左旋氨氯地平对自发性高血压大鼠心脏及血管的保护作用研究
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摘要
第一部左旋氨氯地平对自发性高血压大鼠左室肥厚及内皮素-1表达的影响
研究背景:
高血压左心室肥厚是心血管事件的独立危险因素,与心律失常、猝死、心力衰竭等密切相关。目前认为高血压引起左室肥厚的主要原因包括血流动力学异常和神经内分泌激活。高血压致左心室负荷增加,心肌细胞受到机械刺激,肾素-血管紧张素-醛固酮系统、内皮素系统过度激活,导致蛋白质合成增加,心肌细胞肥大,间质胶原增多,进而引起心脏扩大,心脏舒张末压和收缩期室壁张力均增高,使左室功能受损。治疗高血压的主要目的是最大限度地降低心血管病发病和死亡的危险性,这就要求在治疗高血压的同时干预患者可逆性心血管病的危险因素。所以对于高血压患者提倡临床上早期干预,控制血压,逆转左室肥厚,改善受损的心功能,从而降低各种心血管并发症发生率,改善原发性高血压患者预后。
研究目的:
观察自发性高血压大鼠(SHR)的心脏形态学及左心室功能的改变;检测SHR心脏内皮素系统的变化及其与左室肥厚和左心室功能的关系;观察钙拮抗剂——左旋氨氯地平干预对SHR血压、左室肥厚及心功能的影响,探讨其与SHR心脏内皮素系统的关系。
研究方法:
1、SHR血压的变化及左旋氨氯地平干预对其影响
20只13周龄的雄性SHR随机分为左旋氨氯地平治疗组(SHR-A),高血压对照组(SHR-C),同周龄Wistar—Kyoto(WKY)大鼠作为正常对照组。采用灌胃法给药,左旋氨氯地平组2mg/(kg·d),溶于2ml生理盐水;对照组给予等量生理盐水,治疗时间为12周。采用尾动脉测压方法于用药前和用药后4、8、12周测定大鼠血压。
2、SHR心室功能的变化及左旋氨氯地平干预对其影响
全部动物末次给药后,25%乌拉坦(1g/kg)腹腔注射麻醉,仰卧固定于手术台上,颈前正中做约4cm的切口,分离出右侧颈总动脉,将导管经右颈总动脉插入左心室,记录心率(HR)、和左心室收缩压(left ventricular systolic pressure,LVSP),左室舒张期末压(leftventricular end-diastolic pressure,LVEDP)和左室内压最大变化速率(±dp/dt_(max))。分别用+dp/dt_(max)/LVSP和-dp/dt_(max)/LVSP来表示左室收缩舒张功能。
3、SHR左室重量指数的变化及左旋氨氯地平干预对其影响
沿室间隔剪开左右心室,称量左心室重量,计算左心室湿重/体重指数(LVW/BW),用以表示左室肥厚程度。
4、SHR心脏组织病理学改变及左旋氨氯地平干预对其影响
实验末剪取心脏组织,行HE染色和Masson染色。使用Image ProPlus 5.0图像分析系统测量计算心肌细胞直径和心肌间质胶原容积分数(interstitial collagen volume fraction,ICVF)。ICVF=心肌间质胶原面积/所测视野面积。
5、SHR左室内皮素-1的变化及左旋氨氯地平对其影响
放射免疫法测定心肌组织ET含量,荧光实时定量PCR(Real-time PCR)法测定心肌preproET-1 mRNA的表达。
研究结果:
1、SHR血压的变化及左旋氨氯地平干预对其影响
左旋氨氯地平可显著降低SHR血压,药物干预12周后,SHR-A组血压显著低于SHR-C组(154.23±7.99 mmHg vs 201.41±5.01 mmHg,P＜0.01)。
2、SHR左心室功能的变化及左旋氨氯地平干预对其影响
与WKY组大鼠相比,SHR-C组的LVSP(191.81±10.81 mmHg vs 106.06±11.49 mmHg,P＜0.01)明显升高,+dp/dtmax/LVSP(55.37±7.96 1/s vs 73.79±8.04 1/s,P＜0.01)与-dp/dtmax/LVSP(39.81±5.21 1/s vs 57.27±8.591/s,P＜0.01)显著降低,表明SHR存在左室收缩和舒张功能障碍;左旋氨氯地平治疗能够改善SHR的左室收缩功能(61.98±5.43 1/s vs 55.37±7.96 1/s,P＜0.05)与舒张功能(46.74±4.79 1/s vs 39.81±5.21 1/s,P＜0.05),但尚未能使其恢复到正常水平。
3、SHR左室重量指数的变化及左旋氨氯地平干预对其影响
SHR-C组LVW/BW比值明显高于WKY组(2.94±0.11 mg/g vs 2.40±0.17 mg/g,P＜0.01),表明SHR发生左室肥厚,而左旋氨氯地平干预组的LVW/BW比值较SHR对照组有明显降低(2.61±0.13 mg/g vs 2.94±0.11 mg/g,P＜0.05),表明左旋氨氯地平在一定程度上能够抑制SHR的左室肥厚。
4、SHR心脏组织病理学改变及左旋氨氯地平干预对其影响
SHR左室心肌细胞直径显著大于WKY大鼠心肌细胞直径(16.13±2.79μm vs 12.57±3.16μm,P＜0.05),左旋氨氯地平治疗后SHR心肌细胞肥大明显减轻,细胞直径与对照组SHR相比有统计学差异(14.3±2.85μm vs 16.13±2.79μm,P＜0.05)。SHR左室ICVF同WKY大鼠相比明显增高(12.38%vs 4.62%,P＜0.01);左旋氨氯地平干预后胶原增生明显减轻,ICVF显著降低(7.36%vs 12.38%,P＜0.01)。
5、SHR左室内皮素-1的变化及左旋氨氯地平对其影响
SHR-C组的心肌ET-1含量与WKY组相比显著升高(207.69±16.09 pg/g vs 151.32±27.89 pg/g,P＜0.05);左旋氨氯地平治疗能够降低SHR-A组心肌ET-1的水平(184.43±16.78pg/g vs 207.69±16.09,P＜0.05)。SHR-C组心肌组织preproET-1 mRNA的表达是WKY组的1.94倍(P＜0.01);SHR-A组心肌组织preproET-1 mRNA的表达量是WKY组的1.54倍,与SHR-C组相比降低约20%,且两组具有显著性差异(P＜0.05)。
研究结论:
1、与WKY大鼠相比SHR发生左心室肥厚,心肌细胞肥大,胶原纤维增生。
2、伴随着左室肥厚,SHR左心室收缩与舒张功能均受损。
3、SHR心肌ET-1含量增加,preproET-1 mRNA表达增加。
4、左旋氨氯地平干预能够降低SHR血压,减轻SHR左室肥厚程度,减少胶原纤维增生,改善SHR左心室收缩与舒张功能,其作用可能是通过降低血压、调节心脏内皮素系统实现的。
第二部分左旋氨氯地平对自发性高血压大鼠内皮功能的保护作用
研究背景:
高血压会导致全身动脉功能和结构损害,早期发现和干预血管病变的进展是延缓和控制心血管事件的重要措施。
研究目的:
观察自发性高血压大鼠(SHR)胸主动脉舒张功能及血管壁结构的变化;观察钙拮抗剂——左旋氨氯地平干预对SHR胸主动脉内皮功能障碍及血管重构的影响并探讨其可能的机制。
研究方法:
1、SHR血压的变化及左旋氨氯地平干预对其影响
20只13周龄的雄性SHR随机分为左旋氨氯地平治疗组(SHR-A),高血压对照组(SHR-C),同周龄Wistar—Kyoto(WKY)大鼠作为正常对照组。采用灌胃法给药,左旋氨氯地平组2mg/(kg·d),溶于2ml生理盐水;对照组给予等量生理盐水,治疗时间为12周。采用尾动脉测压方法于用药前和用药后4、8、12周测定大鼠血压。
2、SHR胸主动脉壁结构的改变及左旋氨氯地平干预对其影响
取大鼠胸主动脉,行HE染色和Masson染色,Image-Pro Plus 5.0图像分析系统测量中膜厚度(media thickness,MT)及截面积(cross—sectional area,CSA),光镜下观察中膜胶原含量变化。
3、SHR主动脉内皮功能的变化及左旋氨氯地平干预对其影响
观察离体胸主动脉对乙酰胆碱(ACh)及硝普钠(SNP)的反应性,比较SHR与WKY内皮功能的差异,以及左旋氨氯地平干预的作用。
4、SHR氧化应力的变化及左旋氨氯地平干预对其影响
检测三组大鼠血中NO、ET及SOD含量,比较SHR与WKY大鼠氧化应力的差异,并观察左旋氨氯地平干预对SHR氧化应力的影响。
研究结果:
1、SHR血压的变化及左旋氨氯地平干预对其影响
研究结果显示,左旋氨氯地平可显著降低SHR血压,药物干预12周后,SHR-A组血压显著低于SHR-C组(154.23±7.99 mmHg vs 201.41±5.01 mmHg,P＜0.01)。
2、SHR胸主动脉壁结构的改变及左旋氨氯地平干预对其影响
与WKY大鼠相比,SHR胸主动脉中膜厚度(97±5μm vs 84±4μm,P＜0.05)及截面积(0.65±0.02 mm~2 vs 0.58±0.03 mm~2,P＜0.05)明显增大,左旋氨氯地平治疗能够明显减小胸主动脉中膜厚度(91±3μm vs 97±5μm,P＜0.05)及截面积(0.62±0.02 mm~2 vs 0.65±0.02 mm~2,P＜0.01)。SHR-C组大鼠主动脉中膜胶原纤维显著增生,排列紊乱,平滑肌细胞肥大增生明显,SHR-A组主动脉中膜弹性纤维较高血压组排列有序,平滑肌细胞肥大和胶原纤维增生减轻。
2、SHR主动脉内皮功能的变化及左旋氨氯地平干预对其影响
与WKY大鼠相比,SHR胸主动脉对ACh引起的内皮依赖性最大舒张反应明显减弱(34.71±9.23%vs 89.92±8.26%,P＜0.01),左旋氨氯地平干预能够减轻内皮依赖性舒张功能障碍(48.39±14.86%vs 34.71±9.23%,P＜0.05),左旋硝基精氨酸甲酯(L-NAME)能够消除这种差异。三组大鼠胸主动脉对SNP引起的非内皮依赖性最大舒张反应无显著差异(P＞0.05)。
5、SHR氧化应力的变化及左旋氨氯地平干预对其影响
SHR血清NO含量较WKY大鼠显著降低(27.98±4.53μmol/L vs 48.59±7.12μmol/,P＜0.01),血清ET含量显著升高(207.69±16.81 ng/L vs 151.32±27.89 ng/L,P＜0.01);左旋氨氯地平治疗组血清NO、SOD水平与对照组SHR相比明显升高(NO:36.66±7.52μmol/Lvs 27.98±4.53μmol/L,P＜0.05;SOD:229.22±20.38×10~3U/L vs 200.13±6.85×10~3U/L,P＜0.01),血浆ET浓度显著降低(184.43±16.78 ng/L vs 207.69±16.81 ng/L,P＜0.05)。
研究结论:
1、SHR主动脉中膜厚度及截面积增大,血管发生重构。
2、SHR的ACh引起的血管内皮依赖性舒张功能降低,内皮功能受损。
3、左旋氨氯地平干预能够抑制SHR血管重构,改善内皮功能,这可能与左旋氨氯地平降低SHR氧化应力有关。
Part 1 Effects of S(-)-amiodipine on left ventricular hypertrophy and expression of Endothelin-1 in spontaneously hypertensive rats
Background:
Left ventricular hypertrophy(LVH) becomes a preclinical disease and an independent risk factor for congestive heart failure,ischemic heart disease,arrhythmia,sudden death,and stroke. Hemodynamic factors and neurohormones derived mainly from the renin-angiotensin system (RAS) may modulate both the extent of cardiac hypertrophy and fibrosis.In addition to appropriate management of additional risk factors and associated clinical conditions,early, intensive and effective BP control is required in the prevention and management of hypertension.
Objective:
in this study,we measured blood pressure,morphology of LV,cardiac function in SHR.we evaluated the expression of preproET-1 in hypertrophied LV myocardium of SHR.To investigate the effect of S(-)-amlodipine on blood pressure,LV morphology,cardic faunction and expression of preproET-1 in LV of SHR.
Method and Results:
1.Research on blood pressure of SHR and effect of S(-)-amlodipine
Twenty male SHR were randomly grouped to receive either S(-)-amlodipine(2mg/kg·d) or vehicle.Age-matched Wistar-Kyoto(WKY) rats served as controls.Systolic blood pressure (SBP) was measured at the beginning,4,8,and 12 weeks of the experiment by tail cuff method.
The results showed that blood pressure of S(-)-amlodipine group was significantly lower than untreatment group(154.23±7.99 mmHg vs 201.41±5.01 mmHg,P＜0.01).
2.The LV function of SHR and effect of S(-)-amlodipine
Rats were anaesthetized with intraperitoneal injection of urethane 1.0g/kg,then the right carotid artery was cannulated with a transducer-tipped catheter,the catheter was advanced further into LV.The recorded or calculated parameters were left ventricle systolic pressure (LVSP),left ventricle end diastolic pressure(LVEDP),the maximal rise rate of left ventricle pressure(+dp/dt_(max)),the maximal decline rate of left ventricle pressure(-dp/dt_(max)) and heart rate(HR).
The results indicated that,S(-)-amlodipine 2mg/kg·d increased the left ventricular +dp/dtmax/LVSP(55.37±7.96 l/s vs 61.98±5.43 l/s,P＜0.05),-dp/dtmax/LVSP(39.81±5.21 1/s vs 46.74±4.79 l/s,P＜0.05).
3.The LVW/BW in SHR and effect of S(-)-amlodipine
The left ventricle(including interventricular septum) samples were weighed after the right and left atria,right ventricular flee wall were dissected.The LV mass index was calculated by dividing the LV weight by the body weight in each animal.
By the end of the experiment,the LVW/body weight ratio(LVW/BW) in SHR-C were significantly greater than that in WKY(2.94±0.11 mg/g vs 2.40±0.17 mg/g,P＜0.01), Compared with SHR-C,after 12 weeks treatment with S(-)-amlodipine,the LVW/BW in SHR-A decreased significantly(2.94±0.11 mg/g vs 2.61±0.13 mg/g,P＜0.01).
4.Pathological analysis of LV in SHR and effect of S(-)-amlodipine
Tissue sections were stained with the hematoxylin-eosin(HE) and Massom stain.The average cardiomyocite diameter and interstitial collagen volume fraction(ICVF) was calculated with the aid of an image analyzer(Image ProPlus 5.0).ICVF=collagen areas/total areas×100%.
The cardiomyocite diameter of SHR-C was significantly larger than that of WKY(16.13±2.79μm 12.57±3.16μm,P＜0.05).Compared with SHR-C,the cardiomyocite diameter in SHR-A decreased significantly(14.3±2.85μm vs 16.13±2.79μm,P＜0.05).ICVF of SHR-C was higher than WKY(12.38%vs 4.62%,P＜0.01),S(-)-amlodipine treatment decreased ICVF of SHR-A(7.36%vs 12.38%,P＜0.01).
5.Endothelin-1 of LV in SHR and effect of S(-)-amlodipin
Endothelin-1(ET-1) concentrations of left ventricular was measured.Left ventricular preproET-1 mRNA expression was measured by real-time PCR.
The results showed that the expression of preproET-1 mRNA of S(-)-amlodipine treated group decreased 20%compared with hypertension group(P＜0.01),and the ET-1 level in the left ventricular were markedly lower in the SHR treated with S(-)-amlodipine than in the hypertension group(184.43±16.78 pg/g vs 207.69±16.09 pg/g,P＜0.05).
Conclusion:
1.In this study,LVH was prominent in SHR.
2.The results of this study confirmed that SHR significantly impaired LV function associated with increased arterial pressure and LVH.
3.The ET-1 level and expression of preproET-1 mRNA in LV of SHR was increased.
4.S(-)-amlodipine could preserve cardiac systolic and diastolic function and inhibit left ventricular hypertrophy in SHR.These effects may partially associate with the decreased ET-1 level of heart.
Part 2 Protective effects of S(-)-amlodipine on endothelial function in spontaneously hypertensive rats
Background:
Hypertension is accompanied and influenced by significant changes in arterial function. Although changes in endothelial and smooth muscle cell function are important in acute control of total peripheral resistance and blood pressure,changes in blood vessel structure also contribute to long-term alterations in arterial function.Vascular remodeling and dysfunction play important role in the pathophysiology of hypertension.
Objective:
In this study,we observed the morphology and of endothelial function of thoracic aortic in SHR,and investigated whether S(-)-amlodipine can improve vascular remodeling and vascular endothelial relaxation of spontaneously hypertensive rats(SHR).
Method and Results:
1.Research on structure of thoracic aortic in SHR and effect of S(-)-amlodipin
Thoracic aortic sections were stained with the hematoxylin-eosin(HE) and Massom stain. The average media thickness(MT) and cross--sectional area(CSA) were calculated with the aid of an image analyzer(Image ProPlus 5.0).
The MT of SHR-C was significantly larger than that of WKY(97±5μm vs 84±4μm, P＜0.05).Compared with SHR-C,MT in SHR-A decreased significantly(91±3μm vs 97±5μm, P＜0.05).CSA of SHR-C was larger than WKY(0.65±0.02 mm~2 vs 0.58±0.03 mm~2,P＜0.05), S(-)-amlodipine treatment decreased CSA of SHR-A(0.62±0.02 mm~2 vs 0.65±0.02 mm~2, P＜0.01).
2.The endothelium function in SHR and effect of S(-)-amlodipin
Rats were studied to observe the endothelium dependent relaxation of thoracic aorta to acetylcholine(ACh) and sodium nitmpruside(SNP).
The maximal endothelium dependent relaxation to ACh was enhanced markedly after treatment with S(-)-amlodipine(48.39±14.86%vs 34.71±9.23%,P＜0.05).The difference of endothelium dependent relaxations between control group and S(-)-amlodipine group was eliminated by L-Nω-Nitro-arginine(L-NAME).The thoracic aorta respons to SNP was no different in all groups(P＞0.05).
3.The oxidation stress in SHR and effect of S(-)-amlodipin
Serum NO,ET and SOD levels of all groups were assahed.
The results showed that the NO level of SHR-C was significantly lower than that of WKY (27.98±4.53μmol/L vs 48.59±7.12μmol/,P＜0.01),and Serum ET levels of SHR-C was higher than WKY(207.69±16.81 ng/L vs 151.32±27.89 ng/L,P＜0.01).Serum NO and SOD concentration were increased in SHR-A group(NO:36.66±7.52μmol/L vs 27.98±4.53μmol/L, P＜0.05;SOD:229.22±20.38×10~3 U/L vs 200.13±6.85×10~3 U/L,P＜0.01).On the other hand,plasma ET level decreased in SHR-A group(184.43±16.78 ng/L vs 207.69±16.81 ng/L, P＜0.05).
Conclusion:
1.The MT and CSA of SHR were significantly larger than thats of WKY,vascular remodeling was observed in thoracic aorta of SHR.
2.The endothelium-dependent vasodilation function was weakened in SHR,the damaged endothelial function was exised in SHR.
3.S(-)-amlodipine couldl improve endothelial relaxation and vascular remodeling in SHR.This effect may be related to an decreased oxidation stress.
研究背景:
高血压左心室肥厚是心血管事件的独立危险因素,与心律失常、猝死、心力衰竭等密切相关。目前认为高血压引起左室肥厚的主要原因包括血流动力学异常和神经内分泌激活。高血压致左心室负荷增加,心肌细胞受到机械刺激,肾素-血管紧张素-醛固酮系统、内皮素系统过度激活,导致蛋白质合成增加,心肌细胞肥大,间质胶原增多,进而引起心脏扩大,心脏舒张末压和收缩期室壁张力均增高,使左室功能受损。治疗高血压的主要目的是最大限度地降低心血管病发病和死亡的危险性,这就要求在治疗高血压的同时干预患者可逆性心血管病的危险因素。所以对于高血压患者提倡临床上早期干预,控制血压,逆转左室肥厚,改善受损的心功能,从而降低各种心血管并发症发生率,改善原发性高血压患者预后。
研究目的:
观察自发性高血压大鼠(SHR)的心脏形态学及左心室功能的改变;检测SHR心脏内皮素系统的变化及其与左室肥厚和左心室功能的关系;观察钙拮抗剂——左旋氨氯地平干预对SHR血压、左室肥厚及心功能的影响,探讨其与SHR心脏内皮素系统的关系。
研究方法:
1、SHR血压的变化及左旋氨氯地平干预对其影响
20只13周龄的雄性SHR随机分为左旋氨氯地平治疗组(SHR-A),高血压对照组(SHR-C),同周龄Wistar—Kyoto(WKY)大鼠作为正常对照组。采用灌胃法给药,左旋氨氯地平组2mg/(kg·d),溶于2ml生理盐水;对照组给予等量生理盐水,治疗时间为12周。采用尾动脉测压方法于用药前和用药后4、8、12周测定大鼠血压。
2、SHR心室功能的变化及左旋氨氯地平干预对其影响
全部动物末次给药后,25%乌拉坦(1g/kg)腹腔注射麻醉,仰卧固定于手术台上,颈前正中做约4cm的切口,分离出右侧颈总动脉,将导管经右颈总动脉插入左心室,记录心率(HR)、和左心室收缩压(left ventricular systolic pressure,LVSP),左室舒张期末压(leftventricular end-diastolic pressure,LVEDP)和左室内压最大变化速率(±dp/dt_(max))。分别用+dp/dt_(max)/LVSP和-dp/dt_(max)/LVSP来表示左室收缩舒张功能。
3、SHR左室重量指数的变化及左旋氨氯地平干预对其影响
沿室间隔剪开左右心室,称量左心室重量,计算左心室湿重/体重指数(LVW/BW),用以表示左室肥厚程度。
4、SHR心脏组织病理学改变及左旋氨氯地平干预对其影响
实验末剪取心脏组织,行HE染色和Masson染色。使用Image ProPlus 5.0图像分析系统测量计算心肌细胞直径和心肌间质胶原容积分数(interstitial collagen volume fraction,ICVF)。ICVF=心肌间质胶原面积/所测视野面积。
5、SHR左室内皮素-1的变化及左旋氨氯地平对其影响
放射免疫法测定心肌组织ET含量,荧光实时定量PCR(Real-time PCR)法测定心肌preproET-1 mRNA的表达。
研究结果:
1、SHR血压的变化及左旋氨氯地平干预对其影响
左旋氨氯地平可显著降低SHR血压,药物干预12周后,SHR-A组血压显著低于SHR-C组(154.23±7.99 mmHg vs 201.41±5.01 mmHg,P＜0.01)。
2、SHR左心室功能的变化及左旋氨氯地平干预对其影响
与WKY组大鼠相比,SHR-C组的LVSP(191.81±10.81 mmHg vs 106.06±11.49 mmHg,P＜0.01)明显升高,+dp/dtmax/LVSP(55.37±7.96 1/s vs 73.79±8.04 1/s,P＜0.01)与-dp/dtmax/LVSP(39.81±5.21 1/s vs 57.27±8.591/s,P＜0.01)显著降低,表明SHR存在左室收缩和舒张功能障碍;左旋氨氯地平治疗能够改善SHR的左室收缩功能(61.98±5.43 1/s vs 55.37±7.96 1/s,P＜0.05)与舒张功能(46.74±4.79 1/s vs 39.81±5.21 1/s,P＜0.05),但尚未能使其恢复到正常水平。
3、SHR左室重量指数的变化及左旋氨氯地平干预对其影响
SHR-C组LVW/BW比值明显高于WKY组(2.94±0.11 mg/g vs 2.40±0.17 mg/g,P＜0.01),表明SHR发生左室肥厚,而左旋氨氯地平干预组的LVW/BW比值较SHR对照组有明显降低(2.61±0.13 mg/g vs 2.94±0.11 mg/g,P＜0.05),表明左旋氨氯地平在一定程度上能够抑制SHR的左室肥厚。
4、SHR心脏组织病理学改变及左旋氨氯地平干预对其影响
SHR左室心肌细胞直径显著大于WKY大鼠心肌细胞直径(16.13±2.79μm vs 12.57±3.16μm,P＜0.05),左旋氨氯地平治疗后SHR心肌细胞肥大明显减轻,细胞直径与对照组SHR相比有统计学差异(14.3±2.85μm vs 16.13±2.79μm,P＜0.05)。SHR左室ICVF同WKY大鼠相比明显增高(12.38%vs 4.62%,P＜0.01);左旋氨氯地平干预后胶原增生明显减轻,ICVF显著降低(7.36%vs 12.38%,P＜0.01)。
5、SHR左室内皮素-1的变化及左旋氨氯地平对其影响
SHR-C组的心肌ET-1含量与WKY组相比显著升高(207.69±16.09 pg/g vs 151.32±27.89 pg/g,P＜0.05);左旋氨氯地平治疗能够降低SHR-A组心肌ET-1的水平(184.43±16.78pg/g vs 207.69±16.09,P＜0.05)。SHR-C组心肌组织preproET-1 mRNA的表达是WKY组的1.94倍(P＜0.01);SHR-A组心肌组织preproET-1 mRNA的表达量是WKY组的1.54倍,与SHR-C组相比降低约20%,且两组具有显著性差异(P＜0.05)。
研究结论:
1、与WKY大鼠相比SHR发生左心室肥厚,心肌细胞肥大,胶原纤维增生。
2、伴随着左室肥厚,SHR左心室收缩与舒张功能均受损。
3、SHR心肌ET-1含量增加,preproET-1 mRNA表达增加。
4、左旋氨氯地平干预能够降低SHR血压,减轻SHR左室肥厚程度,减少胶原纤维增生,改善SHR左心室收缩与舒张功能,其作用可能是通过降低血压、调节心脏内皮素系统实现的。
第二部分左旋氨氯地平对自发性高血压大鼠内皮功能的保护作用
研究背景:
高血压会导致全身动脉功能和结构损害,早期发现和干预血管病变的进展是延缓和控制心血管事件的重要措施。
研究目的:
观察自发性高血压大鼠(SHR)胸主动脉舒张功能及血管壁结构的变化;观察钙拮抗剂——左旋氨氯地平干预对SHR胸主动脉内皮功能障碍及血管重构的影响并探讨其可能的机制。
研究方法:
1、SHR血压的变化及左旋氨氯地平干预对其影响
20只13周龄的雄性SHR随机分为左旋氨氯地平治疗组(SHR-A),高血压对照组(SHR-C),同周龄Wistar—Kyoto(WKY)大鼠作为正常对照组。采用灌胃法给药,左旋氨氯地平组2mg/(kg·d),溶于2ml生理盐水;对照组给予等量生理盐水,治疗时间为12周。采用尾动脉测压方法于用药前和用药后4、8、12周测定大鼠血压。
2、SHR胸主动脉壁结构的改变及左旋氨氯地平干预对其影响
取大鼠胸主动脉,行HE染色和Masson染色,Image-Pro Plus 5.0图像分析系统测量中膜厚度(media thickness,MT)及截面积(cross—sectional area,CSA),光镜下观察中膜胶原含量变化。
3、SHR主动脉内皮功能的变化及左旋氨氯地平干预对其影响
观察离体胸主动脉对乙酰胆碱(ACh)及硝普钠(SNP)的反应性,比较SHR与WKY内皮功能的差异,以及左旋氨氯地平干预的作用。
4、SHR氧化应力的变化及左旋氨氯地平干预对其影响
检测三组大鼠血中NO、ET及SOD含量,比较SHR与WKY大鼠氧化应力的差异,并观察左旋氨氯地平干预对SHR氧化应力的影响。
研究结果:
1、SHR血压的变化及左旋氨氯地平干预对其影响
研究结果显示,左旋氨氯地平可显著降低SHR血压,药物干预12周后,SHR-A组血压显著低于SHR-C组(154.23±7.99 mmHg vs 201.41±5.01 mmHg,P＜0.01)。
2、SHR胸主动脉壁结构的改变及左旋氨氯地平干预对其影响
与WKY大鼠相比,SHR胸主动脉中膜厚度(97±5μm vs 84±4μm,P＜0.05)及截面积(0.65±0.02 mm~2 vs 0.58±0.03 mm~2,P＜0.05)明显增大,左旋氨氯地平治疗能够明显减小胸主动脉中膜厚度(91±3μm vs 97±5μm,P＜0.05)及截面积(0.62±0.02 mm~2 vs 0.65±0.02 mm~2,P＜0.01)。SHR-C组大鼠主动脉中膜胶原纤维显著增生,排列紊乱,平滑肌细胞肥大增生明显,SHR-A组主动脉中膜弹性纤维较高血压组排列有序,平滑肌细胞肥大和胶原纤维增生减轻。
2、SHR主动脉内皮功能的变化及左旋氨氯地平干预对其影响
与WKY大鼠相比,SHR胸主动脉对ACh引起的内皮依赖性最大舒张反应明显减弱(34.71±9.23%vs 89.92±8.26%,P＜0.01),左旋氨氯地平干预能够减轻内皮依赖性舒张功能障碍(48.39±14.86%vs 34.71±9.23%,P＜0.05),左旋硝基精氨酸甲酯(L-NAME)能够消除这种差异。三组大鼠胸主动脉对SNP引起的非内皮依赖性最大舒张反应无显著差异(P＞0.05)。
5、SHR氧化应力的变化及左旋氨氯地平干预对其影响
SHR血清NO含量较WKY大鼠显著降低(27.98±4.53μmol/L vs 48.59±7.12μmol/,P＜0.01),血清ET含量显著升高(207.69±16.81 ng/L vs 151.32±27.89 ng/L,P＜0.01);左旋氨氯地平治疗组血清NO、SOD水平与对照组SHR相比明显升高(NO:36.66±7.52μmol/Lvs 27.98±4.53μmol/L,P＜0.05;SOD:229.22±20.38×10~3U/L vs 200.13±6.85×10~3U/L,P＜0.01),血浆ET浓度显著降低(184.43±16.78 ng/L vs 207.69±16.81 ng/L,P＜0.05)。
研究结论:
1、SHR主动脉中膜厚度及截面积增大,血管发生重构。
2、SHR的ACh引起的血管内皮依赖性舒张功能降低,内皮功能受损。
3、左旋氨氯地平干预能够抑制SHR血管重构,改善内皮功能,这可能与左旋氨氯地平降低SHR氧化应力有关。
Part 1 Effects of S(-)-amiodipine on left ventricular hypertrophy and expression of Endothelin-1 in spontaneously hypertensive rats
Background:
Left ventricular hypertrophy(LVH) becomes a preclinical disease and an independent risk factor for congestive heart failure,ischemic heart disease,arrhythmia,sudden death,and stroke. Hemodynamic factors and neurohormones derived mainly from the renin-angiotensin system (RAS) may modulate both the extent of cardiac hypertrophy and fibrosis.In addition to appropriate management of additional risk factors and associated clinical conditions,early, intensive and effective BP control is required in the prevention and management of hypertension.
Objective:
in this study,we measured blood pressure,morphology of LV,cardiac function in SHR.we evaluated the expression of preproET-1 in hypertrophied LV myocardium of SHR.To investigate the effect of S(-)-amlodipine on blood pressure,LV morphology,cardic faunction and expression of preproET-1 in LV of SHR.
Method and Results:
1.Research on blood pressure of SHR and effect of S(-)-amlodipine
Twenty male SHR were randomly grouped to receive either S(-)-amlodipine(2mg/kg·d) or vehicle.Age-matched Wistar-Kyoto(WKY) rats served as controls.Systolic blood pressure (SBP) was measured at the beginning,4,8,and 12 weeks of the experiment by tail cuff method.
The results showed that blood pressure of S(-)-amlodipine group was significantly lower than untreatment group(154.23±7.99 mmHg vs 201.41±5.01 mmHg,P＜0.01).
2.The LV function of SHR and effect of S(-)-amlodipine
Rats were anaesthetized with intraperitoneal injection of urethane 1.0g/kg,then the right carotid artery was cannulated with a transducer-tipped catheter,the catheter was advanced further into LV.The recorded or calculated parameters were left ventricle systolic pressure (LVSP),left ventricle end diastolic pressure(LVEDP),the maximal rise rate of left ventricle pressure(+dp/dt_(max)),the maximal decline rate of left ventricle pressure(-dp/dt_(max)) and heart rate(HR).
The results indicated that,S(-)-amlodipine 2mg/kg·d increased the left ventricular +dp/dtmax/LVSP(55.37±7.96 l/s vs 61.98±5.43 l/s,P＜0.05),-dp/dtmax/LVSP(39.81±5.21 1/s vs 46.74±4.79 l/s,P＜0.05).
3.The LVW/BW in SHR and effect of S(-)-amlodipine
The left ventricle(including interventricular septum) samples were weighed after the right and left atria,right ventricular flee wall were dissected.The LV mass index was calculated by dividing the LV weight by the body weight in each animal.
By the end of the experiment,the LVW/body weight ratio(LVW/BW) in SHR-C were significantly greater than that in WKY(2.94±0.11 mg/g vs 2.40±0.17 mg/g,P＜0.01), Compared with SHR-C,after 12 weeks treatment with S(-)-amlodipine,the LVW/BW in SHR-A decreased significantly(2.94±0.11 mg/g vs 2.61±0.13 mg/g,P＜0.01).
4.Pathological analysis of LV in SHR and effect of S(-)-amlodipine
Tissue sections were stained with the hematoxylin-eosin(HE) and Massom stain.The average cardiomyocite diameter and interstitial collagen volume fraction(ICVF) was calculated with the aid of an image analyzer(Image ProPlus 5.0).ICVF=collagen areas/total areas×100%.
The cardiomyocite diameter of SHR-C was significantly larger than that of WKY(16.13±2.79μm 12.57±3.16μm,P＜0.05).Compared with SHR-C,the cardiomyocite diameter in SHR-A decreased significantly(14.3±2.85μm vs 16.13±2.79μm,P＜0.05).ICVF of SHR-C was higher than WKY(12.38%vs 4.62%,P＜0.01),S(-)-amlodipine treatment decreased ICVF of SHR-A(7.36%vs 12.38%,P＜0.01).
5.Endothelin-1 of LV in SHR and effect of S(-)-amlodipin
Endothelin-1(ET-1) concentrations of left ventricular was measured.Left ventricular preproET-1 mRNA expression was measured by real-time PCR.
The results showed that the expression of preproET-1 mRNA of S(-)-amlodipine treated group decreased 20%compared with hypertension group(P＜0.01),and the ET-1 level in the left ventricular were markedly lower in the SHR treated with S(-)-amlodipine than in the hypertension group(184.43±16.78 pg/g vs 207.69±16.09 pg/g,P＜0.05).
Conclusion:
1.In this study,LVH was prominent in SHR.
2.The results of this study confirmed that SHR significantly impaired LV function associated with increased arterial pressure and LVH.
3.The ET-1 level and expression of preproET-1 mRNA in LV of SHR was increased.
4.S(-)-amlodipine could preserve cardiac systolic and diastolic function and inhibit left ventricular hypertrophy in SHR.These effects may partially associate with the decreased ET-1 level of heart.
Part 2 Protective effects of S(-)-amlodipine on endothelial function in spontaneously hypertensive rats
Background:
Hypertension is accompanied and influenced by significant changes in arterial function. Although changes in endothelial and smooth muscle cell function are important in acute control of total peripheral resistance and blood pressure,changes in blood vessel structure also contribute to long-term alterations in arterial function.Vascular remodeling and dysfunction play important role in the pathophysiology of hypertension.
Objective:
In this study,we observed the morphology and of endothelial function of thoracic aortic in SHR,and investigated whether S(-)-amlodipine can improve vascular remodeling and vascular endothelial relaxation of spontaneously hypertensive rats(SHR).
Method and Results:
1.Research on structure of thoracic aortic in SHR and effect of S(-)-amlodipin
Thoracic aortic sections were stained with the hematoxylin-eosin(HE) and Massom stain. The average media thickness(MT) and cross--sectional area(CSA) were calculated with the aid of an image analyzer(Image ProPlus 5.0).
The MT of SHR-C was significantly larger than that of WKY(97±5μm vs 84±4μm, P＜0.05).Compared with SHR-C,MT in SHR-A decreased significantly(91±3μm vs 97±5μm, P＜0.05).CSA of SHR-C was larger than WKY(0.65±0.02 mm~2 vs 0.58±0.03 mm~2,P＜0.05), S(-)-amlodipine treatment decreased CSA of SHR-A(0.62±0.02 mm~2 vs 0.65±0.02 mm~2, P＜0.01).
2.The endothelium function in SHR and effect of S(-)-amlodipin
Rats were studied to observe the endothelium dependent relaxation of thoracic aorta to acetylcholine(ACh) and sodium nitmpruside(SNP).
The maximal endothelium dependent relaxation to ACh was enhanced markedly after treatment with S(-)-amlodipine(48.39±14.86%vs 34.71±9.23%,P＜0.05).The difference of endothelium dependent relaxations between control group and S(-)-amlodipine group was eliminated by L-Nω-Nitro-arginine(L-NAME).The thoracic aorta respons to SNP was no different in all groups(P＞0.05).
3.The oxidation stress in SHR and effect of S(-)-amlodipin
Serum NO,ET and SOD levels of all groups were assahed.
The results showed that the NO level of SHR-C was significantly lower than that of WKY (27.98±4.53μmol/L vs 48.59±7.12μmol/,P＜0.01),and Serum ET levels of SHR-C was higher than WKY(207.69±16.81 ng/L vs 151.32±27.89 ng/L,P＜0.01).Serum NO and SOD concentration were increased in SHR-A group(NO:36.66±7.52μmol/L vs 27.98±4.53μmol/L, P＜0.05;SOD:229.22±20.38×10~3 U/L vs 200.13±6.85×10~3 U/L,P＜0.01).On the other hand,plasma ET level decreased in SHR-A group(184.43±16.78 ng/L vs 207.69±16.81 ng/L, P＜0.05).
Conclusion:
1.The MT and CSA of SHR were significantly larger than thats of WKY,vascular remodeling was observed in thoracic aorta of SHR.
2.The endothelium-dependent vasodilation function was weakened in SHR,the damaged endothelial function was exised in SHR.
3.S(-)-amlodipine couldl improve endothelial relaxation and vascular remodeling in SHR.This effect may be related to an decreased oxidation stress.
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