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Renal Protective Effects of Olmesartan on Ressure-Overload Hypertrophied Rats

Author: WangJianPing
Tutor: GuanGuangJu
School: Shandong University
Course: Internal Medicine
Keywords: Echocardiography Olmesartan Left ventricular hypertrophy Cardiac FibrillationOlmesartan Abdominal aortic banding Tubulointerstitial fibrosis Angiotensin Ⅱ Apoptosis
CLC: R965
Type: PhD thesis
Year: 2012
Downloads: 60
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Abstract


ObjectiveTo 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.MethodsWistar 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 parameters1. Left ventricular posterior wallLeft 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 diastoleIVSd 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 massLeft 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 rateHeart 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 dimensionLeft 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 shorteningFractional 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 aortaThe 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 myocardium1.MFDMFD 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 ContentsCollagen 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).ConclusionHigh 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. ObjectiveThe purpose of this study was to investigate protective effects of olmesartan on kidney injury in rats with pressure-overload hypertrophy and explore possible mechanism.MethodsThe 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 ultrasonography1. Renal parenchymal echogenicityIncreased 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 sizeThere was no significant difference in renal size among three groups (P>0.05).3. Renal artery resistive indexRI 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 ⅡDetermination 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 tissuesAng 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 ScrPlasma 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 BUNPlasma 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 features1. Masson staining1.1Tubulointerstitial 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.2.1BaxThe 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-2The 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/BaxThe 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-3The 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).ConclusionOlmesartan 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.

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