目的: 探讨肾素抑制剂SPH3127对两肾一夹(2K1C)高血压大鼠的血压调控作用及其对心肌细胞的保护机制。方法: 将100只雄性SD大鼠分为假手术组、高血压模型组、SPH3127组(10 mg/kg SPH3127)、SPH3127+ZnPP组(10 mg/kg SPH3127+20 mg/kg ZnPP)以及缬沙坦组(10 mg/kg)。采用尾动脉测量法测定大鼠收缩压(systolic blood pressur, SBP),通过超声心动图评估左室射血分数(left ventricular ejection fraction, LVEF)、左室短轴缩短率(left ventricular short axis shortening rate, LVFS)、左室舒张末期内径(left ventricular end-diastolic diameter, LVEDD)和左室收缩末期内径(left ventricular end-systolic diameter,LVESD)。观察心肌细胞形态变化并检测心肌组织内胶原纤维的含量;检测血清中血管紧张素Ⅱ(angiotensin Ⅱ, Ang Ⅱ)、心肌组织中活性氧(reactive oxygen species, ROS)和超氧化物歧化酶(superoxide dismutase, SOD)的含量,测定心肌组织中血红素加氧酶-1(heme oxygenase-1, HO-1)和过氧化物酶体增殖物激活受体γ共激活因子-1α(peroxide-activating receptor γ-coactivator 1α,PGC-1α)的mRNA及蛋白表达水平。结果: 建模前各组大鼠的SBP差异无统计学意义(P＞0.05)。经过药物干预后,相较于模型组,各组大鼠SBP均明显降低(P＜0.05),且SPH3127组和缬沙坦组SBP低于SPH3127+ZnPP组(P＜0.05)。药物干预4周后,药物干预的三组大鼠与模型组相比LVEF和LVFS值升高(P＜0.05),而LVEDD和LVESD值降低(P＜0.05)。与假手术组相比,模型组大鼠的心肌纤维化程度加重,Ang Ⅱ和ROS含量均增加(P＜0.05),而SOD含量则降低(P＜0.05)。与模型组相比,SPH3127组、缬沙坦组以及SPH3127+ZnPP组的心肌纤维化面积减少(P＜0.05),Ang Ⅱ和ROS含量也降低(P＜0.05)。模型组大鼠心肌组织的HO-1和PGC-1α的mRNA及蛋白表达水平较假手术组降低(P＜0.05),而SPH3127组的HO-1和PGC-1α mRNA及蛋白表达水平较模型组升高(P＜0.05)。与SPH3127组相比,SPH3127+ZnPP组的HO-1和PGC-1α mRNA及蛋白表达水平降低(P＜0.05)。结论: SPH3127不仅具有降压作用,还能通过激活HO-1/PGC-1α信号通路,抑制氧化应激,发挥心肌保护作用。

Objective: To investigate the effect of SPH3127 on blood pressure regulation and its protective mechanism on cardiomyocytes in two-kidney one-clip (2K1C) hypertensive rats. Methods: A total of 100 male SD rats were divided into sham operation group, hypertension model group, SPH3127 group (10 mg/kg SPH3127), SPH3127+ZnPP group (10 mg/kg SPH3127+20 mg/kg ZnPP) and valsartan group (10 mg/kg). Systolic blood pressur (SBP) was measured by tail artery method. Left ventricular ejection fraction (LVEF), left ventricular short axis shortening rate (LVFS), left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were evaluated by echocardiography. The morphological changes of myocardial cells were observed and the content of collagen fibers in myocardial tissue was detected. The contents of angiotensinⅡ(Ang Ⅱ) in serum, reactive oxygen species (ROS) and superoxide dismutase (SOD) in myocardial tissue were detected. The mRNA and protein expression levels of heme oxygenase-1 (HO-1) and peroxide-activating receptor γ-coactivator 1α (PGC-1α) in myocardial tissue were determined. Results: There was no significant difference in SBP between the groups before modeling (P＞0.05). After drug intervention, compared with the model group, the SBP of rats in each group was significantly decreased (P＜0.05), and the SBP of SPH3127 group and valsartan group was lower than that of SPH3127+ZnPP group (P＜0.05). After 4 weeks of drug intervention, the LVEF and LVFS values of the three groups of rats with drug intervention were higher than those of the model group (P＜0.05), while the LVEDD and LVESD values were lower (P＜0.05). Compared with the sham operation group, the degree of myocardial fibrosis in the model group was aggravated, the contents of AngⅡ and ROS were increased (P＜0.05), while the content of SOD was decreased (P＜0.05). Compared with the model group, the area of myocardial fibrosis in SPH3127 group, valsartan group and SPH3127+ZnPP group was decreased (P＜0.05), and the contents of Ang Ⅱand ROS were also decreased (P＜0.05). The mRNA and protein expression levels of HO-1 and PGC-1α in myocardial tissue of rats in the model group were lower than those in the sham operation group (P＜0.05), while the mRNA and protein expression levels of HO-1 and PGC-1α in the SPH3127 group were higher than those in the model group (P＜0.05). Compared with SPH3127 group, the expression levels of HO-1 and PGC-1α mRNA and protein in SPH3127+ZnPP group were decreased (P＜0.05). Conclusion: SPH3127 not only has a blood pressure-lowering effect, but also can exert myocardial protective effects by activating the HO-1/PGC-1α signaling pathway and inhibiting oxidative stress.