摘要
第一部分PM_(2.5)对正常及动脉粥样硬化大鼠离体心脏心律及冠脉血流的影响
研究目的:通过研究PM_(2.5)对正常及动脉粥样硬化大鼠离体心脏心率、心律及冠脉血流的影响,探讨PM_(2.5)对动脉粥样硬化大鼠心脏毒性作用的可能机制。
研究方法:36只雄性Wistar-kyoto(WKY)大鼠,随机分为:正常对照组和动脉粥样硬化组。正常对照组大鼠给予基础饲料和普通自来水;动脉粥样硬化组给予动脉粥样硬化饲料(4%胆固醇,0.5%胆酸钠,0.2%丙基硫氧嘧啶,10%猪油,维生素D_31.25×10U/kg和85.3%基础饲料)和普通自来水,肌注维生素D_330万U/kg,共喂养12周,12周后动脉粥样硬化大鼠模型制作成功。两组大鼠制备离体灌注的Langendorff心脏,分别给予0.25%、0.5%、1%的PM_(2.5)酸溶性成份(ASC)溶液及硝苯地平10mg灌注,记录心电图(ECG),分析心率(HR)和心律失常的发生情况;分别测量两组大鼠基础状态下、PM_(2.5)ASC灌注后、硝苯地平灌注后的冠脉血流(CF)。
研究结果:1、PM_(2.5)引起实验大鼠HR明显减慢,呈剂量依赖性。其中0.25%、0.5%、1%PM_(2.5)分别使正常对照组大鼠的HR由(268.50±10.58)、(269.67±7.01)、(269.33±7.94)次/分分别减慢为(229.17±12.27)、(180.67±8.17)、(140.33±8.36)次/分;使动脉粥样硬化组大鼠的HR由(274.83±13.27)、(275.17±9.41)、(273.50±7.79)次/分分别减慢为(223.17±10.82)、(170.67±9.75)、(135.50±7.94)次/分。给予PM_(2.5)前后HR比较具有显著性差异(P＜0.001),两组间HR比较无统计学差异,浓度与组间交互作用有显著性(P＜0.001)。硝苯地平灌注后各组HR与灌注前比较无显著性变化(P＞0.05)。2、PM_(2.5)引起CF明显下降,呈剂量依赖性。0.25%、0.5%、1%PM_(2.5)分别使正常对照组大鼠的CF由(8.82±0.87)、(8.90±0.81)、(8.83±0.89)ml/min分别下降到(7.02±0.86)、(5.25±0.87)、(4.32±0.81)ml/min;使动脉粥样硬化组大鼠的CF由(7.95±0.92)、(7.92±0.81)、(7.98±1.41)ml/min下降到(6.30±1.06)、(3.73±0.79)、(3.23±0.72)ml/min。给予PM_(2.5)前后CF比较具有显著性差异(P＜0.001),给予0.25%、1%PM_(2.5)的两组间CF比较无统计学差异,浓度与组间交互作用无显著性。给予0.5%PM_(2.5)的两组间CF比较有显著性差异,浓度与组间交互作用有显著性。硝苯地平干预后两组CF均有所恢复(P＜0.001)。3、PM_(2.5)引起室性心律失常,其发生率和严重程度呈剂量依赖性。动脉粥样硬化组大鼠室性心动过速(VT)的发生时间提前(7.19±2.48)vs(12.83±2.79)分(P＜0.05),而且明显延长了动脉粥样硬化组大鼠的VT累加时间(109.50±18.51)vs(57.67±12.96)秒(P＜0.05)。
研究结论:1、PM_(2.5)可对正常及动脉粥样硬化大鼠心脏产生直接影响,而不依赖PM_(2.5)对肺的作用。2、PM_(2.5)可引起离体灌注的Langendorff心脏心率减慢、冠脉血流减少,诱发室性心律失常的发生。可以解释与PM_(2.5)暴露相关的缺血性心脏病发生率增加的原因。3、PM_(2.5)对动脉粥样硬化大鼠心脏毒性作用更强,PM_(2.5)可引起动脉粥样硬化病变进展。
第二部分PM_(2.5)致动脉粥样硬化大鼠在体心脏心肌梗死的实验研究
研究目的:通过PM_(2.5)短期暴露致正常及动脉粥样硬化大鼠心肌梗死的作用,探讨PM_(2.5)对动脉粥样硬化大鼠在体心脏的毒性作用及可能机制。
研究方法:40只雄性WKY正常大鼠,随机分为两组:正常对照组和动脉粥样硬化组。12周造模成功后,两组分别进行腹腔内注射戊巴比妥钠(40mg/kg)麻醉后,气管滴入10mg/kg体重的PM_(2.5)ASC溶液。观察PM_(2.5)ASC暴露前、暴露后1小时的HR,暴露前、暴露后2小时的血压(BP)改变情况;观察PM_(2.5)ASC暴露前、暴露后24小时血清心肌肌钙蛋白T(cTnT)、血清高敏C反应蛋白(hs-CRP)、血浆D-二聚体(D-dimer)、血浆纤溶酶原激活物抑制剂-1(PAI-1)水平(酶联免疫吸附法)和血清白介素-6(IL-6)(放射免疫法)表达水平。
研究结果:1、PM_(2.5)引起HR增快:正常组由基础状态的(282.10±10.52)次/分增加到(286.05±16.87)次/分,动脉粥样硬化组由基础状态的(291.10±9.70)次/分增加到(297.00±14.33)次/分。PM_(2.5)滴注后,两组HR均增快(P＜0.01),组间有差别(P＜0.05)。2、PM_(2.5)引起BP升高:正常组由基础状态的(105.50±6.58/91.65±7.00)mmHg升高到(108.45±9.65/95.55±10.48)mmHg,动脉粥样硬化组由基础状态的(108.20±6.98/92.50±6.79)mmHg升高到(113.40±9.91/99.35±10.03)mmHg。PM_(2.5)滴注后,两组BP均升高(P＜0.001),组间无差别(P＞0.05)。3、PM_(2.5)可诱发急性心肌梗死(AMI)的发作,正常对照组2/20只大鼠发生AMI,动脉粥样硬化组8/20只大鼠发生AMI。4、(1)PM_(2.5)引起正常大鼠及动脉粥样硬化大鼠血清IL-6(P＜0.001)、血清hs-CRP(P＜0.001)、血浆D-dimer(P＜0.01)、血浆PAI-1(P＜0.001)水平升高;(2)PM_(2.5)滴注前后血清IL-6(P＜0.001)、血清hs-CRP水平(P＜0.001)、血浆D-dimer(P＜0.01)、血浆PAI-1水平(P＜0.05)动脉粥样硬化组较正常对照组高。(3)PM_(2.5)滴注后动脉粥样硬化组中血浆D-dimer非梗死组vs梗死组为(4.44±1.80)ng/dl vs(16.98±7.26)ng/dl(P＜0.01)。PM_(2.5)滴注后动脉粥样硬化组中血浆PAI-1非梗死组vs梗死组为(73.67±32.88)ng/dl vs(142.50±28.70)ng/dl(P＜0.001)。
研究结论:1、PM_(2.5)短期暴露可诱发急性心肌梗死的发作,动脉粥样硬化组大鼠急性心肌梗死的发生率高。提示动脉粥样硬化大鼠对PM_(2.5)的心血管毒性作用更敏感。2、PM_(2.5)对心血管系统产生毒性作用可能主要通过两条途径:一是通过引起炎症反应及继发的高凝状态,二是通过改变自主神经功能。
Part 1 Effects of PM_(2.5) on Heart Rate,Rhythm and Coronary Flow in in-vitro Hearts of Normal and Atherosclerosis Rats
Objective:To explore the possible mechanism of PM_(2.5) inducing cardiatoxicity of atherosclerosis rats by observing effects of PM_(2.5) on heart rate,arrhythmia and coronary flow in normal and atherosclerosis rats.
Method:36 male Wistar-kyoto(WKY) rats were randomly divided into 2 groups:normal and atherosclerosis group.The rats in normal group were fed with basic food and water.The rats in atherosclerosis group were fed with atherosclerosis diets(4%cholesterol,0.5%sodium cholate,0.2%propylthiouracil,10%leaf fat,1.25×10U/kg body cholecalciferol,85.3%basic food) and were injected with 300,000 U/kg body cholecalciferol in right legs.The rats were fed 12 weeks.After 12 weeks of atherosclerosis diets,atherosclerosis rat model were successfully made.Isolated perfused Langendorff hearts were preparated.0.25%,0.5%,1%PM_(2.5) acide-soluble components(ASC) solution and 10mg nifedipine were perfused respectively. Electrocardiogram(ECG) was recorded for analyzing heart rate(HR) and cardiac arrhythmias. Coronary flow(CF) was measured in baseline and after PM_(2.5) ASC perfusion and after nifedipine perfusion.
Results:(1) PM_(2.5) dose-dependently decreased HR significantly.0.25%,0.5%and 1% PM_(2.5) decreased HR to(229.17±12.27)、(180.67±8.17)、(140.33±8.36)BPM,respectively,from (268.50±10.58)、(269.67±7.01)、(269.33±7.94)BPM in normal group and decreased HR to (223.17±10.82)、(170.67±9.75)、(135.50±7.94)BPM,respectively,from(274.834±13.27)、(275.17±9.41)、(273.50±7.79)BPM in atherosclerosis group.There were significant changes of HR between before and after PM_(2.5)(P＜0.001).There were no significant changes between the two groups.There were no significant changes of HR after nifedipine perfusion(P＞0.05).(2) PM_(2.5) dose-dependently reduced CF.0.25%,0.5%and 1%PM_(2.5) reduced CF to(7.02±0.86)、(5.25±0.87)、(4.32±0.81)ml/min,respectively,from(8.82±0.87)、(8.90±0.81)、(8.83±0.89)ml/min in normal group and reduced CF to(6.30±1.06)、(3.73±0.79)、(3.23±0.72)ml/min,respectively,from(7.95±0.92)、(7.92±0.81)、(7.98±1.41)ml/min in atherosclerosis group.There were significant changes of CF between before and after PM_(2.5) (P＜0.001).CF of two groups restored after perfusing nifedipine(P＜0.001).(3) PM_(2.5) dose-dependently triggered cardiac arrhythmias.1%PM_(2.5) made ventricular tachycardia(VT) occurrence ahead of time(7.19±2.48) minutes in atherosclerosis group vs(12.83±2.79) minutes in normal group and prolonged accumulated VT time to(109.50±18.51) seconds in atherosclerosis group vs(57.67±12.96) seconds in normal group.
Conclusion:(1) PM_(2.5) has a direct effect on cardiovascular system,independent of the effect of PM_(2.5) on pulmonary circulation.(2) PM_(2.5) decreases HR,reduces CF and triggers venticular arrhythmias in isolated perfused hearts,which may explain the increase in the incidence of ischemic heart diseases in clinic association with elevated PM_(2.5) exposure.(3) PM_(2.5) has bigger cardiotoxicity to atherosclerosis rats.PM_(2.5) makes atherosclerosis progress.
Part 2 Experiment investigation of PM_(2.5) Inducing Acute Myocardial Infarction in in-vivo Atherosclerosis Rats
Objiective:To explore the effects and the possible mechanism of PM_(2.5) causing cardiotoxicity of atherosclerosis rats by triggering acute myocardial infarction(AMI) in normal and atherosclerosis rats.
Methods:40 male Wistar-kyoto(WKY) rats were randomly divided into 2 groups:normal and atherosclerosis group.Atherosclerosis rat models were successfully established by fed with atherosclerosis diets for 12 weeks.After anaesthesia by intraperitoneally injected with pentobarbitone 40mg/kg body weight,two groups rats were exposed by intratracheal instillation of PM_(2.5) solution 10mg/kg body weight.Heart rate(HR) was recorded in baseline(before instillation of PM_(2.5)) and after PM_(2.5) exposure 1 hour.Blood pressure(BP) was measured in baseline and after PM_(2.5) exposure 2 hours.Blood markers:serum cardiac troponin T(cTnT), serum high sensitive C-reactive protein(hs-CRP),serum interleukin-6(IL-6),plasma D-dimer, plasma plasminogen activator inhibitor-1(PAI-1) were measured in baseline and after PM_(2.5) exposure 24 hours by enzyme linked immunosorbent assay and radio-immunity assay.
Results:1.PM_(2.5) induced HR increase.HR increased to(286.05±16.87) BPM from (282.10±10.52) BPM in normal group and increased to(297.00±14.33) BPM from(291.10±9.70) BPM in atherosclerosis group.HR of two groups increased after instillating PM_(2.5)(P＜0.01). There were significant changes of HR between two groups(P＜0.05).2.PM_(2.5) induced BP increase.BP increased to(108.45±9.65/95.65±10.48)mmHg from (105.50±6.58/91.65±7.00)mmHg in normal group and increased to (113.40±9.91/99.35±10.03)mmHg from(108.20±6.98/92.50±6.79)mmHg in atherosclerosis group.BP of two groups increased after instillating PM_(2.5)(P＜0.001).There were no significant changes of BP between two groups(P＞0.05).3.PM_(2.5) triggered onset of AMI.2/20 rats occurred AMI in normal group and 8/20 rats occurred AMI in atherosclerosis group.4.(1) PM_(2.5) increased serum IL-6(P＜0.001),serum hs-CRP(P＜0.001),plasma D-dimer(P＜0.01) and plasma PAI-1(P＜0.001) concentration.(2) The serum concentration of IL-6,hs-CRP and plasma D-dimer,PAI-1 were higher in atherosclerosis group both before and after PM_(2.5) instillation.(3) After PM_(2.5) instillation,the level of plasma D-dimer and PAI-1 were significantly higher in atherosclerosis rats with AMI.The level of plasma D-dimer is(4.44±1.80)ng/dl vs (16.98±7.26)ng/dl(P＜0.01) of non-AMI vs AMI group.The level of plasma PAI-1 is (73.67±32.88) ng/dl vs(142.50±28.70 ) ng/dl(P＜0.001) of non-AMI vs AMI group.
Conclusion:(1) PM_(2.5) short-term exposure triggers onset of AMI.AMI incidence is higher in atherosclerosis group.The atherosclerosis rats are more susceptible to PM_(2.5) than normal rats. (2) PM_(2.5) causes adverse effects on cardiovascular system by two passways:inflammation and changes of autonomic nervous function.
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