin-aldosterone system of renovascular hypertensive rats

目的探讨依那普利、厄贝沙坦、氨氯地平单用及两者联用等不同治疗方案对肾血管性高血压大鼠左心室肥厚和左心室肾素血管紧张素醛固酮系统的影响。方法选用8～12周雄性Sprague Dawley(SD)大鼠,采用两肾一夹制成肾血管性高血压大鼠模型,随机分为假手术组、模型组、依那普利组、厄贝沙坦组、氨氯地平组、依那普利+氨氯地平组、依那普利+厄贝沙坦组和厄贝沙坦+氨氯地平组,每组6只。测量各组大鼠术前、术后血压,用药6周后,测量大鼠左心室质量指数(LVMI),采用放射免疫法检测心室肾素活性、血管紧张素Ⅱ(AngⅡ)、醛固酮水平及血浆AngⅡ水平,Real-time PCR测定左心室组织AngⅡ1型受体(AT1R)和2型受体(AT2R)mRNA表达。结果所有用药组均能明显降低血压和LVMI,且依那普利+氨氯地平及厄贝沙坦+氨氯地平的效应大于对应单药的效应之和,具有协同效应(P<0.01)。除单用氨氯地平外,其他用药组均能降低血浆AngⅡ水平,且所有联合用药均具有协同效应[依那普利+厄贝沙坦组(190.70±89.38)、依那普利+氨氯地平组(221.08±67.28)、厄贝沙坦+氨氯地平组(589.22±85.81),比依那普利组(319.75±91.46)、厄贝沙坦组(799.34±198.88)、氨氯地平组(1414.00±130.42)pg/mL;均P<0.01]。所有用药组均能抑制肾素活性,且所有联合用药均具有协同效应(P<0.01)。除单用厄贝沙坦及厄贝沙坦+氨氯地平外,其他用药组均能降低左心室AngⅡ水平;单用厄贝沙坦及厄贝沙坦+氨氯地平可引起左心室醛固酮水平升高(P<0.01)。所有用药组均能下调AT1RmRNA表达,依那普利+氨氯地平具有协同效应(P<0.01);单用厄贝沙坦可上调AT2RmRNA表达;除单用氨氯地平外,其他用药组均能升高AT2R/AT1R,依那普利+氨氯地平具有协同效应(P<0.01)。结论氨氯地平联合依那普利或厄贝沙坦具有协同降血压和逆转左心室肥厚作用;依那普利联合氨氯地平在降低AngⅡ水平、抑制左心室肾素活性、下调AT1RmRNA表达及升高AT2R/AT1R方面具有协同效应。

Objective To investigate the effects of either separate or combined use of enalapril, irbesartan or amlo- dipine on left ventricular hypertrophy and renin-angiotensin-aldosterone system （RAAS） in renovascular hypertensive rats （RHR）. Methods Male SD rats between the ages of eight to twelve weeks old were chosen to establish 2-kid- ney-l-clip renovaslcular hypertensive models, and then were randomly divided into sham-operated group, RHR mod- el group, enalapril group, irbesartan group, amlodipine group, enalapril＋ amlodipine group, enalapril＋ irbesartan group, and irbesartan＋amlodipine group （n= 6）. The blood pressure was measured before and after the opera- tion. Left ventricular mass index （LVMI） was measured after six weeks of medication. Renin activity, angioten- sin Ⅱ （Ang Ⅱ ）, aldosterone （Ald） levels, as well as plasma Ang Ⅱ , in left ventricle were detected by radioimmu- noassay. Real-Time PCR assay was employed to determine the mRNA expressions of angiotensin Ⅱ 1 receptor （AT1R）and type 2 receptor（AT2R） in left ventricle. Results All the drugs could significantly lower blood pressureand LVMI, and the effect of enalapril or irbesartan combined with amlodipine was greater than the accumulative effects of the corresponding single medicine （P〈0.01）. Except for the single use of amlodipine, all the other drugs could all decrease plasma Ang Ⅱ levels, and all the combination medication had synergistic effects [enalapril＋ irbesartan group（ 190.70 ± 89.38 ）, enalapri＋ amlodipine group （ 221.08 ± 67.28）, irbesartan ＋ amlodipine group （ 589.22± 85.81 ） vs enalapril group （ 319.75 ± 91.46 ）, irbesartan group （ 799.34 ± 198.88 ）, amlodipine group （1414.00±130.42） pg/mL; all P〈0.01]. All the drugs could inhibit renin activity, and all combined medication had synergistic effects（P〈0.01）. Except for the single use of irbesartan and the combined use of irhesartan and amlodipine, all the other drugs could decrease left ventricular AngⅡ levels（P〈0.01）. The single use of irbesar- tan and combination use of irbesartan and amlodipine could elevate left ventricular aldosterone levels（P〈0.01 ）. All the drugs could down-regulate the AT1R mRNA expression, and enalapril combined with amlodipine had syner- gistic effects （P〈0.01）. Single use of irbesartan could up-regulated the expression of AT2 R mRNA. Except for the single use of amlodipine, the rest of the drugs could increase AT2 R/AT1 R, and the effect of enalapril combined with amlodipine had synergistic effects（P〈0.01）. Conehlsions Amlodipine combined with enalapril or irbesartan has synergistic effects on lowering blood pressure and reversing left ventricular hypertrophy. Enalapril combined with amlodipine has synergistic effects on bringing down Ang Ⅱ levels, inhibiting left ventricular renin activity, down-regulating AT1R mRNA expression and increasing AT2 R/ATIR.