血管紧张素转换酶抑制剂和血管紧张素Ⅱ-1型受体拮抗剂联合应用对内皮型一氧化氮合酶的影响

目的探讨血管紧张素转换酶抑制剂(福辛普利)、血管紧张素Ⅱ1型(ATⅡ1)受体拮抗剂(依贝沙坦)及二者合用对内皮型一氧化氮和酶(eNOS)及心室重构的影响。方法将86只心肌梗死后24h的大鼠分为(1)安慰剂组(22只);(2)福辛普利组(20只,10mg·kg-1·d-1);(3)依贝沙坦组(23只,50mg·kg-1·d-1);(4)福辛普利+依贝沙坦组(21只,10mg·kg-1·d-1+50mg·kg-1·d-1);另设假手术正常对照组(18只)。分别于心肌梗死后2周及6周检查(1)测平均动脉压、左室舒张末压(LVEDP);(2)心室重量/体重;(3)免疫组化及图像分析方法测非梗死区总胶原;(4)RT PCR法测定eNOSmRNA表达及免疫组化方法测eNOS蛋白质表达。结果安慰剂组比假手术组大鼠LVEDP升高(P<0.05),心室重量指数增加(P<0.01),非梗死区总胶原含量2周(6.1%±0.7%比3.6%±0.5%)、6周(5.1%±0.8%比3.6%±0.4%,均P<0.01)明显增加;福辛普利、依贝沙坦及两药合用后这些指标均降低。心肌梗死后6周时依贝沙坦组和联合组总胶原含量较福辛普利组降低更明显(3.4%±0.7%和3.3%±0.7%比4.2%±0.6%,均P<0.05)。两药单独应用eNOSmRNA表达在心肌梗死后2周时高于假手术组和安慰剂组,差异无统计学意义,但在心肌梗死后6周时增加,差异有统计学意义。而联合用药组在2、6周均较其余各组有显著增加(分别

Effects of combination therapy with angiotensin I-converting enzyme inhibitor and angiotensin 1 receptor antagonist on ventricular remodeling and expression of endothelial nitric oxide synthase

OBJECTIVE: To evaluate the effects of ACEI, AT1 receptor antagonism, and combination of these two drugs on ventricular remodeling, and the vary of eNOS in rats with myocardial infarction (MI). METHODS: Eighty-six rats were randomly divided into four groups at twenty-four hours after MI, and treated for 2 weeks and 6 weeks. (1) MI-placebo (n = 22); (2) MI-Fosinopril (n = 20, 10 mg.kg(-1).d(-1)); (3) MI-Irbesartan (n = 23, 50 mg.kg(-1).d(-1)); (4) MI-Fosinopril + Irbesartan (n = 21, 10 mg.kg(-1).d(-1) + 50 mg.kg(-1).d(-1)); and sham-ligation. Mean blood pressure and left ventricular end diastolic pressure (LVEDP) were evaluated, as well as ventricular weight (VW)/body weight (BW) ratio. The total collagen was quantified by histomorphometry. The expressions of eNOS mRNA and protein within the noninfarction zone were determined by RT-PCR and histomorphometry. RESULTS: Acute myocardial infarction resulted in a significant increase of LVEDP (P < 0.05), LVDd (P < 0.01), and VW/BW (P < 0.01), and total collagen (at 2 weeks 6.1 +/- 0.7 vs 3.6 +/- 0.5 and at 6 weeks 5.1 +/- 0.8 vs 3.6 +/- 0.4, P < 0.01) in noninfarcted region. Treatment with fosinopril, irbesartan and combination of these two drugs improved them. At the sixth week, irbesartan and combination therapy decreased more significantly total collagen compared with fosinopril (3.4 +/- 0.7 and 3.3 +/- 0.7 vs 4.2 +/- 0.6, P < 0.05). The level of eNOS mRNA expression increased more significantly in combination therapy group than in fosinopril or irbesartan group alone (at 2 weeks 1.55 +/- 0.17, at 6 weeks 1.61 +/- 0.16, P < 0.01). eNOS protein increased. CONCLUSION: Fosinopril or irbesartan alone, and combination of these two drugs can improve hemodynamics, limited myocardial hypertrophy, attenuated the development of myocardial interstitial fibrosis in the noninfarcted left ventricule. The use of irbesartan, especially combined with fosinopril was more effective than fosinopril alone in the suppression interstitial fibrosis. Combination therapy was more effective than fosinopril and irbesartan alone in enhancing eNOS mRNA and protein expression.