ARB类药物对2K1C型肾血管性高血压大鼠左室重构方面的类效应及作用研究
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摘要
目的以氯沙坦、缬沙坦、替米沙坦、厄贝沙坦4种血管紧张素Ⅱ受体阻滞剂(ARB)类药物对二肾一夹(2K1C)型肾血管性高血压大鼠进行干预,观察其血压、心脏指数、左心室指数、Ⅰ型胶原、Ⅲ型胶原及核因子-κB(NF-κB)的改变,研究4种ARB类药物在改善2K1C型肾血管性高血压大鼠左室重构方面的类效应,并初步探讨NF-κB在2K1C型肾血管性高血压大鼠左室重构中的作用。方法将56只雄性SD大鼠随机分为空白对照组(n=8)、假手术组(n=8)以及模型组(n=40),模型以改良的二肾一夹方法建立。模型建立成功后,模型组随机分为4个治疗组及模型对照组(n=8),治疗组按照药品说明书对临床使用的推荐剂量分别给予氯沙坦(30 mg/kg)、缬沙坦(30 mg/kg)、替米沙坦(30 mg/kg)、厄贝沙坦(50 mg/kg)灌胃;假手术组、空白对照组及模型对照组分别给予相同体积的生理盐水灌胃,每日1次。比较各组血压、心脏指数、左心室指数、Ⅰ型胶原、Ⅲ型胶原含量的改变以及NF-κB的表达。结果模型对照组与空白对照组比较,心脏指数及左心室指数均增高,差异有统计学意义(P <0.05)。各治疗组与模型对照组比较,用药8周血压、心脏指数、左心室指数均降低,差异有统计学意义(P <0.05)。假手术组与空白对照组比较,NF-κB、Ⅰ型胶原、Ⅲ型胶原差异无统计学意义(P>0.05)。模型对照组与空白对照组比较,NF-κB、Ⅰ型胶原、Ⅲ型胶原的表达明显增高,差异有统计学意义(P <0.05)。4个治疗组与模型对照组比较,NF-κB、Ⅰ型胶原、Ⅲ型胶原的表达明显减少,差异有统计学意义(P <0.05)。氯沙坦组NF-κB的表达高于厄贝沙坦组、替米沙坦组以及缬沙坦组,各治疗组Ⅰ型胶原、Ⅲ型胶原的表达比较差异无统计学意义(P>0.05)。结论 NF-κB参与了高血压大鼠左室重构的病理过程。4种ARB类药物均可通过抑制NF-κB的表达来改善2K1C型高血压大鼠左室重构的发生与发展,具有类效应。
Objective To investigate the effect of angiotensin Ⅱ receptor blockers (ARBs) such as losartan,valsartan,telmisartan and irbesartan on blood pressure (BP),cardiac index,left ventricular index,type I collagen,type Ⅲ collagen and the expression of nuclear factor-κB (NF-κB) in 2-kidney,one-clip (2K1C) renovascular hypertensive rats,and investigate the role of NF-κB in left ventricular remodeling in 2K1C renovascular hypertensive rats.Methods Fifty-six male Sprague-Dawley (SD) rats were randomly devided into three groups: blank control group (n = 8),sham operation group (n = 8),and model group (n = 40).The rat model were established by 2 K1C.After the model was successfully established,the rats in model group were randomly divided into losartan group,valsartan group,telmisartan group,irbesartan group,and model control group,8 rats in each group.The rats were administrated by normal saline for gavage in blank control group,sham operation group,and model control group. The rats were administrated by losartan (30 mg/kg),valsartan (30 mg/kg),telmisartan (30 mg/kg),and irbesartan (50 mg/kg) for gavage in losartan group,valsartan group,telmisartan group,and irbesartan group,respectively.After eight weeks of administration,blood pressure,heart index,left ventricular index,type Ⅰ collagen,type Ⅲ collagen,and NF-κB expression were observed.Results Compared with the blank control group,the cardiac index,left ventricular index increased in model control group (P <0.05).Compared with the model control group,blood pressure,cardiac index and left ventricular index were decreased in losartan group,valsartan group,telmisartan group,and irbesartan group at 8 weeks of administration (P <0.05).There was no significant difference in the expressions of NF-κB,type Ⅰ collagen and type Ⅲ collagen between the sham operation group and the blank control group (P >0.05).Compared with the blank control group,the expressions of NF-κB,type Ⅰ collagen and type Ⅲ collagen were significantly increased in the model control group (P <0.05).Compared with the model control group,the expressions of NF-κB,type Ⅰ collagen and type Ⅲ collagen were significantly decreased in losartan group,valsartan group,telmisartan group,and irbesartan group (P <0.05).The expression of NF-κB in losartan group was higher than that in irbesartan group,telmisartan group and valsartan group.There was no significant difference in the expression of type Ⅰ collagen and type Ⅲ collagen among losartan group,valsartan group,telmisartan group,and irbesartan group (P >0.05).Conclusion NF-κB is involved in the pathological process of left ventricular remodeling in 2K1C hypertensive rats.Four kinds of ARBs (losartan,valsartan,telmisartan,and irbesartan) can improve the occurrence and development of left ventricular remodeling in 2K1C hypertensive rats by inhibiting the expression of NF-κB,which have the class effect.
Objective To investigate the effect of angiotensin Ⅱ receptor blockers (ARBs) such as losartan,valsartan,telmisartan and irbesartan on blood pressure (BP),cardiac index,left ventricular index,type I collagen,type Ⅲ collagen and the expression of nuclear factor-κB (NF-κB) in 2-kidney,one-clip (2K1C) renovascular hypertensive rats,and investigate the role of NF-κB in left ventricular remodeling in 2K1C renovascular hypertensive rats.Methods Fifty-six male Sprague-Dawley (SD) rats were randomly devided into three groups: blank control group (n = 8),sham operation group (n = 8),and model group (n = 40).The rat model were established by 2 K1C.After the model was successfully established,the rats in model group were randomly divided into losartan group,valsartan group,telmisartan group,irbesartan group,and model control group,8 rats in each group.The rats were administrated by normal saline for gavage in blank control group,sham operation group,and model control group. The rats were administrated by losartan (30 mg/kg),valsartan (30 mg/kg),telmisartan (30 mg/kg),and irbesartan (50 mg/kg) for gavage in losartan group,valsartan group,telmisartan group,and irbesartan group,respectively.After eight weeks of administration,blood pressure,heart index,left ventricular index,type Ⅰ collagen,type Ⅲ collagen,and NF-κB expression were observed.Results Compared with the blank control group,the cardiac index,left ventricular index increased in model control group (P <0.05).Compared with the model control group,blood pressure,cardiac index and left ventricular index were decreased in losartan group,valsartan group,telmisartan group,and irbesartan group at 8 weeks of administration (P <0.05).There was no significant difference in the expressions of NF-κB,type Ⅰ collagen and type Ⅲ collagen between the sham operation group and the blank control group (P >0.05).Compared with the blank control group,the expressions of NF-κB,type Ⅰ collagen and type Ⅲ collagen were significantly increased in the model control group (P <0.05).Compared with the model control group,the expressions of NF-κB,type Ⅰ collagen and type Ⅲ collagen were significantly decreased in losartan group,valsartan group,telmisartan group,and irbesartan group (P <0.05).The expression of NF-κB in losartan group was higher than that in irbesartan group,telmisartan group and valsartan group.There was no significant difference in the expression of type Ⅰ collagen and type Ⅲ collagen among losartan group,valsartan group,telmisartan group,and irbesartan group (P >0.05).Conclusion NF-κB is involved in the pathological process of left ventricular remodeling in 2K1C hypertensive rats.Four kinds of ARBs (losartan,valsartan,telmisartan,and irbesartan) can improve the occurrence and development of left ventricular remodeling in 2K1C hypertensive rats by inhibiting the expression of NF-κB,which have the class effect.
引文
[1]罗富里,蔡得汉,杨林,等.血管紧张素转换酶抑制剂/血管紧张素Ⅱ受体拮抗剂与维持性腹膜透析患者心肾获益的Meta分析[J].肾脏病与透析肾移植杂志,2014,23(3):240-246.
[2]刘佳敏,葛蕾,李静,等.高危冠心病患者血管紧张素转换酶抑制剂类药物应用现况调查[J].中华心血管病杂志,2013,41(1):18-22.
[3]崔贞玉,韩素霞.ARB与ACEI改善心肌梗死患者心室重构的Meta分析[J].实用药物与临床,2014,17(2):139-146.
[4]王建美,高东来,陈艳君,等.缬沙坦对高血压患者血管内皮功能影响的研究[J].中国药物与临床,2015(3):392-394.
[5]沈琪,欧阳小林,黄献文,等.抗高血压类药物治疗Ig A肾病的Meta分析[J].中国全科医学,2013,16(8):904-910.
[6]Oudart N.The rennin angiotention system:current data[J].Ann Pharm Fr,2005(63):144-153
[7]Benson SC,Pershadsingh HA,Ho CI,et al.Identification of telmisartan as a unique angiotensinⅡreceptor antagonist with selective PPAR(gamma)modulating activity[J].Hypertension,2004(43):993-1002
[8]Kostis JB.Treating hypertension in the very old[J].Engl Med,2008,358(18):1958-1960.
[9]Chae CU,Lee RT,Rifai N,et al.Blood pressure and inflammation in apparently healthy men[J].Hypertension,2001,38(3):399-403.
[10]Shiota N,Rysa J,Kovanen PT,et al.A role for cardiac mast cells in the pathogenesis of hypertensive heart disease[J].Hypertens,2003,21(10):1823-1825.
[11]Kalra D,Baumgarten G,Dibbs Z,et al.Nitric oxide provokes tumor necrosis factor alpha expression in adult feline myocardium through a c GMP dependent pathway[J].Circulation,2000,102(11):1302-1307.
[12]王伯瑶,黄宁,吴琦.炎症信号转导Toll/NF-κB通路[J].中国病理生理杂志,1999,8(15):763-764.
[13]Cohn JN.New concepts regarding events that lead to end-stage heart disease[J].Cardiovasc Drug Therapy,1995,9(Suppl3):489-492.
[14]Frantz S,Fraccarollo D,Wagner H,et al.Sustained activation of nuclea factor-kappa B and activator protein 1 in chronic heart failure[J].Cardiovasc Res,2003,57(3):749-756.
[15]Rysa J.ARBs in the pathogenesis of hypertensive heart disease[J].Hypertens,2003,21(10):1823-1825.
[2]刘佳敏,葛蕾,李静,等.高危冠心病患者血管紧张素转换酶抑制剂类药物应用现况调查[J].中华心血管病杂志,2013,41(1):18-22.
[3]崔贞玉,韩素霞.ARB与ACEI改善心肌梗死患者心室重构的Meta分析[J].实用药物与临床,2014,17(2):139-146.
[4]王建美,高东来,陈艳君,等.缬沙坦对高血压患者血管内皮功能影响的研究[J].中国药物与临床,2015(3):392-394.
[5]沈琪,欧阳小林,黄献文,等.抗高血压类药物治疗Ig A肾病的Meta分析[J].中国全科医学,2013,16(8):904-910.
[6]Oudart N.The rennin angiotention system:current data[J].Ann Pharm Fr,2005(63):144-153
[7]Benson SC,Pershadsingh HA,Ho CI,et al.Identification of telmisartan as a unique angiotensinⅡreceptor antagonist with selective PPAR(gamma)modulating activity[J].Hypertension,2004(43):993-1002
[8]Kostis JB.Treating hypertension in the very old[J].Engl Med,2008,358(18):1958-1960.
[9]Chae CU,Lee RT,Rifai N,et al.Blood pressure and inflammation in apparently healthy men[J].Hypertension,2001,38(3):399-403.
[10]Shiota N,Rysa J,Kovanen PT,et al.A role for cardiac mast cells in the pathogenesis of hypertensive heart disease[J].Hypertens,2003,21(10):1823-1825.
[11]Kalra D,Baumgarten G,Dibbs Z,et al.Nitric oxide provokes tumor necrosis factor alpha expression in adult feline myocardium through a c GMP dependent pathway[J].Circulation,2000,102(11):1302-1307.
[12]王伯瑶,黄宁,吴琦.炎症信号转导Toll/NF-κB通路[J].中国病理生理杂志,1999,8(15):763-764.
[13]Cohn JN.New concepts regarding events that lead to end-stage heart disease[J].Cardiovasc Drug Therapy,1995,9(Suppl3):489-492.
[14]Frantz S,Fraccarollo D,Wagner H,et al.Sustained activation of nuclea factor-kappa B and activator protein 1 in chronic heart failure[J].Cardiovasc Res,2003,57(3):749-756.
[15]Rysa J.ARBs in the pathogenesis of hypertensive heart disease[J].Hypertens,2003,21(10):1823-1825.