外源性四氢生物蝶呤对高血压大鼠左心室舒张功能的影响及机制

Tetrahydrobiopterin postpones left ventricular diastolic dysfunction through increasing nitric oxide production

目的 探讨外源性四氢生物蝶呤(BH4)改善自发性高血压大鼠(SHR)左心室舒张障碍的作用与心肌组织氧化应激水平的关系.方法 10周龄SPF级雄性大鼠分为WKY组、WKY+BH4组、SHR组和SHR+BH4组(每组各16只).WKY+BH4组和SHR+BH4组给予200 mg·kg-1·d-1的BH4灌胃,对照WKY组和SHR组予以等量的无菌水灌胃.干预1个月后,测定鼠尾动脉压、超声评价心脏结构及左心功能、有创血流动力学测量心功能参数、高效液相色谱法检测心肌组织BH4和二氢生物蝶呤(BH2)含量、ELISA法检测心肌组织氧化应激指标.结果 与WKY组比较,SHR组左心室明显增厚,左心室舒张功能指标包括舒张功能早期与晚期二尖瓣血流峰值流速比(E/A)、舒张早期二尖瓣口血流峰值流速与二尖瓣环组织峰值流速比(E/E′)和左心室等容舒张时间(LVRT)明显增加,而舒张早期与晚期二尖瓣环组织峰流速比(E′/A′)和二尖瓣血流传播速度(Vp)减低(P<0.05).BH4干预后SHR+BH4组E/E′低于SHR组(P均<0.05).有创血流动力学各指标显示SHR组大鼠左室收缩末压、收缩末期压力-容积关系、左心室舒张末压、舒张末期压力-容积关系及Tau指数均显著高于WKY组,BH4干预后SHR+BH4组舒张末期压力-容积关系和Tau指数明显低于SHR组(P均<0.05).与SHR组相比,SHR+BH4组心肌细胞BH4含量和BH4/BH2比值明显增加(P均<0.05),一氧化氮含量和超氧化物歧化酶活性明显增高(P均<0.01).结论 外源性BH4可能通过降低心肌组织氧化应激水平,增加一氧化氮的生成来减轻高血压大鼠左心室舒张功能的障碍.

Objective To investigate the effect of exogenous tetrahydrobiopterin(BH4)on improving left ventricular diastolic dysfunction and the association with cardiac oxidative stress in spontaneously hypertensive rats(SHR).Methods 10-week aged specific pathogen free male rats were divided into 4 groups:Wistar-Kyoto(WKY),WKY+BH4,SHR and SHR+BH4(with 16 rats in each group).Rats in WKY+BH4 and SHR+BH4 groups were given BH4 with 200 mg·kg-1·d-1 by lavage administration,while rats in the WKY and SHR control groups received the same volume of sterile water.After one month intervention,hemodynamic and echocardiographic parameters were used to assess left ventricular structure and function.High performance liquid chromatography analysis was used to measure cardiac biopterins.Myocardial cyclic guanosine monophosphate(cGMP),malondialdehyde(MDA),superoxide dismutase(SOD)and nitric oxide(NO)were detected by ELISA analysis.Results Compared with WKY group,rats in SHR group showed significant cardiac hypertrophy,and 020><the left ventricular diastolic function indexes including the peak velocity ratio of mitral flow in early and late of diastolic phase(E/A),the peak velocity ratio of mitral flow to mitral annulus in early diastolic phase(E/E′)and the isovolumic relaxation time(IVRT)significantly increased(P<0.05),while the peak velocity ratio of mitral annulus in early and late of diastolic phase(E′/A′),the propagation velocity of mitral flow(Vp)significantly decreased(P<0.05).After one month BH4 adminstration,the E/E′ratio was significant lower in SHR+BH4 group when compared with WKY group and SHR group(all P<0.05).Compared with WKY group,the left ventricular end-systolic pressure(LVESP),left ventricular end-diastolic pressure(LVEDP),left ventricular end-diastolic pressure volume relationship(EDPVR)and Tau index were significantly higher in SHR group.After treated with BH4,rats in SHR+BH4 groups had significant lower EDPVR and Tau index than those in SHR group(all P<0.05).Compared with SHR group,the BH4 levels(P<0.05),BH4/BH2 ratio<3859>(P<0.05),NO production(P<0.01)and SOD activities(P<0.01)in SHR+BH4 group were significantly higher.Conclusion Exogenous BH4 can improve left ventricular diastolic dysfunction by increasing NO production and reducing cardiac oxidative stress.