可溶性鸟苷酸环化酶激活剂Cinaciguat对2型糖尿病大鼠血管并发症的作用

Effect of soluble guanglate cyclase activator Cinaciguat on the vascular lesions in rats with type 2 diabetes mellitus

目的探讨可溶性鸟苷酸环化酶激活剂Cinaciguat对2型糖尿病大鼠血管并发症的干预作用。方法雄性SD大鼠28只,8只采用普通饲料喂养者为对照组,20只高脂饲料喂养4周后给予小剂量链脲佐菌素腹腔注射制备2型糖尿病大鼠模型,16只大鼠造模成功并随机分为模型组和干预组各8只。继续饲养12周,干预组给予Cinaciguat7μg/(kg·d)腹腔注射,模型组和对照组大鼠给予等量质量分数0.1%DMSO腹腔注射,疗程均为2周。测定各组大鼠血清空腹血糖、糖化血红蛋白、碱性磷酸酶、钙、磷、一氧化氮和一氧化氮合酶水平,并对胸主动脉行组织病理学检查。结果模型组大鼠血清碱性磷酸酶活性[(886.63±527.08)u/L]明显高于干预组[(564.17±475.89)u/L]和对照组[(139.00±32.29)u/L],干预组高于对照组,差异有统计学意义(P<0.01);模型组一氧化氮水平[(43.20±7.49)μmol/L]、一氧化氮合酶活性(12.23±2.32)u/mL]明显低于干预组[(49.18±8.38)μmol/L、(17.43±4.27)u/mL]和对照组[(62.23±10.04)μmol/L、(24.90±5.39)u/mL](P<0.05),干预组低于对照组(P<0.05);干预组和模型组空腹血糖[(24.89±4.79)、(24.60±4.42)mmol/L]及糖化血红蛋白[(11.38±0.61)%、(12.13±0.78)%]水平明显高于对照组[(5.02±0.65)mmol/L、(4.60±0.51)%](P<0.01),模型组与干预组比较差异无统计学意义(P>0.05);对照组、模型组与干预组大鼠血清钙[(1.75±0.17)、(1.89±0.50)、(1.97±0.52)mmol/L]和磷[(2.48±0.12)、(2.85±0.19)、(2.62±0.09)mmol/L]水平比较差异均无统计学意义(P>0.05);组织病理检查结果显示对照组大鼠胸主动脉内膜连续、光滑,中膜平滑肌细胞走行清晰、无增生;模型组大鼠胸主动脉血管壁增厚,中膜平滑肌细胞增生且排列不规则;干预组大鼠胸主动脉壁较为完整、连续,中膜平滑肌细胞稍有增生,排列较规则,走行无明显异常。结论 Cinaciguat能有效改善2型糖尿病大鼠的抗氧化能力,为2型糖尿病血管并发症干预治疗提供了新思路和依据。

Objective To study the effects of soluble guanglate cyclase activator Cinaciguat on the vascular lesions in rats with type 2 diabetes mellitus. Methods In 28 male SD rats, 8 rats received common feed （control group）, and 20 rats received low-dose streptozotocin after 4-week high-lipid diet, in which 16 rats were successfuly established type 2 diabetic models and were divided into model group （n=8） and intervention group （n=8）. After another 12-week high-lipid diet, intervention group was given intraperitoneal injection of cinaciguat 7 μg/（kg · d） for 2 weeks, and model group and control group were given intraperitoneal injection of same volume of DMSO for 2 weeks. The levels of fasting plasma glucose, glycosylated hemoglobin A1 c, alkaline phosphatase, calcium, phosphorus, nitric oxide and nitric oxide synthase were detected in all groups. The thoracic aorta underwent histopathological examination. Results The alkaline phosphatase level was significantly higher in model group （（886. 63 ± 527. 08） u/L） than that in intervention group （（564.17±475.89） u/L） and control group （（139. 00± 32. 29） u/L）, and higher in intervention group than that in control group （P〈0.01）. The levels of nitric oxide （（43. 20 ± 7. 49） μmol/L） and nitric oxide synthase （（12. 23 ±2.32） u/mL） in model group were significantly lower than those in intervention group （（49. 18 ± 8. 38） μmol/L, （17.43±4.27） u/mL） （P〈0.05） and control group （（62.23±10.04） μmol/L, （24.90±5.39） u/mL） （P〈0.05）, and lower in intervention group than those in control group （P〈0.05）. The levels of fasting plasma glucose, and glycosylated hemoglobin A1 c were significantly higher in intervention group （ （24.89 ±4.79） mmol/L, （ 11.38 ± 0.61 ） % ） and model group （（24.60±4.42） mmol/L, （12. 13±0.78）%） than those in control group （（5.02±0.65） mmol/L, （4. 60± 0.51） %） （P〈0.01）, and there were no significant differences between model group and intervention group （P〉0.05）. There were no significant differences in the levels of serum calcium （（1. 75 ±0. 17）, （1. 89 ± 0. 50）, （1. 97 ± 0.52） mmol/L） and phosphorus （（2.48±0.12）, （2. 85±0.19）, （2.62±0.09） mmol/L） between each two of controlgroup, model group and intervention group （P〈0.05）. The histopathologic examination results showed continuous and smooth thoracic aortic intima, and clear smooth muscle cell of tunica media, with no hyperplasia in control group; thickened thoracic aorta vascular wall, and proliferated and irregularly arranged smooth muscle cells of tunica media in model group; and complete and continuous thoracic aortic wall, proliferated smooth muscle cells of tunica media, regular arrangement and normal direction in intervention group. Conclusion Cinaciguat can improve anti-oxidative stress, providing new thought and theory evidence for the treatment of vascular complications of type 2 diabetes mellitus.