摘要
研究目的
奥美沙坦是血管紧张素Ⅱ受体拮抗剂,应用腹主动脉结扎方法建立大鼠左心室肥厚模型,运用高频超声心动图研究奥美沙坦对腹主动脉缩窄术后大鼠左室心肌肥厚和纤维化的防治作用。研究方法
39只七周大Wistar大鼠,按随机原则分为假手术组(n=13)和手术组(n=26)。术后10天将手术组大鼠随机分为模型组及奥美沙坦组(1mg/Kg/d灌胃)。连续用药7周后应用高频彩色超声心动图测定麻醉后大鼠心脏,测定指标如下：左室后壁厚度(Left ventricular posterior wall)、室间隔的厚度(Interventricular septal thickness at diastole)、左心室质量(Left ventriclular mass)、左心室质量指数(LVMI)、心率(Heart rate)、左室舒张末期内径(Left ventricular end diastolic dimension)、左室短轴缩短率(Fractional shortening)、左室射血分数(Ejection fraction)。腹部二维超声引导多谱勒血流检测腹主动脉缩窄处血管内径大小和血流速度的快慢。同时也测量假手术组大鼠相同部位的腹主动脉。病理切片HE染色测量心肌细胞直径(myocardial fiber dimension, MFD),苦味酸-天狼猩红染色观察心肌组织纤维病变。
研究结果
一、高频超声测量心脏指标比较。
1.左室后壁厚度
模型组左室后壁厚度2.65±0.38mm显著高于假手术组1.82±0.199mm(P<0.001)；经奥美沙坦治疗后左室后壁厚度显著降低(1.85±0.24mm vs2.65±0.38mm,P<0.001),并且与未结扎腹主动脉大鼠比较没有差别(1.85±0.24mm vs1.82±0.199mm,P>0.05)。
2.室间隔的厚度
模型组与假手术组比较室间隔的厚度显著增加(2.94±0.399vs1.97±0.18mm,P<0.001)；经奥美沙坦治疗后室间隔厚度显著降低(与模型组对比,1.99±0.38mm vs2.94±0.399,P<0.001；与假手术组对比,1.99±0.38mm vs1.97±0.18mm,P>0.05)。
3.左心室质量
模型组与假手术组比较左心室质量均显著增加(1.72±0.33vs1.296±0.11g，P<0.01)；奥美沙坦治疗组与模型组相比,左心室质量显著降低(1.39±0.18g vs1.72±0.33g,P<0.01),与假手术组比较没有统计学差异(1.39±0.18g vs1.296±0.11g,P>0.05)。
4.心率
假手术组、模型组、奥美沙坦组心率分别为335.61±74.47bpm、373.88±57.66bpm、392.55±60.21bpm,三组之间数据比较没有统计学差异(P>0.05)。
5.左心室舒张末期内径
假手术组、模型组、奥美沙坦组LVIDd分别为7.1240.43mm、6.02±1.08mm、7.01±0.39mm。模型组与假手术组比较左心室舒张末期内径显著缩小(6.02±1.08mm vs7.124±0.43mm,P<0.01)；经奥美沙坦治疗后左心室舒张末内径大小恢复正常(与模型组对比,7.01±0.39mm vs7.124±0.43mm,P<0.001；与假手术组对比,7.01±0.39mm vs7.124±0.43mm,P>0.05)。
6.左心室短轴缩短率
模型组、假手术组、奥美沙坦组左室短轴缩短率分别为41.40±5.74%、43.65±5.0%、43.09±2.899%。从统计学意义上来说,以上不同组别大鼠之间FS比较没有差别(P>0.05)。
7.左心室射血分数
假手术组、模型组、奥美沙坦组左室射血分数分别为79.51±4.97%、76.98±6.25%、79.28±3.12%。三个组别的EF数值都高于正常值,提示所有大鼠心功能正常,无心功能衰竭情况出现,并且三组之间EF数值没有差异(P>0.05)。
8.左心室质量指数
模型组与假手术组比较左心室舒张末期内径显著缩小(33.51±4.57vs25.86±1.96,P<0.001)；应用奥美沙坦药物干预后与模型组相比LVMI下降(26.36±3.88vs33.51±4.57,P<0.01),并且与假手术组大鼠比较没有差异(26.36±3.88vs25.86±1.96,P>0.05)。
二、腹部多普勒超声检测腹主动脉
腹部多普勒超声显示腹主动脉结扎组(包括模型组和奥美沙坦组)动脉结扎处血管内径平均缩窄率65%。主动脉结扎组动脉缩窄部位平均内径0.6±0.07mm,缩窄局部血液流速2.02±0.61m/s；假手术组相对应部位的腹主动脉内径和血液流速数值分别为2.03±0.30mm,0.53±0.13m/s。故腹主动脉结扎后,手术结扎部位的血管腔径变小(0.6±0.07vs2.03±0.30mm,P<0.01),伴随血液流速出现明显增加的现象(2.02±0.61vs0.53±0.13m/s,P<0.01)。
三、心脏病理组织学变化。
1.MFD的测量值
模型组大鼠与假手术组相比出现心肌细胞横径显著变大(19.10±1.08μm vs9.89±0.98μ m,P<0.001),奥美沙坦组心肌细胞横径明显变小(与模型组相比,10.19±1.02u m vs19.10±1.08μ m,P<0.001；与假手术组相比,10.19±1.02μ m vs9.89±0.98μ m,P>0.05)。
2.心肌胶原纤维含量
假手术组、模型组、奥美沙坦组胶原纤维含量分别为1.7±0.53,8.4±0.96,2.4±0.76。模型组与假手术组相比,大鼠心肌出现大量胶原纤维沉积病变(8.4±0.96vs1.7±0.53,P<0.001)；奥美沙坦药物治疗后,与模型组相比心肌胶原纤维减少(2.4±0.76vs8.4±0.96,P<0.001),但仍没有回归正常(2.4±0.76vs1.7±0.53,P<0.001)。
结论
腹主动脉结扎术能成功建立左心室肥厚的模型,并且心脏发生心肌肥厚病变的同时出现了心肌纤维化的病变。奥美沙坦酯具有预防高血压左心室发生肥厚病变的功能,同时也能防止心肌出现纤维化病变,说明心肌肥厚病变与心肌纤维化的产生密切相关。本研究结果提示了高血压患者早期应用奥美沙坦对左心室肥厚并纤维化的发生可能具有防治作用,故及早对高血压病人血压进行干预,可以避免心脏发生进一步的病变。
研究目的
观察左心室肥厚大鼠肾脏损害,探讨奥美沙坦对肾脏损害的保护作用及可能的作用机制。研究方法
进行肾脏多普勒超声检查,检测大鼠肾脏形态、大小、回声以及其他病理征象,在二维图像条件下测量肾脏长、宽、厚数值,并测定肾动脉阻力指数(RI)的变化。应用双抗体夹心酶联免疫酶标法(enzyme-linked immunosorbent assay, ELISA)方法观察血浆和肾脏血管紧张素Ⅱ(AngⅡ)的变化,测定血浆肌酐(Scr)、尿素氮(BUN),肾脏组织Masson染色观察大鼠肾脏胶原纤维沉积情况,用免疫组化方法检测Bax、Bcl-2、Caspase-3蛋白。
研究结果
一、肾脏多普勒超声检查。
1.肾脏实质回声
肾脏多普勒超声检查显示模型组肾脏实质回声增强,奥美沙坦药物组实质回声同假手术组。
2.肾脏大小测定值
测定大鼠肾脏长径、前后径、厚度数值,3组间大鼠肾脏大小比较未出现差异。
3.肾动脉阻力指数RI
模型组与假手术组相比,肾动脉阻力指数RI显著增高(0.71±0.022vs0.41±0.018,p<0.001)；奥美沙坦治疗组肾动脉血流阻力降低(与模型组相比,0.51±0.016vs0.71±0.022,P<0.001；与假手术组相比,(0.51±0.016vs0.41±0.018，P<0.01)。
二、血浆、肾脏肾组织中AngⅡ的含量和血浆Scr、BUN的检测
1.应用ELISA方法检测血浆AngⅡ
模型组与假手术组相比血浆AngⅡ浓度显著升高(1023.2±16.2pg.L-1vs51.31±18.6pg.L-1,P<0.001)；奥美沙坦组与模型组相比,血浆AngⅡ浓度显著降低(192.6±31.6pg.L-1vs1023.2±16.2pg.L-1,P<0.001)；奥美沙坦组与假手术组相比,血浆AngⅡ浓度显著升高(192.6±31.6pg.L-1vs51.31±18.6pg.L-1,P<0.001)
2.应用ELISA方法检测肾脏组织AngⅡ
模型组与假手术组相比,肾脏组织中AngⅡ浓度显著升高(139.3±16.7pg/Lvs22.4±11.9pg/L,P<0.001)；奥美沙坦组与模型组相比,肾脏组织中AngⅡ浓度显著降低(77.4±9.8pg/L vs139.3±16.7pg/L,P<0.001)；奥美沙坦组与假手术组相比,肾脏组织中Ang Ⅱ浓度显著升高(77.4±9.8pg/L vs22.4±11.9pg/L,P<0.001)
3.血浆Scr
假手术组、模型组、奥美沙坦组血浆Scr33±3.0umol/L、35±2.0umol/L34±2.8umol/L。从数据统计角度来看上述不同组别大鼠之间Scr未出现差别(P>0.05)。
4.血浆BUN
假手术组、模型组、奥美沙坦组血浆BUN5.81±2.31mmol/L、6.98±1.98mmol/L、6.30±1.89mmol/L。以上不同组别大鼠之间BUN数据未出现统计差别(P>0.05)。
三、肾脏病理组织学变化
1.病理组织Masson染色
1.1肾小管间质胶原含量
模型组与假手术组相比,肾小管间质胶原含量增多(6089.21±976.3vs585.1±131.64,P<0.001)；奥美沙坦组与模型组相比肾小管间质胶原含量显著减少(607.43±138.54vs6089.21±976.3,P<0.001)。奥美沙坦组与假手术组相比,肾小管间质胶原含量没有统计学差别(P>0.05)。所以造模后大鼠肾小管间质出现明显纤维化病变,而应用奥美沙坦药物治疗阻止肾脏发生纤维化病变。
1.2肾小管间质损伤
模型组与假手术组相比,肾小管间质出现明显损伤病理改变(2.84±0.788vs0.12±0.05,P<0.001),应用奥美沙坦药物治疗后与模型组相比,肾小管间质损伤减轻(1.55±0.41vs2.84±0.788,P<0.001),但是肾小管间质损伤没有恢复到正常(1.55±0.41vs0.12±0.05,P<0.01)。
2.1Bax
假手术组、模型组、奥美沙坦组Bax测定值分别为1.31±0.42%、4.92±1.23%、2..09±0.39%。模型组与假手术组相比,Bax阳性表达显著增多(4.92±1.23vs1.31±0.42,P<0.001)；奥美沙坦组与模型组相比,Bax阳性表达明显减少(2.09±0.39vs4.92±1.23,P<0.001)；奥美沙坦组与假手术组相比,Bax阳性表达增强(2..09±0.39vs1.31±0.42,P<0.001)
2.2Bcl-2
模型组与假手术组相比,Bcl-2阳性表达显著增多(4.79±1.21%vs1.76±0.39%,P<0.001)；奥美沙坦组与模型组相比,Bcl-2阳性表达明显减少(2.81±0.42%vs4.79±1.21%,P<0.001)；奥美沙坦组与假手术组相比,Bcl-2阳性表达明显增强(2.81±0.42%vs1.76±0.39%,P<0.001)
2.3Bcl-2/Bax
模型组与假手术组相比,Bcl-2/Bax阳性表达显著降低(0.92±0.61vs1.52±0.19,P<0.01)；奥美沙坦组与模型组相比,Bcl-2/Bax阳性表达增加(1.41±0.18vs0.92±0.61,P<0.05)；奥美沙坦组与假手术组相比,Bcl-2/Bax比值没有差异(P>0.05)。
2.4Caspase-3
假手术组、模型组、奥美沙坦组Caspase-3测定值分别为12.15±1.61%、23.41±2.13%、14.54±1.72%。模型组与假手术组相比,Caspase-3阳性表达显著增多(23.41±2.13vs12.15±1.61%,P<0.001)；奥美沙坦组与模型组相比,Caspase-3阳性表达明显减少(14.54±1.72vs23.41±2.13%,P<0.001)；奥美沙坦组与假手术组相比,Caspase-3阳性表达增加(P<0.01)
结论
1.肾脏多普勒超声检查显示腹主动脉缩窄大鼠肾脏大小无变化,肾脏实质回声增强,肾动脉阻力指数显著增高。应用奥美沙坦药物治疗后,肾脏实质回声无异常,肾动脉阻力指数降低。
2.腹主动脉缩窄术后模型组血浆和组织中Ang Ⅱ浓度显著升高,奥美沙坦药物治疗后Ang Ⅱ浓度降低,但仍显著高于正常大鼠浓度。
3.腹主动脉缩窄模型组大鼠肾小管间质纤维化程度明显,肾小管间质损伤严重。应用奥美沙坦治疗后肾小管间质纤维化病变消失,’肾小管间质损伤程度减轻。
4.腹主动脉缩窄模型组Bax、Bcl-2、Caspase-3在模型组阳性表达显著增多,奥美沙坦组阳性表达明显减少。
综上所述,腹主动脉结扎术能导致模型组大鼠肾间质纤维化,奥美沙坦药物治疗能阻止肾间质纤维化的形成,机制可能是药物阻断Ang Ⅱ对肾脏的作用以及抑制凋亡发生。
Objective
To establish rat models with left ventricular hypertrophy induced by coarctation of abdominal aorta above superior mesenteric artery. The purpose of this study was to evaluate the protective effects of olmesartan on left ventricular hypertrophy.
Methods
Wistar rats,7weeks old, were randomly divided into sham-operated group (n=13) and abdominal aortic-banded group (n=26) with the ligation of abdominal aorta. After10days, the aortic-banded rats were subdivided into olmesartan-treated group (1mg/Kg/d) and hypertension (HTN) group.7weeks after treatment, all rat hearts were analyzed in vivo using M-mode echocardiography. The following parameters, in systole, were measured on the echocardiographic images:left ventricular posterior wall (LVPWd), interventricular septal thickness at diastole (IVSd), left ventriclular mass(LV Mass), left ventricular mass index (LVMI), heart rate (HR),1eft ventricular end diastolic dimension (LVIDd), fraction shortening (FS), ejection fraction (EF).
Furthermore, blood flow velocity and lumen diameter around proximal end (1cm) to the banded site of abdominal aorta were measured by abdominal sonography in aortic banded rats. As far as sham rats were concerned, the same regions of abdominal aorta also underwent the examination. Hearts were excised for histomorphology analyses. Myocardial fiber dimension (MFD) was detected by pathological sections stained with_hematoxylin/eosin (H-E). In addition, cardiac fibrillation was observed by pathological sections with Picro-Sirius red staining.
Results
一、Echocardiographical parameters
1. Left ventricular posterior wall
Left ventricular posterior wall was statistically thicker in HTN group than in sham group (2.65±0.38mm vs1.82±0.199mm, P<0.001) and olmesartan group (2.65±0.38mm vs1.85±0.24mm, P<0.001). Furthermore, there was no significant difference between olmesartan and sham group (P>0.05).
2. Interventricular septal thickness at diastole
IVSd in HTN group was statistically higher than that in sham group (2.94±0.399mm vs1.97±0.18mm, P<0.001) and olmesartan group (2.94±0.399mm vs1.99±0.38mm, P<0.001). Meanwhile ivsd was similar in olmesartan group as in sham group (P>0.05).
3. Left ventricular mass
Left ventricular mass in sham group, HTN group, olmesartan group was1.296±0.11g,1.72±0.33g and1.39±0.18g, respectively. LV mass was higher in HTN group compared with the sham group (P<0.01). But olmesartan was able to significantly decrease LV mass (olmesartan group vs HTN group, P<0.01) and get it to the normal level (olmesartan group vs sham group, P>0.05).
4. Heart rate
Heart rate in sham group, HTN group and olmesartan group was335.61±74.47BPM,373.88±57.66BPM and392.55±60.21BPM, respectively. There was no significant difference among the three groups (P>0.05).
5. Left ventricular end diastolic dimension
Left ventricular end diastolic dimension in sham group, HTN group and olmesartan group was7.124±0.43mm,6.02±1.08mm and7.01±0.39mm, respectively. LVIDd in HTN group was significantly lower compared with the sham group (P<0.01), which surggested that left ventricular cavity in HTN group was significantly smaller. However, left ventricular cavity in olmesartan group was significantly bigger in comparison with HTN group (P<0.01).
6. Fractional shortening
Fractional shortening in sham group, HTN group and olmesartan group was43.65±5%,41.40±5.74%and43.09±2.899%, respectively. There was no significant difference among the three groups (P>0.05).
7. Ejection fraction (EF)
Ejection fraction in sham group, HTN group and olmesartan group was79.51±4.97%,76.98±6.25%and79.28±3.12%, respectively. EF values in all groups were above the normal range (>60%), which meant heart failure didn't occur. There was no significant difference among the three groups (P>0.05).
8. Left ventricular mass index (LVMI)
Left ventricular mass index in sham group, HTN group and olmesartan group was25.86±1.96,33.51±4.57and26.36±3.88respectively. Left ventricular mass index in HTN group was obviously higher than sham group (P<0.01); However olmesartan significantly decreased it after a course of six weeks treatment (P<0.01). There was no significant difference between olmesartan group and sham group (P>0.05).
二、Sonographic parameters of abdominal aorta
The percentage of aortic luminal coarctation was65%in the aortic banded groups. The banded sites were measured for lumen diameter and blood flow velocity in the aortic banded groups, which included HTN group and olmesartan group. Lumen diameter was2.03±0.30vs0.6±0.07mm in the sham and aortic banded groups (P<0.01). Blood flow velocity was0.53±0.13vs2.02±0.61m/s in the sham and aortic banded groups (P<0.01). Therefore, sonographic studies showed that not only aortic lumen diameter was significantly narrowed but also blood flow velocity around the constriction site was significantly increased in aortic banded groups compared with sham group.
三、The changes of histomorphology in myocardium
1.MFD
MFD in sham group, HTN group and olmesartan group was9.89±0.98μm,19.10±1.08μm and10.19±1.02μm. MFD was obviously higher in HTN group than in sham group (P<0.001). MFD in olmesartan group was not different from sham group (Olmesartan vs HTN group, P<0.001; olmesartan vs sham group, P>0.05).
1. Collagen fiber Contents
Collagen fiber Contents in sham, HTN and olmesartan groups was1.7±0.53,8.4±0.96,2.4±0.76. Picro-Sirus red stain showed that collagen fibers were obvious in HTN group than in sham group (P<0.001). However, olmesartan was able to attenuate the development of cardiac fibrillation (Olmesartan vs HTN group, P<0.001; olmesartan vs sham group, P<0.001).
Conclusion
High frequency echocardiographic measurements showed that rat model of left ventricular hypertrophy were able to be successfully established by abdominal aortic ligation. Olmesartan could inhibit the development of left ventricular hypertrophy and cardiac fibrillation. In summary, this study suggests that early olmesartan interventions in hypertensive patients might have cardiac protective effects and provide benefits beyond blood-pressure-lowering effects.
Objective
The purpose of this study was to investigate protective effects of olmesartan on kidney injury in rats with pressure-overload hypertrophy and explore possible mechanism.
Methods
The whole kidney and renal artery in rats were detected in vivo by abdominal ultrasonography as soon as high frequency echocardiographical examination was completed. Ultrasonographic parameters included renal size, parenchymal echogenicity and renal artery resistive index (RI). Angiotensin Ⅱ (Ang Ⅱ) in plasma and renal tissue was measured by enzyme-linked immunosorbent assay (ELISA) kit. Plasma creatinine (Scr) and blood urea nitrogen (BUN) were measured. Renal histomorphological features and collagen deposition in kidneys were examined with staining of Masson and HE. Specifically, fibrosis of kidneys was assessed from Masson' trichrome-stained sections. Expressions of Bax, Bcl-2and Caspase-3were evaluated by immunohistochemistry.
Results
一、Kidney examination by ultrasonography
1. Renal parenchymal echogenicity
Increased renal parenchymal echogenicity in HTN group was a strong predictor of renal injuries. After treatment with olmesartan, renal parenchymal echogenicity was nearly to sham group.
2. Kidney size
There was no significant difference in renal size among three groups (P>0.05).
3. Renal artery resistive index
RI in sham group, HTN group and olmesartan group was0.41±0.018,0.71±0.022and0.51±0.016respectively. RI in HTN group was obviously higher than sham group (P<0.001). Meanwhile olmesartan significantly decreased RI (olmesartan vs HTN group, P<0.001; olmesartan vs sham group, P<0.01).
二、The determination of angiotensin Ⅱ (Ang Ⅱ) in plasma and renal tissue, Plasma creatinine (Scr) and blood urea nitrogen (BUN)
1. Plasma Ang Ⅱ
Determination of plasma Ang Ⅱ in sham group, HTN group and olmesartan group was51.31±18.6pg.L-1,1023.2±16.2pg.L-1and192.6±31.6pg.L-1. Plasma Ang Ⅱ levels in HTN group were much higher than the other two groups (P<0.001). But the concentration in olmesartan group was still higher than sham group (P<0.001).
2. Ang Ⅱ in renal tissues
Ang Ⅱ contents in renal tissues in sham group, HTN group and olmesartan group were22.4±11.9pg/L,139.3±16.7pg/L and77.4±9.8pg/L in sequence. Ang Ⅱ concentrations in HTN group were much higher in comparison with sham group (P<0.001). However olmesartan significantly decreased Ang Ⅱ levels in the local kidney tissue compared with the HTN group (P<0.001).
3. Plasma Scr
Plasma Scr concentrations in sham group, HTN group and olmesartan group were33±3Umol/L,35±2Umol/L and34±2.8Umol/L in sequence. There was no statistically significant difference among the three groups (P>0.05).
4. Plasma BUN
Plasma BUN contents in sham group, HTN group and olmesartan group were5.81±2.31mmol/L,6.98±1.98mmol/L and6.30±1.89mmol/L respectively. There was no statistically significant difference among the three groups (P>0.05).
三, Renal histomorphological features
1. Masson staining
1.1Tubulointerstitial fibrosis index (TFI)
TFI was statistically higher in HTN group than that in Sham group (6089.21±976.3vs585.1±131.64, P<0.001). There was no statistically significant difference between olmesartan group (607.43±138.54) and sham group (P>0.05). Kidney tissue sections stained with Masson showed that tubulointerstitial fibrosis was obvious in HTN group. In contrast to HTN group, the lesions of tubulointerstitial fibrosis were not apparent in sham and olmesartan group.1.2Tubulointerstitial damage index TDI was statistically higher in HTN group than sham group (2.84±0.788vs0.12±0.05, P<0.001) and olmesartan group (2.84±0.788vs1.55±0.41, P<0.001). But tubulointerstitial lesions in olmesartan group did not completely return to normal in comparison with sham group (P<0.01).
2. Expression of Bax, Bcl-2and Caspase-3was evaluated by immunohistochemistry.
2.1Bax
The expression of Bax in sham group, HTN group, olmesartan group was1.31±0.42%,4.92±1.23%,2.09±0.39%, respectively. The expression was significantly increased in HTN group compared with sham group (P<0.001) and dramatically decreased following the administration of olmesartan (P<0.001).
2.2Bcl-2
The expression of Bcl-2was statistically higher in HTN group than sham group (4.79±1.21%vs1.76±0.39%, P<0.001) and olmesartan group (4.79±1.21%vs2.81±0.42%,P<0.001).
2.3Bcl-2/Bax
The expression of Bcl-2/Bax was statistically lower in HTN group than sham group (0.92±0.61vs1.52±0.19, P<0.01). But the expression was statistically higher in olmesartan group than HTN group (1.41±0.18vs0.92±0.61, P<0.05). There was no statistically significant difference between olmesartan group and sham group (P>0.05).
2.4Caspase-3
The expression of Caspase-3was statistically higher in HTN group than sham group (23.41±2.13%vs12.15±1.61%, P<0.001) and olmesartan group (23.41±2.13%vs14.54±1.72%, P<0.001). But the expression of Caspase-3in olmesartan group was still higher than sham group (P<0.01).
Conclusion
Olmesartan was able to protect against kidney injury induced by abdominal aortic banding, which might contribute to decrease AngⅡ in the kidney and inhibit the pathway of apoptosis.
引文
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