联合瑞舒伐他汀和氨氯地平对老龄自发性高血压大鼠心脏保护作用的研究

Cardiac protective effects of rosuvastatin and amlodipine in elderly spontaneous hypertensive rats

目的研究联合瑞舒伐他汀和氨氯地平对老龄自发性高血压大鼠(spontaneously hypertensive rat,SHR)心脏保护作用。方法选取20月龄雄性SHR及年龄匹配的雄性(Wistar Kyoto,WKY)大鼠,分为WKY对照组、SHR空白组、SHR瑞舒伐他汀组、SHR氨氯地平组、SHR瑞舒伐他汀-氨氯地平组(联合用药组),每组10只。氨氯地平10 mg/kg/d,瑞舒伐他汀钙40mg/kg/d,喂养10周。测量各组大鼠体重、鼠尾动脉血压、血脂;实验结束时心脏超声测量室壁厚度、左心室内径、射血分数、二尖瓣E/A及组织多普勒Sm、Em等指标,左心室插管及股动脉插管行血流动力学检查,测量左心室舒张末压(left ventricular enddiastolic pressure,LVEDP)、左心室内压上升最大速率(+dp/dtmax)、左心室内压下降最大速率(-dp/dtmax)、舒张时间常数τ。结果瑞舒伐他汀组用药前后无创血压无明显变化,氨氯地平和联合用药组用药前后血压明显下降;SHR空白组心肌间质纤维化较WKY对照组明显增加,而氨氯地平和瑞舒伐他汀组心肌间质纤维化较SHR空白组明显减轻,联合用药组SHR心肌间质纤维化较各单药组进一步显著减轻;各SHR组左心室舒张末期室间隔和左心室后壁较WKY对照组均显著增厚,左心室内径、射血分数、E/A、Sm各组间均未见显著差异,但SHR的E/Em显著升高,3用药组E/Em均较SHR空白组明显回落;各组间+dP/dtmax未见显著性差异。与WKY对照组比较,SHR空白组的-dP/dtMax、左心室舒张末压和舒张时间常数τ均显著升高,氨氯地平组和瑞舒伐他汀组较SHR空白组有明显回落,联合用药组则进一步降至与WKY对照组一致的水平;TUNEL染色心肌细胞凋亡指数明显升高,氨氯地平和瑞舒伐他汀组较SHR空白组明显下降,联合用药组则进一步降至WKY对照同等水平。结论瑞舒伐他汀在氨氯地平降压的基础上,可以进一步逆转老龄大鼠心肌纤维化,改善左心室舒张功能。

Objective To explore the role of rosuvastatin and amlodipine in cardiac protective effects on elderly spontaneously hypertensive rats （SHR）. Methods Fourty male 20-month-old SHRs were randomly assigned to four groups： rosuvastatin group, amlodipine group, rosuvastatin-amlodipine combination group and SHR control group. The rats were given 40 mg/kg/d rosuvastatin, 10 mg/kg/d amlodipine, both for 10 weeks. Age-matched male Wistar Kyoto （WKY） rats were set for control. Left ventricular （LV） interventricular septal and posterior wall thickness 0VST and PWT）,LV end-diastolic dimension （LVEDD）, IN end-systolic dimension （LVESD）,and LV ejection fraction （LVEF）. The E/A ratio and the septal mitral annulus systolic and early diastolic velocity （Sin and Em） were also assessed. Invasive left ventricular hemodynamic measurement was performed. LV end-diastolic pressure （LVEDP）, maximal slope of systolic pressure increment （＋ dP/dtmax） and diastolic pressure decrement （-dP/dtmax）, time constant of LV pressure decay （τ） were all calculated. Results Blood pressure decreased significantly after treatment of amlodipine alone or combined with rosuvastatin. Interstitial fibrosis deposition increased significantly in SHR control group and decreased significantly in amlodipine and rosuvastatin group. Co-administration of both medications gave rise to an even more significant decrease in interstitial fibrosis deposition. There was a significant increase in IVST and PWT and no alteration in LVEDD,LVEF,E/A ratio or Sm in SHR groups. The E/Era ratio rose significantly in SHR groups,but decreased significantly in groups with medication compared to SHR control. There was no significant difference in ＋dP/dtmax among the study groups. -dP？dtMax,LVEDP and τ increased significantly in StIR control but decreased significantly in amlodipine and rosuvastatin group. Co-administration group shared the same level of these values with WKY control. SHR control represented increased plasma and cardiac MDA concentration and a higher apoptosis index, which was ameliorated in both medication groups and even to the same level of WKY control in co-administration group. Conclusion In elderly SHR with amlodipine, rosuvastatin can further reverse cardiac fibrosis deposition and improve IN diastolic function.