消旋TJ0711长期给药对肾性高血压大鼠的药效学研究

Pharmacodynamic study of racemic TJ0711 on renal hypertensive rats after long-term administration

观察消旋TJ0711长期给药对肾性高血压大鼠的血压、心率的影响及对心血管的保护作用。制备两肾一夹型肾性高血压大鼠模型(renal hypertensive rats,RHR),将血压升高4 kPa的大鼠随机分为消旋TJ071110、20及40 mg.kg 1剂量组、卡维地洛阳性对照组和模型组以及假手术组(n=10)。每日1次灌胃给药。每周测量给药前后的血压和心率。于6～8周尾部取血,测定血浆丙二醛(MDA)、肾素、血管紧张素II(Ang II)和内皮素-1(ET-1)含量;9周后取左心室测左心室重量指数(LVWI)和羟脯氨酸含量。给药4周后,TJ0711 40 mg.kg 1剂量组的血压较第1周给药前显著降低,该作用一直延续至实验结束。TJ0711 10、20及40 mg.kg 1剂量组血浆中MDA、肾素、Ang II和ET-1含量均显著低于模型组(P<0.05,P<0.01),LVWI和心肌羟脯氨酸含量有降低趋势。结果显示,TJ0711连续给药后使给药前的血压值持续下降,除了直接阻断肾上腺素α和β受体产生降压外,其持续降压作用与减少血浆中缩血管物质和氧化产物MDA有关,这有利于对心血管发挥保护作用。

The study is to observe the effect of racemic TJ0711 on blood pressure and heart rate as well as protection of cardiovascular system of renal hypertensive rats after long-term administration.The renal hypertensive models were established by the two-kidney,one-clip（2K1C） method in Wistar rats.Four weeks later,assigned the rats whose SBP had increased at least 4 kPa randomly into 5 groups： racemic TJ0711 10,20 and 40 mg·kg？1 groups,carvedilol control group,model group and sham group（n = 10）,ig administration once daily.The changes of BP（blood press） and HR（heart rate） before and after administration were measured by tail-cuff method weekly.Plasma samples of all animals were taken in 6？8 weeks,and plasma MDA as well as renin,angiotensin II（Ang II） and endothelin-1（ET-1） levels were measured.Left ventricle was cut off after 9 weeks,and left ventricular weight index（LVWI） and hydroxyproline were measured.The significant decrease of the BP of TJ0711 40 mg·kg？1 group was observed after TJ0711 ig administration for 4 weeks,and this effect remained till the end of the study.In 8th week,the systolic blood pressure values were： TJ0711 40 mg·kg？1 group 18.93 ± 1.82 kPa（vs 21.30 ± 2.30 kPa,P 〈 0.05）;20 mg·kg？1 group 20.68 ± 3.29 kPa（vs 22.19 ± 2.88 kPa）.The plasma MDA level of all treated groups was significantly lower than that of model group,so were the plasma renin,Ang II and ET-1 levels（P 〈 0.05）.LVWI and hydroxyproline content of myocardial tissue decreased to some extent,but was not significant as compared with that of model group.The study showed that TJ0711 repeated dosing could reduce BP level beginning from drug administration;besides block adrenal α and β receptors to play an antihypertensive role.The sustained antihypertensive effect also related to reduce plasma vasoconstrictor substances and oxidation product MDA.These effects benefited cardiovascular protection.