阿托伐他汀对野百合碱诱发的大鼠肺动脉重构的影响
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摘要
第一部分大鼠肺动脉压增高中的肺小动脉重构
目的:
探讨野百合碱诱发的大鼠肺小动脉重构与肺动脉压力增高的关系。
方法:
雄性SD大鼠32只,体重200-230g,随机均分为肺动脉高压组(PAH)和对照组(Ctr)。肺动脉高压组一次性腹腔注射野百合碱40mg/Kg,对照组一次性腹腔注射相同体积的生理盐水。于注射MCT后2周及4周,分别从以上两组大鼠中随机选择8只,测定肺动脉平均压(MPAP)和右心室肥厚指数(RVHI),并运用ipp6.0图像分析软件分析肺组织切片,测定肺小动脉管壁厚度(WT)占血管外径(ED)的百分比(WT%)及管壁面积(WA)占血管总面积的百分比(WA%)。
结果:
腹腔注射MCT 2周后MPAP和RVHI在Ctr与PAH间无统计学差异[(23.6±2.1)vs(26.0±2.8)mmHg,(23.4±4.6)vs(24.7±3.9)%,P均>0.05],但是与Ctr相比,PAH的WT%、WA%均明显增高[WT:(39.1±2.8)vs(50.8±3.1)%,WA:( 51.2±3.0)vs(74.5±2.9)%,P均<0.05];4周后与Ctr相比,PAH的MPAP、RVHI、WT%、WA%都明显增高[(24.0±3.0)vs(35.7±3.1)mmHg,RVHI:(24.2±3.7)vs(44.6±4.3)%,P均<0.01;WT:(40.1±3.1)vs(57.5±2.0)%,WA:(51.1±2.0)vs(78.3±2.0)%,P均<0.05]。
结论:
大鼠肺小动脉的重构先于肺动脉压力的增高。
第二部分阿托伐他汀对野百合碱诱发的大鼠肺动脉重构的影响
目的:
探讨阿托伐他汀、氯沙坦、地尔硫卓及贝那普利对野百合碱诱发的大鼠肺动脉重构的影响。
方法:
雄性Sprague-Dawley大鼠60只,体重200-230g,分为正常对照组(Ctr)、肺动脉高压组(PAH)、氯沙坦治疗组(Los)、阿托伐他汀治疗组(Ato)、地尔硫卓组(Dil)和贝那普利组(Ben)。后五组一次性腹腔注射野百合碱40mg/Kg,对照组一次性腹腔注射1ml的生理盐水。注射野百合碱4周后,Los组、Ato组、Dil组和Ben组分别给予氯沙坦50mg/Kg/d、阿托伐他汀5mg/Kg/d、地尔硫卓25mg/Kg/d和贝那普利10mg/Kg/d灌胃治疗,Ctr组和PAH组给予相同体积生理盐水灌胃,共持续4周。待药物干预满4周后,分别测定大鼠的肺动脉平均压(MPAP)、右心室肥厚指数(RVHI)、肺小动脉管壁厚度占管径的百分比(WT%)及管壁面积占血管总面积的百分比(WA%)。留取大鼠的肺动脉干,并采用Western-Blot法测定各组大鼠肺动脉Cavα1c、SERCA-2a、IP3R-1和RyR-3蛋白的表达。
结果:
(1)PAH组大鼠的MPAP和RVHI均高于Ctr组,经氯沙坦、阿托伐他汀、地尔硫卓及贝那普利治疗后MPAP和RVHI均明显降低[MPAP: Ctr(23.22±3.27), PAH(36.12±4.17) , Los(29.80±4.76) , Ato(27.57±4.07) , Dil(25.27±6.18) vs Ben(28.11±6.02)mmHg ; RVHI : Ctr(25.58±2.94) , PAH(45.60±3.81) ,Los(38.53±6.40),Ato(37.72±5.96),Dil(39.96±2.61) vs Ben(39.50±4.90)%,P均<0.05]。
(2)PAH组大鼠的WT%和WA%均明显高于Ctr组,而经氯沙坦、阿托伐他汀、地尔硫卓及贝那普利治疗后,WT%和WA%均明显降低,其中贝那普利组的WT%和WA%均明显低于氯沙坦及地尔硫卓组[WT: Ctr(37.63±3.63),PAH(58.48±4.59) , Los(44.89±5.69) , Ato(42.76±2.87) , Dil(43.04±4.96) vs Ben(37.41±4.35)%;WA:Ctr(51.37±6.40),PAH(76.84±7.04),Los(61.27±5.46) ,Ato(59.27±3.36),Dil(61.74±4.90) vs Ben(53.86±5.53)%,P均<0.05]。
(3)与Ctr组相比,PAH组大鼠肺动脉Cavα1c和RyR-3表达明显增强(P均<0.05)。经氯沙坦、阿托伐他汀、地尔硫卓及贝那普利治疗后,Cavα1c和RyR-3的表达均较PAH组明显降低,且阿托伐他汀组RyR-3的表达明显低于其余各药物组[Cavα1c: Ctr(0.071±0.023) , PAH(0.295±0.046) , Los(0.117±0.025) ,Ato(0.109±0.037) , Dil(0.125±0.012) vs Ben(0.134±0.034) ; RyR-3 :Ctr(0.711±0.016),PAH(0.757±0.023),Los(0.532±0.017),Ato(0.441±0.027),Dil(0.474±0.021) vs Ben(0.488±0.023),P均<0.05]。SERCA-2a和IP3R-1在PAH组中的表达均较Ctr组明显减弱(P <0.05);经氯沙坦、阿托伐他汀治疗后,SERCA-2a和IP3R-1的表达比PAH组明显增强(P均<0.05);经地尔硫卓和贝那普利治疗后,IP3R-1的表达较PAH组减少[SERCA-2a: Ctr(0.369±0.014),PAH(0.137±0.028),Los(0.289±0.013),Ato(0.285±0.019),Dil(0.122±0.030) vs Ben(0.107±0.032) ; IP3R-1 : Ctr(0.402±0.021) , PAH(0.315±0.033) ,Los(0.360±0.023),Ato(0.371±0.020),Dil(0.083±0.016) vs Ben(0.074±0.022),P均<0.05]。
结论:
(1)阿托伐他汀、氯沙坦、地尔硫卓和贝那普利均能有效地降低野百合碱诱发的肺动脉高压大鼠的肺动脉压力,减轻右心室肥厚,改善肺小动脉的重构。
(2)肺动脉高压大鼠肺动脉存在Cavα1c、SERCA-2a、IP3R-1和RyR-3等钙离子通道蛋白表达异常。
(3)阿托伐他汀、氯沙坦、地尔硫卓和贝那普利可以不同程度地改善Cavα1c、SERCA-2a、IP3R-1和RyR-3等钙离子通道蛋白的重构。
PartⅠPulmonary Arteriolar Remodelling in the Pulmonary Arterial hypertension in Rats
Objective
To eveluate the relationship between the remodelling of pulmonary arteriolar structure induced by monocrotaline and the increase of pulmonary arterial pressure in rats.
Methods
Thirty-two Sprague-Dawley rats were randomly divided into two groups: normal control (Ctr group) and pulmonary arterial hypertension (PAH group). The pulmonary arterial hypertension was induced by an injection of 40mg/Kg monocrotaline intraperitoneally. After 2 and 4 weeks, mean of Pulmonary Arterial Pressure (MPAP) and Right Ventricular Hypertrophy Index(RVHI)were measured,and WT% and WA% of pulmonary arterioles were evaluated by ipp6.0 Image Analysis Software.
Results
After 2 weeks, no significant difference was found between PAH and Ctr group in MPAP and RVHI[(23.6±2.1)vs(26.0±2.8)mmHg,(23.4±4.6)vs(24.7±3.9)%, P >0.05]. However, in comparison with Ctr guoup, WT% and WA% of pulmonary arterioles in PAH group were significantly increased[WT:(39.1±2.8)vs(50.8±3.1)%, WA:( 51.2±3.0)vs(74.5±2.9)%, P <0.05]. Afer 4 weeks, compared with Ctr group, MPAP、RVHI、WT% and WA% in PAH group were significantly increased [MPAP:(24.0±3.0)vs(35.7±3.1)mmHg, RVHI:(24.2±3.7)vs(44.6±4.3)%, P<0.01; WT:(40.1±3.1)vs(57.5±2.0)%, WA:(51.1±2.0)vs(78.3±2.0)%, P <0.05].
Conclusions
Monocrotaline-induced pulmonary arteriolar remodelling is prior to the increase of pulmonary arterial pressure in rats.
PartⅡEffects of Atorvastatin on Monocrotaline-induced Pulmonary Arterial Remodelling in Rats
Objective
To investigate the effects of atorvastatin, losartan, diltiazem and benazepril on monocrotaline-induced pulmonary arterial remodelling in rats.
Methods
Sixty Sprague-Dawley rats were randomly assigned to six groups:normal control (Ctr), pulmonary arterial hypertension (PAH), losartan (Los), atorvastatin (Ato), diltiazem (Dil) and benazepril (Ben) treated groups. The rats were given a dose of 40mg/Kg monocrotaline intraperitoneally in PAH, losartan, atorvastatin, diltiazem and benazepril treated groups and untreated rats were given 1ml normal saline intraperitoneally as control. After 4 weeks, the rats were given 50mg/Kg/d of losartan, 5mg/Kg/d of atorvastatin, 25mg/Kg/d of diltiazem and 10mg/Kg/d of benazepril by gavage respectively in losartan, atorvastatin, diltiazem and benazepril treated groups for 4 weeks. 4 weeks after medication, mean of pulmonary arterial pressure and right ventricular hypertrophy index were measured, and WT% and WA% of pulmonary arterioles were evaluated. The pulmonary arterial trunks from each group were collected. The protein expression for Cavα1c, SERCA-2a, IP3R-1, RyR-3 in pulmonary artery was determined by Western-Blot and densitometry.
Results
(1) MPAP and RVHI were significantly higher in PAH, as compared with Ctr group. MPAP and RVHI were significantly decreased after treatment of atorvastatin, losartan, diltiazem and benazepril. [MPAP: Ctr(23.22±3.27), PAH(36.12±4.17), Los(29.80±4.76), Ato(27.57±4.07), Dil(25.27±6.18) vs Ben(28.11±6.02)mmHg; RVHI: Ctr(25.58±2.94), PAH(45.60±3.81), Los(38.53±6.40), Ato(37.72±5.96), Dil(39.96±2.61) vs Ben(39.50±4.90)%, P <0.05 respectively]
(2) WT% and WA% were significantly increased in PAH, in comparison with Ctr group. Administration of atorvastatin, losartan, diltiazem and benazepril, they were significantly reduced. WT% and WA% in benazepril treated group was lower than that in losartan and diltiazem treated groups. [WT: Ctr(37.63±3.63), PAH(58.48±4.59), Los(44.89±5.69), Ato(42.76±2.87), Dil(43.04±4.96) vs Ben(37.41±4.35)%; WA: Ctr(51.37±6.40), PAH(76.84±7.04), Los(61.27±5.46), Ato(59.27±3.36), Dil(61.74±4.90) vs Ben(53.86±5.53)%, P <0.05 respectively]
(3) In comparison with PAH, Cavα1c and RyR-3 expression was obviously decreased after treatment of atorvastatin, losartan, diltiazem and benazepril. And RyR-3 expression in atorvastatin treated group was lower than that in other medicine treated groups [Cavα1c: Ctr(0.071±0.023), PAH(0.295±0.046), Los(0.117±0.025), Ato(0.109±0.037), Dil(0.125±0.012) vs Ben(0.134±0.034); RyR-3: Ctr(0.711±0.016), PAH(0.757±0.023), Los(0.532±0.017), Ato(0.441±0.027), Dil(0.474±0.021) vs Ben(0.488±0.023), P <0.05 respectively]. There was an significant increase in the expression of SERCA-2a after treatment of atorvastatin and losartan [SERCA-2a: Ctr(0.369±0.014), PAH(0.137±0.028), Los(0.289±0.013), Ato(0.285±0.019), Dil(0.122±0.030) vs Ben(0.107±0.032), P<0.05 respectively]. IP3R-1 was upregulated after treatment of atorvastatin and losartan and downregulated after treatment of diltiazem and benazepril [IP3R-1: Ctr(0.402±0.021), PAH(0.315±0.033), Los(0.360±0.023), Ato(0.371±0.020), Dil(0.083±0.016) vs Ben(0.074±0.022), P<0.05 respectively].
Conclusions
(1) Pulmonary arterial pressure was reduced and right ventricular hypertrophy and pulmonary arterioles remodelling were attenuated by atorvastatin, losartan, diltiazem and benazepril in monocrotaline-induced pulmonary hypertensive rats.
(2) The expression of calcium channel proteins such as Cavα1c, SERCA-2a, IP3R-1, RyR-3 was markedly changed in pulmonary artery in monocrotaline-induced pulmonary hypertensive rats.
(3) Atorvastatin, losartan, diltiazem and benazepril could regulate the expression of Cavα1c, SERCA-2a, IP3R-1, RyR-3 differently in pulmonary artery.
目的:
探讨野百合碱诱发的大鼠肺小动脉重构与肺动脉压力增高的关系。
方法:
雄性SD大鼠32只,体重200-230g,随机均分为肺动脉高压组(PAH)和对照组(Ctr)。肺动脉高压组一次性腹腔注射野百合碱40mg/Kg,对照组一次性腹腔注射相同体积的生理盐水。于注射MCT后2周及4周,分别从以上两组大鼠中随机选择8只,测定肺动脉平均压(MPAP)和右心室肥厚指数(RVHI),并运用ipp6.0图像分析软件分析肺组织切片,测定肺小动脉管壁厚度(WT)占血管外径(ED)的百分比(WT%)及管壁面积(WA)占血管总面积的百分比(WA%)。
结果:
腹腔注射MCT 2周后MPAP和RVHI在Ctr与PAH间无统计学差异[(23.6±2.1)vs(26.0±2.8)mmHg,(23.4±4.6)vs(24.7±3.9)%,P均>0.05],但是与Ctr相比,PAH的WT%、WA%均明显增高[WT:(39.1±2.8)vs(50.8±3.1)%,WA:( 51.2±3.0)vs(74.5±2.9)%,P均<0.05];4周后与Ctr相比,PAH的MPAP、RVHI、WT%、WA%都明显增高[(24.0±3.0)vs(35.7±3.1)mmHg,RVHI:(24.2±3.7)vs(44.6±4.3)%,P均<0.01;WT:(40.1±3.1)vs(57.5±2.0)%,WA:(51.1±2.0)vs(78.3±2.0)%,P均<0.05]。
结论:
大鼠肺小动脉的重构先于肺动脉压力的增高。
第二部分阿托伐他汀对野百合碱诱发的大鼠肺动脉重构的影响
目的:
探讨阿托伐他汀、氯沙坦、地尔硫卓及贝那普利对野百合碱诱发的大鼠肺动脉重构的影响。
方法:
雄性Sprague-Dawley大鼠60只,体重200-230g,分为正常对照组(Ctr)、肺动脉高压组(PAH)、氯沙坦治疗组(Los)、阿托伐他汀治疗组(Ato)、地尔硫卓组(Dil)和贝那普利组(Ben)。后五组一次性腹腔注射野百合碱40mg/Kg,对照组一次性腹腔注射1ml的生理盐水。注射野百合碱4周后,Los组、Ato组、Dil组和Ben组分别给予氯沙坦50mg/Kg/d、阿托伐他汀5mg/Kg/d、地尔硫卓25mg/Kg/d和贝那普利10mg/Kg/d灌胃治疗,Ctr组和PAH组给予相同体积生理盐水灌胃,共持续4周。待药物干预满4周后,分别测定大鼠的肺动脉平均压(MPAP)、右心室肥厚指数(RVHI)、肺小动脉管壁厚度占管径的百分比(WT%)及管壁面积占血管总面积的百分比(WA%)。留取大鼠的肺动脉干,并采用Western-Blot法测定各组大鼠肺动脉Cavα1c、SERCA-2a、IP3R-1和RyR-3蛋白的表达。
结果:
(1)PAH组大鼠的MPAP和RVHI均高于Ctr组,经氯沙坦、阿托伐他汀、地尔硫卓及贝那普利治疗后MPAP和RVHI均明显降低[MPAP: Ctr(23.22±3.27), PAH(36.12±4.17) , Los(29.80±4.76) , Ato(27.57±4.07) , Dil(25.27±6.18) vs Ben(28.11±6.02)mmHg ; RVHI : Ctr(25.58±2.94) , PAH(45.60±3.81) ,Los(38.53±6.40),Ato(37.72±5.96),Dil(39.96±2.61) vs Ben(39.50±4.90)%,P均<0.05]。
(2)PAH组大鼠的WT%和WA%均明显高于Ctr组,而经氯沙坦、阿托伐他汀、地尔硫卓及贝那普利治疗后,WT%和WA%均明显降低,其中贝那普利组的WT%和WA%均明显低于氯沙坦及地尔硫卓组[WT: Ctr(37.63±3.63),PAH(58.48±4.59) , Los(44.89±5.69) , Ato(42.76±2.87) , Dil(43.04±4.96) vs Ben(37.41±4.35)%;WA:Ctr(51.37±6.40),PAH(76.84±7.04),Los(61.27±5.46) ,Ato(59.27±3.36),Dil(61.74±4.90) vs Ben(53.86±5.53)%,P均<0.05]。
(3)与Ctr组相比,PAH组大鼠肺动脉Cavα1c和RyR-3表达明显增强(P均<0.05)。经氯沙坦、阿托伐他汀、地尔硫卓及贝那普利治疗后,Cavα1c和RyR-3的表达均较PAH组明显降低,且阿托伐他汀组RyR-3的表达明显低于其余各药物组[Cavα1c: Ctr(0.071±0.023) , PAH(0.295±0.046) , Los(0.117±0.025) ,Ato(0.109±0.037) , Dil(0.125±0.012) vs Ben(0.134±0.034) ; RyR-3 :Ctr(0.711±0.016),PAH(0.757±0.023),Los(0.532±0.017),Ato(0.441±0.027),Dil(0.474±0.021) vs Ben(0.488±0.023),P均<0.05]。SERCA-2a和IP3R-1在PAH组中的表达均较Ctr组明显减弱(P <0.05);经氯沙坦、阿托伐他汀治疗后,SERCA-2a和IP3R-1的表达比PAH组明显增强(P均<0.05);经地尔硫卓和贝那普利治疗后,IP3R-1的表达较PAH组减少[SERCA-2a: Ctr(0.369±0.014),PAH(0.137±0.028),Los(0.289±0.013),Ato(0.285±0.019),Dil(0.122±0.030) vs Ben(0.107±0.032) ; IP3R-1 : Ctr(0.402±0.021) , PAH(0.315±0.033) ,Los(0.360±0.023),Ato(0.371±0.020),Dil(0.083±0.016) vs Ben(0.074±0.022),P均<0.05]。
结论:
(1)阿托伐他汀、氯沙坦、地尔硫卓和贝那普利均能有效地降低野百合碱诱发的肺动脉高压大鼠的肺动脉压力,减轻右心室肥厚,改善肺小动脉的重构。
(2)肺动脉高压大鼠肺动脉存在Cavα1c、SERCA-2a、IP3R-1和RyR-3等钙离子通道蛋白表达异常。
(3)阿托伐他汀、氯沙坦、地尔硫卓和贝那普利可以不同程度地改善Cavα1c、SERCA-2a、IP3R-1和RyR-3等钙离子通道蛋白的重构。
PartⅠPulmonary Arteriolar Remodelling in the Pulmonary Arterial hypertension in Rats
Objective
To eveluate the relationship between the remodelling of pulmonary arteriolar structure induced by monocrotaline and the increase of pulmonary arterial pressure in rats.
Methods
Thirty-two Sprague-Dawley rats were randomly divided into two groups: normal control (Ctr group) and pulmonary arterial hypertension (PAH group). The pulmonary arterial hypertension was induced by an injection of 40mg/Kg monocrotaline intraperitoneally. After 2 and 4 weeks, mean of Pulmonary Arterial Pressure (MPAP) and Right Ventricular Hypertrophy Index(RVHI)were measured,and WT% and WA% of pulmonary arterioles were evaluated by ipp6.0 Image Analysis Software.
Results
After 2 weeks, no significant difference was found between PAH and Ctr group in MPAP and RVHI[(23.6±2.1)vs(26.0±2.8)mmHg,(23.4±4.6)vs(24.7±3.9)%, P >0.05]. However, in comparison with Ctr guoup, WT% and WA% of pulmonary arterioles in PAH group were significantly increased[WT:(39.1±2.8)vs(50.8±3.1)%, WA:( 51.2±3.0)vs(74.5±2.9)%, P <0.05]. Afer 4 weeks, compared with Ctr group, MPAP、RVHI、WT% and WA% in PAH group were significantly increased [MPAP:(24.0±3.0)vs(35.7±3.1)mmHg, RVHI:(24.2±3.7)vs(44.6±4.3)%, P<0.01; WT:(40.1±3.1)vs(57.5±2.0)%, WA:(51.1±2.0)vs(78.3±2.0)%, P <0.05].
Conclusions
Monocrotaline-induced pulmonary arteriolar remodelling is prior to the increase of pulmonary arterial pressure in rats.
PartⅡEffects of Atorvastatin on Monocrotaline-induced Pulmonary Arterial Remodelling in Rats
Objective
To investigate the effects of atorvastatin, losartan, diltiazem and benazepril on monocrotaline-induced pulmonary arterial remodelling in rats.
Methods
Sixty Sprague-Dawley rats were randomly assigned to six groups:normal control (Ctr), pulmonary arterial hypertension (PAH), losartan (Los), atorvastatin (Ato), diltiazem (Dil) and benazepril (Ben) treated groups. The rats were given a dose of 40mg/Kg monocrotaline intraperitoneally in PAH, losartan, atorvastatin, diltiazem and benazepril treated groups and untreated rats were given 1ml normal saline intraperitoneally as control. After 4 weeks, the rats were given 50mg/Kg/d of losartan, 5mg/Kg/d of atorvastatin, 25mg/Kg/d of diltiazem and 10mg/Kg/d of benazepril by gavage respectively in losartan, atorvastatin, diltiazem and benazepril treated groups for 4 weeks. 4 weeks after medication, mean of pulmonary arterial pressure and right ventricular hypertrophy index were measured, and WT% and WA% of pulmonary arterioles were evaluated. The pulmonary arterial trunks from each group were collected. The protein expression for Cavα1c, SERCA-2a, IP3R-1, RyR-3 in pulmonary artery was determined by Western-Blot and densitometry.
Results
(1) MPAP and RVHI were significantly higher in PAH, as compared with Ctr group. MPAP and RVHI were significantly decreased after treatment of atorvastatin, losartan, diltiazem and benazepril. [MPAP: Ctr(23.22±3.27), PAH(36.12±4.17), Los(29.80±4.76), Ato(27.57±4.07), Dil(25.27±6.18) vs Ben(28.11±6.02)mmHg; RVHI: Ctr(25.58±2.94), PAH(45.60±3.81), Los(38.53±6.40), Ato(37.72±5.96), Dil(39.96±2.61) vs Ben(39.50±4.90)%, P <0.05 respectively]
(2) WT% and WA% were significantly increased in PAH, in comparison with Ctr group. Administration of atorvastatin, losartan, diltiazem and benazepril, they were significantly reduced. WT% and WA% in benazepril treated group was lower than that in losartan and diltiazem treated groups. [WT: Ctr(37.63±3.63), PAH(58.48±4.59), Los(44.89±5.69), Ato(42.76±2.87), Dil(43.04±4.96) vs Ben(37.41±4.35)%; WA: Ctr(51.37±6.40), PAH(76.84±7.04), Los(61.27±5.46), Ato(59.27±3.36), Dil(61.74±4.90) vs Ben(53.86±5.53)%, P <0.05 respectively]
(3) In comparison with PAH, Cavα1c and RyR-3 expression was obviously decreased after treatment of atorvastatin, losartan, diltiazem and benazepril. And RyR-3 expression in atorvastatin treated group was lower than that in other medicine treated groups [Cavα1c: Ctr(0.071±0.023), PAH(0.295±0.046), Los(0.117±0.025), Ato(0.109±0.037), Dil(0.125±0.012) vs Ben(0.134±0.034); RyR-3: Ctr(0.711±0.016), PAH(0.757±0.023), Los(0.532±0.017), Ato(0.441±0.027), Dil(0.474±0.021) vs Ben(0.488±0.023), P <0.05 respectively]. There was an significant increase in the expression of SERCA-2a after treatment of atorvastatin and losartan [SERCA-2a: Ctr(0.369±0.014), PAH(0.137±0.028), Los(0.289±0.013), Ato(0.285±0.019), Dil(0.122±0.030) vs Ben(0.107±0.032), P<0.05 respectively]. IP3R-1 was upregulated after treatment of atorvastatin and losartan and downregulated after treatment of diltiazem and benazepril [IP3R-1: Ctr(0.402±0.021), PAH(0.315±0.033), Los(0.360±0.023), Ato(0.371±0.020), Dil(0.083±0.016) vs Ben(0.074±0.022), P<0.05 respectively].
Conclusions
(1) Pulmonary arterial pressure was reduced and right ventricular hypertrophy and pulmonary arterioles remodelling were attenuated by atorvastatin, losartan, diltiazem and benazepril in monocrotaline-induced pulmonary hypertensive rats.
(2) The expression of calcium channel proteins such as Cavα1c, SERCA-2a, IP3R-1, RyR-3 was markedly changed in pulmonary artery in monocrotaline-induced pulmonary hypertensive rats.
(3) Atorvastatin, losartan, diltiazem and benazepril could regulate the expression of Cavα1c, SERCA-2a, IP3R-1, RyR-3 differently in pulmonary artery.
引文
[1] Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension: a morphometric and immunohistochemical study [J]. Am J Respir Crit Care Med, 2000, 162:1577–1586.
[2] Strauss BH, Rabinovitch M. Adventitial fibroblasts: defining a role in vessel wall remodeling [J]. Am J Respir Cell Mol Biol, 2000, 22:1–3.
[3] 谢良地,林志鸿,许昌声. 氟伐他汀抑制高血压大鼠血管平滑肌细胞增殖. 中国病理生理杂志. 2002,18(5):483-485.
[4] 林志鸿,谢良地,吴可贵. 氟伐他汀对自发性高血压大鼠心肌纤维化的抑制作用. 中华医学杂志. 2002, 80(9):76-77.
[5] 林志鸿,谢良地,吴可贵. 氟伐他汀对自发性高血压大鼠阻力血管结构与功能的影响. 中国心血管病杂志.1999, 27:56-60.
[6] 欧阳秋芳. 氟伐他汀对自发性高血压大鼠血管平滑肌细胞 LTCC(α1C)、SERCA2、IP3R-1表达的影响[D]. 福建医科大学, 2006:15-19.
[7] 杨月榕,吴欣,陈佳,谢良地. 氟伐他汀对老年高血压病患者内皮依赖性血管舒张功能影响的研究. 中国全科医学. 2003, l6 (1):32-34.
[8] Nishimura T, Faul JL, Berry GJ, et al. Simvastatin Attenuates Smooth Muscle Neointimal Proliferation and Pulmonary Hypertension in Rats [J]. Am J Respir Crit Care Med ,2002,166(10):1403-1408.
[9] Marleen H. M. Hessel, Paul Steendijk, Brigit den Adel, et al. Characterization of right ventricular function after monocrotaline-induced pulmonary hypertension in the intact rat [J] .Am J Physiol Heart Circ Physiol, Nov 2006, 291: H2424 - H2430.
[10] Pravin B. Sehgal, Somshuvra Mukhopadhyay, Fang Xu, et al. Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension [J]. Am J Physiol Lung Cell Mol Physiol, Jun 2007, 292: L1526 - L1542.
[11] Rory E. Morty, Bozena Nejman, Grazyna Kwapiszewska, et al. Dysregulated Bone Morphogenetic Protein Signaling in Monocrotaline-Induced Pulmonary Arterial [J]. Hypertension Arterioscler. Thromb. Vasc. Biol., May 2007, 27: 1072 - 1078.
[12] 林培森, 谢筱露, 谢良地, 许昌声. 大鼠肺小动脉重构发生在肺动脉压增高之前.中华高血压杂志.2007, Vol. 15. No.10:839-843.
[13]Chen-Fuh Lam, Timothy E. Peterson, Anthony J. Croatt, et al. Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension [J]. Am J Physiol Heart Circ Physiol, Dec 2005, 289: H2334 - H2341.
[14] Kyle Northcote Cowan, Adrian Heilbut, Tilman Humpl, et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nature Medicine, Jun 2000, 6: 698 - 702.
[15]周光德,陈瑞芬,刘国贞等.野百合碱引起肺血管重建的观察.中国病理生理杂志,2001,17(6):573-4.
[16]Sartore. S, Chiavegato. A, Faggin. E, et al. Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ Res, 2001, 89:1111-1121.
[17] Ryan W. Kobs, Nidal E. Muvarak, Jens C. Eickhoff, et al. Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia-induced hypertension [J]. Am J Physiol Heart Circ Physiol, Mar 2005, 288: H1209 - H1217.
[18]Laimute Taraseviciene-Stewart, Mark R. Nicolls, Donatas Kraskauskas, et al. Absence of T Cells Confers Increased Pulmonary Arterial Hypertension and Vascular Remodeling [J]. Am. J. Respir. Crit. Care Med., Jun 2007, 175: 1280 - 1289.
[19] Todd L, Mullen M, Olley P, Rabinovitch M. Pulmonary toxicity of monocrotaline differs at critical periods of lung development. Pediatr Res, 1985, 19: 731-737.
[20] Huxtable RJ. Activation and pulmonary toxicity of pyrrolizidine alkaloids. Pharmacol Ther, 1990, 47: 371–389.
[21] Rosenberg HC, Rabinovitch M. Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension [J]. Am J Physiol, 1988, 255: H1484–H1491.
[22] Wilson DW, Segall HJ, Pan LC, et al. Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol, 1992, 22:307–325.
[23] Pan LC, Wilson DW, Segall HJ. Strain differences in the response of Fischer 344 and Sprague-Dawley rats to monocrotaline induced pulmonary vascular disease. Toxicology, 1993, 79:21–35.
[24] Lame MW, Jones AD, Wilson DW, et al. Protein targets of monocrotaline pyrrole in pulmonaryartery endothelial cells. J Biol Chem, 2000, 275:29091–29099.
[25] Van Suylen RJ, Smits JF, Daemen MJ. Pulmonary artery remodeling differs in hypoxia-and monocrotaline-induced pulmonary hypertension [J]. Am J Respir Crit Care Med, 1998, 157: 1423–1428.
[26] Rabinovitch M. EVE and beyond, retro and prospective insights [J]. Am J Physiol Lung Cell Mol Physiol, 1999, 277: L5–L12.
[27] Lappin PB, Roth RA. Hypertrophy and prolonged DNA synthesis in smooth muscle cells characterize pulmonary arterial wall thickening after monocrotaline pyrrole administration to rats. Toxicol Pathol, 1997 Jul-Aug, 25(4):372-80.
[28] Laudi S, Trump S, Schmitz V, et al. Serotonin transporter in pulmonary hypertensive rats treated with atorvastatin [J]. Am J Physiol Lung Cell Mol Physiol, 2007 Sep, 293(3): L630-8.
[29] Souza-Costa DC, Figueiredo-Lopes L, Alves-Filho JC, et al. Protective effects of atorvastatin in rat models of acute pulmonary embolism: involvement of matrix metalloproteinase-9. Crit Care Med, 2007 Jan, 35 (1):239-45.
[30] Rakotoniaina Z, Guerard P, Lirussi F, et al. The protective effect of HMG-CoA reductase inhibitors against monocrotaline-induced pulmonary hypertension in the rat might not be a class effect: comparison of pravastatin and atorvastatin. Naunyn Schmiedebergs Arch Pharmacol, 2006 Dec, 374(3):195-206.
[31] Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol, 2008 Jan, 44(1):14-30.
[32] Yang XR, Lin MJ, Yip KP, Jeyakumar LH, Fleischer S, Leung GP, Sham JS. Multiple ryanodine receptor subtypes and heterogeneous ryanodine receptor-gated Ca2+ stores in pulmonary arterial smooth muscle cells [J]. Am J Physiol Lung Cell Mol Physiol, 2005, 289: L338-L348.
[33] 王颖,李智,刘立宾,丛华等. 肺动脉高压大鼠肺动脉平滑肌细胞 Ryanodine 受体亚型的变化. 中国药理学通报. 2000 Dec, 16(6):628-630.
[34] 谢良地, 欧阳秋芳, 王华军. 地尔硫卓对自发性高血压大鼠左心室舒张功能的影响及其可能的机制. 国际心血管病杂志. 2007, 4:284-288.
[35] Zheng Xia, Hu Shenjiang. Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacologica Sinica, 2005 Jun, 26: 696-704.
[36] Antonella Liantonio, Viviana Giannuzzi, Valentina Cippone. Fluvastatin and atorvastatin affect calcium homeostasis of rat skeletal muscle fibers in vivo and in vitro by impairing the sarcoplasmic reticulum/mitochondria Ca2+-Release System. J. Pharmacol. Exp. Ther., May 2007, 321: 626 - 634.
[37] Sacher J, Weigl L, Werner M, Szegedi C, Hohenegger M.Delineation of myotoxicity induced by 3-hydroxy-3-methylglutaryl CoA reductase inhibitors in human skeletal muscle cells. J Pharmacol Exp Ther., 2005 Sep, 314(3):1032-41.
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[2] Strauss BH, Rabinovitch M. Adventitial fibroblasts: defining a role in vessel wall remodeling [J]. Am J Respir Cell Mol Biol, 2000, 22:1–3.
[3] 谢良地,林志鸿,许昌声. 氟伐他汀抑制高血压大鼠血管平滑肌细胞增殖. 中国病理生理杂志. 2002,18(5):483-485.
[4] 林志鸿,谢良地,吴可贵. 氟伐他汀对自发性高血压大鼠心肌纤维化的抑制作用. 中华医学杂志. 2002, 80(9):76-77.
[5] 林志鸿,谢良地,吴可贵. 氟伐他汀对自发性高血压大鼠阻力血管结构与功能的影响. 中国心血管病杂志.1999, 27:56-60.
[6] 欧阳秋芳. 氟伐他汀对自发性高血压大鼠血管平滑肌细胞 LTCC(α1C)、SERCA2、IP3R-1表达的影响[D]. 福建医科大学, 2006:15-19.
[7] 杨月榕,吴欣,陈佳,谢良地. 氟伐他汀对老年高血压病患者内皮依赖性血管舒张功能影响的研究. 中国全科医学. 2003, l6 (1):32-34.
[8] Nishimura T, Faul JL, Berry GJ, et al. Simvastatin Attenuates Smooth Muscle Neointimal Proliferation and Pulmonary Hypertension in Rats [J]. Am J Respir Crit Care Med ,2002,166(10):1403-1408.
[9] Marleen H. M. Hessel, Paul Steendijk, Brigit den Adel, et al. Characterization of right ventricular function after monocrotaline-induced pulmonary hypertension in the intact rat [J] .Am J Physiol Heart Circ Physiol, Nov 2006, 291: H2424 - H2430.
[10] Pravin B. Sehgal, Somshuvra Mukhopadhyay, Fang Xu, et al. Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension [J]. Am J Physiol Lung Cell Mol Physiol, Jun 2007, 292: L1526 - L1542.
[11] Rory E. Morty, Bozena Nejman, Grazyna Kwapiszewska, et al. Dysregulated Bone Morphogenetic Protein Signaling in Monocrotaline-Induced Pulmonary Arterial [J]. Hypertension Arterioscler. Thromb. Vasc. Biol., May 2007, 27: 1072 - 1078.
[12] 林培森, 谢筱露, 谢良地, 许昌声. 大鼠肺小动脉重构发生在肺动脉压增高之前.中华高血压杂志.2007, Vol. 15. No.10:839-843.
[13]Chen-Fuh Lam, Timothy E. Peterson, Anthony J. Croatt, et al. Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension [J]. Am J Physiol Heart Circ Physiol, Dec 2005, 289: H2334 - H2341.
[14] Kyle Northcote Cowan, Adrian Heilbut, Tilman Humpl, et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nature Medicine, Jun 2000, 6: 698 - 702.
[15]周光德,陈瑞芬,刘国贞等.野百合碱引起肺血管重建的观察.中国病理生理杂志,2001,17(6):573-4.
[16]Sartore. S, Chiavegato. A, Faggin. E, et al. Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ Res, 2001, 89:1111-1121.
[17] Ryan W. Kobs, Nidal E. Muvarak, Jens C. Eickhoff, et al. Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia-induced hypertension [J]. Am J Physiol Heart Circ Physiol, Mar 2005, 288: H1209 - H1217.
[18]Laimute Taraseviciene-Stewart, Mark R. Nicolls, Donatas Kraskauskas, et al. Absence of T Cells Confers Increased Pulmonary Arterial Hypertension and Vascular Remodeling [J]. Am. J. Respir. Crit. Care Med., Jun 2007, 175: 1280 - 1289.
[19] Todd L, Mullen M, Olley P, Rabinovitch M. Pulmonary toxicity of monocrotaline differs at critical periods of lung development. Pediatr Res, 1985, 19: 731-737.
[20] Huxtable RJ. Activation and pulmonary toxicity of pyrrolizidine alkaloids. Pharmacol Ther, 1990, 47: 371–389.
[21] Rosenberg HC, Rabinovitch M. Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension [J]. Am J Physiol, 1988, 255: H1484–H1491.
[22] Wilson DW, Segall HJ, Pan LC, et al. Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol, 1992, 22:307–325.
[23] Pan LC, Wilson DW, Segall HJ. Strain differences in the response of Fischer 344 and Sprague-Dawley rats to monocrotaline induced pulmonary vascular disease. Toxicology, 1993, 79:21–35.
[24] Lame MW, Jones AD, Wilson DW, et al. Protein targets of monocrotaline pyrrole in pulmonaryartery endothelial cells. J Biol Chem, 2000, 275:29091–29099.
[25] Van Suylen RJ, Smits JF, Daemen MJ. Pulmonary artery remodeling differs in hypoxia-and monocrotaline-induced pulmonary hypertension [J]. Am J Respir Crit Care Med, 1998, 157: 1423–1428.
[26] Rabinovitch M. EVE and beyond, retro and prospective insights [J]. Am J Physiol Lung Cell Mol Physiol, 1999, 277: L5–L12.
[27] Lappin PB, Roth RA. Hypertrophy and prolonged DNA synthesis in smooth muscle cells characterize pulmonary arterial wall thickening after monocrotaline pyrrole administration to rats. Toxicol Pathol, 1997 Jul-Aug, 25(4):372-80.
[28] Laudi S, Trump S, Schmitz V, et al. Serotonin transporter in pulmonary hypertensive rats treated with atorvastatin [J]. Am J Physiol Lung Cell Mol Physiol, 2007 Sep, 293(3): L630-8.
[29] Souza-Costa DC, Figueiredo-Lopes L, Alves-Filho JC, et al. Protective effects of atorvastatin in rat models of acute pulmonary embolism: involvement of matrix metalloproteinase-9. Crit Care Med, 2007 Jan, 35 (1):239-45.
[30] Rakotoniaina Z, Guerard P, Lirussi F, et al. The protective effect of HMG-CoA reductase inhibitors against monocrotaline-induced pulmonary hypertension in the rat might not be a class effect: comparison of pravastatin and atorvastatin. Naunyn Schmiedebergs Arch Pharmacol, 2006 Dec, 374(3):195-206.
[31] Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol, 2008 Jan, 44(1):14-30.
[32] Yang XR, Lin MJ, Yip KP, Jeyakumar LH, Fleischer S, Leung GP, Sham JS. Multiple ryanodine receptor subtypes and heterogeneous ryanodine receptor-gated Ca2+ stores in pulmonary arterial smooth muscle cells [J]. Am J Physiol Lung Cell Mol Physiol, 2005, 289: L338-L348.
[33] 王颖,李智,刘立宾,丛华等. 肺动脉高压大鼠肺动脉平滑肌细胞 Ryanodine 受体亚型的变化. 中国药理学通报. 2000 Dec, 16(6):628-630.
[34] 谢良地, 欧阳秋芳, 王华军. 地尔硫卓对自发性高血压大鼠左心室舒张功能的影响及其可能的机制. 国际心血管病杂志. 2007, 4:284-288.
[35] Zheng Xia, Hu Shenjiang. Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacologica Sinica, 2005 Jun, 26: 696-704.
[36] Antonella Liantonio, Viviana Giannuzzi, Valentina Cippone. Fluvastatin and atorvastatin affect calcium homeostasis of rat skeletal muscle fibers in vivo and in vitro by impairing the sarcoplasmic reticulum/mitochondria Ca2+-Release System. J. Pharmacol. Exp. Ther., May 2007, 321: 626 - 634.
[37] Sacher J, Weigl L, Werner M, Szegedi C, Hohenegger M.Delineation of myotoxicity induced by 3-hydroxy-3-methylglutaryl CoA reductase inhibitors in human skeletal muscle cells. J Pharmacol Exp Ther., 2005 Sep, 314(3):1032-41.
[1] Rubin LJ,Rich S.Medical management.In:Rubin L,Rich S ,eds.Primary pulmonary hypertension.New York:Marcel Dekker,1997.271-286.
[2] Frank H,Mlczoch J,Huber K,et a1.The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension.Chest,1997,1 12(3):714-721.
[3] Rich S,Kaufmann E,Levy PS.The efect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.N Engl J Med,1992,327(2):76-81.
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