【作者】 陈国忠；

【导师】 傅国胜；

【作者基本信息】 浙江大学 ， 临床医学， 2004， 硕士

【摘要】 目的：通过对替米沙坦、安体舒通及其合用防治大鼠急性心肌梗死（AMI）后左室重构的作用研究，评价：（1）选择性血管紧张素Ⅱ Ⅰ型受体拮抗剂替米沙坦和醛固酮受体拮抗剂安体舒通对大鼠AMI左室重构的影响，对比它们单用和合用对左室重构的防治效果；（2）它们单用和合用对血浆和非梗死心肌血管紧张素Ⅱ（AngⅡ）、醛固酮（Ald）以及血浆肿瘤坏死因子-α（TNF-α）水平的影响。 方法：160只雄性SD大鼠，其中148只行冠脉前降支结扎，致急性心肌梗死，术后24小时存活的72只大鼠，随机分成下列四组：（1）心肌梗死对照组18只；（2）替米沙坦组(10 mg·kg^-1·d^-1)18只；（3）安体舒通组(20 mg·kg^-1·d^-1)18只；（4）替米沙坦(10 mg·kg^-1·d^-1)和安体舒通(20 mg·kg^-1·d^-1)合用组18只；另12只大鼠设为（5）假手术组。均以直接灌胃法给药。治疗6周后各组大鼠均作心脏多普勒超声检查；锁骨下静脉采血，测血浆AngⅡ、Ald及TNF-α水平；再以导管法行血流动力学测定；然后离体心脏，称重，垂直于左室长轴，于其中点切取厚度为2-3mm的左室截面，固定后对其进行病理分析。去除梗死面积＜20％和＞35％的心脏标本（假手术组除外）。取部份左室非梗死室间隔，匀浆后，测组织AngⅡ、Ald水平及蛋白定量。激素测定均采用放射性免疫法。心肌匀浆蛋白定量采用Bradford法。 结果：最终获得完整实验指标的大鼠共40只，其中（1）假手术组9只；（2）心肌梗死对照组8只；（3）替米沙坦组9只；（4）安体舒通组7只；（5）两药合用晰仁大李硕士李位份我组7只;心肌梗死各组大鼠平均梗死面积分别为25%一28%，组间对比均无显著差异（P均>0.05）。与假手术组相比，心肌梗死组和安体舒通组的左心室舒张末压（LvEoP）均显著增高（9.8士2.8二Hg对5.2士2.OllUnHg，P<0.001，和8.6士1 .SlnmHg对5.2士2.ommHg，P<0.01）。与心肌梗死组相比，替米沙坦组及其与安体舒通合用组的LVEop均显著降低（6.1士2.2 nunHg、 5.6士2.7 mmHg分别对9.8士2.8 InmHg，P均<0 .01），而两药合用并无叠加效应;安体舒通组的LvEDP有所降低，但无统计学意义。 与假手术组相比，心肌梗死组大鼠左心室实际及其相对重量、右心室相对重量、室间隔厚度及左室截面内周长均显著增加（732士18mg对676士36mg，P<0 .01:2.3士0 .1 7mg/g对1 .96士0.1 lmg/g，P<0.001;0.5士0.06mg/g对0.42士0.04mg/g，P<0 .01;1 .8士0.Zlmm对1.56士0.16nun，P<0.01;11.6士1.7nun对9.2士1.Znun，P<0.05）。与心肌梗死组相比，安体舒通组的左、右心室实际及其相对重量、室间隔厚度及左室截面内周长均无显著改变（P> 0.05），但其左、右心室重量、室间隔厚度有减少趋势;而替米沙坦组及其与安体舒通合用组的左心室实际及其相对重量、右心室相对重量、室间隔厚度及左室截面内周长均有显著减少（LvAw:684土52mg、683士46 mg分别对732士18 mg，P均<0.05;LVRW:1.97士0.lmg/g、1.96士0.18 mg/g分别对2.3士0.17 mg/g，P<0.001;RVRW:0.43士0.05mg/g、0.41士0.1 mg/g分别对0 .5士0.06 mg/g，P<0.05一0.01;IVS thiek:1.6士0.17mm、1.58士0.14nun分别对1.8士0.Zlllun，P均<0.05:左室截面内周长:10.1士1.3Inm、10.1士1.Illun分别对n.6士1.7Inln，P均<0 .05）。但替米沙坦组与两药合用组之间的这些指标对比，均无显著变化（P）0.05)。 与假手术组相比，心肌梗死组的非梗死区室间隔的非血管区胶原容积分数（CVF）有显著升高（4.81士0.38%对1.84士0.26%，P<0.001）。与心肌梗死组相比，替米沙坦组、安体舒通组及其两药合用组的CVF均有显著减少（2.61士0.28%、2.87士0.26%和2.57士0，25%分别对4.81士0.38%，P均<0.001）。. 与假手术组相比，心肌梗死组的左室每搏输出量（SV）、射血分数（EF），短轴缩短率（FS）、左室内压上升最大速率（+dp/dtmax）和左室内压下降最大速率 （一dp/dtmax）均显著降低(Sv:0.3士0.14ml对0.5士0.16ml，P（0.05;EF:73.66士9 .55%对82.92士6.96%，P<0，05;FS:39.55士4.33%对50.43士6.14%，P<0.01;嘴气寸晰卜大考硕士李位格义乍t八、甲+dp/dtmax:1 1510士1448对13520土1568InlnHg/s，P<0.01;一dp/dtmax:6908士1172对8582士1018InlnHg，P<0.01）。与心肌梗死组相比，替米沙坦组及其两药合用组的SV、EF、FS、士dp/dtmax均显著增加(P（0.05一0.01），而这些指标在该二组之lhJ比较均无显著差异（尸>0 .05）;安体舒通组无明显改变这些指标。 与假手术组相比，心肌梗死组和安体舒通组的血浆Angll、Ald均无显著差别（P>0.05）;而替米沙坦组及其与安体舒通合用组的血浆AngH浓度均有显著升高、血浆Ald浓度均有显著下降（Ang 11:673.33士141.78pg/ml、657.71士154.83pg/ml分别对406.56土134.58pg/ml，P<0.01一0.001;Ald:515.76士113.79pg/ml、506.8士188.81pg/ml分别对650.79士102.23pg/ml，P均<0.05）;心肌梗死组和安体舒通组的左室非心梗室间隔区Angn、Ald含量均有显著增加(Angn:44.49士8.6lpg/mg蛋白、41.94士14.15pg/mg蛋白分别对23.79士12.66pg/mg蛋白，P均<0.01;更多还原

【Abstract】 Comparison of the effects of telmisartan, spironolactone and their combination in the prevention of left ventricular remodeling after acute myocardial infarction Objectives: The aims of this experiment were (1) to compare the effects of selective angiotensin II type 1 receptor blocker (ARB) telmisartan , aldosterone blockade (AB) spironolactone and combination of them on the prevention of left ventricular (LV) remodeling after acute myocardial infarction (AMI) in the rats . and (2) to investigate the effect of them on the levels of angiotensin II (Ang II ),aldosterone (Ald) and tumor necrosis factor-alpha (TNF- @ ) in plasma and non-infarcted zone (NIZ) in myocardial infarction rats.Methods: Of 160 male SD rats, 148 had their left coronary ligated to induce AMI. Twenty-four hours after AMI, the 72 surviving rats were randomly assigned to one of the following groups (1) AMI controls (n=18),(2) telmisartan (10 mg kg-1d-1) (n=18),(3) spironolactone (20mg kg-1d-1) (n=18),(4) concomitant telmisartan (10mg kg-1d-1) and spironolactone ( 20 mg kg-1d-1 ) (n=18) groups. The other 12 rats were sham-operated to serve as noninfarction control group. Telmisartan and spironolactone were administered to rats after MI by direct gastric gavage once a day. At 6 weeks after MI, hemodynamics, cardiac function by Doppler echocardiography, the levels of Ang II ,Ald and TNF- a in plasma and non-infarcted myocardial zone by radioimmunoassay were assessed in each group of rat. The heart was excided after the completion of hemodynamic studies.Perpendicular to the long axis of the heart and at its middle point ,a 2-3mm cross-section was cut and fixed in 10% formalin for pathological examination. The hearts with the MI size<20% or >35% were excluded except those of sham-operated.The protein concentration of cardiac homogenate was determined according to the method of Bradford.Results: Complete experimental variables were obtained in 40 rats.The number of rat treated for 6 weeks in each experiment group are: (1) sham-operated controls(n=9),(2)AMI controls (n=8), (3) telmisartan (n=9), (4) spironolactone (n=7), (5) concomitant telmisartan and spironolactone (n=7).The mean MI size of each group was 25%-28%.There was no significant difference in MI size among all groups when compared.Compared with sham-operated rats, left ventricular end diastolic pressures (LVEDP) were all significantly elevated in AMI controls and spironolactone treatment group (9.8 2.8mmHg vs 5.2 2.0mmHg, P<0.001, and 8.6 1.8mmHg vs 5.2 2.0mmHg, P <0.01) . Compared with AMI controls, LVEDPs were all significantly reduced in telmisartan treatment group and two drugs combination treatment group (6.1 2.2 mmHg, 5.6 2.7 mmHg vs 9.8 2.8 mmHg respectively, all P<0.01) .Additionally.there was no significant difference in LVEDP between telmisartan and two drugs combination treatment group.Compared with sham-operated rats,LV absolute weight (LVAW) and relative weight (LVRW),right ventricular relative weight (RVRW), interventricular septal (IVS) thickness, LV cross-section in-perimeter (LVSPM) and collagen volume fraction (CVF) in the NIZ were all significantly increased in AMI controls (732 18mg vs676 36mg, P<0.01; 2.3 0.17mg/gvs 1.96 0.11 mg/g, P<0.001; 0.5 0.06mg/gvs0.42 0.04mg/g, P< 0.01; 1.8 0.21mmvs 1.56 0.16mm,P<0.01; 11.6 1.7mm vs9.2 1.2mm, P<0.05; 4.81 0.38% vs 1.84 0.26%, P<0.001 ) . Compared with AMI controls,all indicators as stated above in the spironolactone treatment group,did not change significantly (P>0.05), except that CVFs in the NIZ were significantly reduced (2.87 0.26% vs 4.81 0.38%, P<0.001).while all indicators as stated above in the telmisartan and two drugs combination treatment group were significantly reduced (LVAW:684 52mg 683 46 mgvs732 18 mg respectively, all P<0.05; LVRW: 1.97 0.1mg/g 1.96 0.18 mg/g vs 2.3 0.17mg/g respectively, P<0.001; RVRW: 0.43 0.05mg 0.41 0.1 mg/g vs 0.5 0.06 mg/g respectively, P<0.05 -0.01; IVS thickness: 1.6 0.17mm 1.58 0.14mmvs 1.8 0.21mm respectively, all P<0.05; LVSPM: 10.1 1.3mm 10.1 1.1 mm vs 1更多还原