Xu Rui, Zhang Yun, Zhang Mei, Li Xiu-chang, Cai Heng, Chen Wen-qiang, Zhu Hui, Ge Zhi-ming, Zhang Wei
Department of Cardiology, Qilu Hospital of Shandong University, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan 250012, China.
Zhonghua Yi Xue Za Zhi. 2005 Nov 30;85(45):3199-204.
To evaluate the effects of losartan, an angiotensin receptor blocker, ramipril, an angiotensin converting enzyme inhibitor, and their combination on left ventricular remodeling and diastolic function in SHR at the same level of blood pressure.
Sixty-two SHRs and 20 WKYs were divided randomly into 5 groups: WKY-control group, SHR-control group, SHR-ramipril group, SHR-losartan group, and SHR-combination group. Twelve weeks after feeding, 6 rats from each group were randomly selected to undergo hemodynamic examination and then killed to undergo further examinations, and 24 weeks after the remaining rats underwent the same examinations. The hemodynamic examination included the systolic blood pressure (SBP) of the caudal artery, left ventricular systolic pressure (LVSP), left ventricle end diastolic pressure (LVEDP), maximum uprising velocity of left ventricle pressure (dP/dtmax), and maximum declining velocity of left ventricle pressure (-dP/dtmax), and tau. Then the hearts were taken out to measure the weight of heart, undergo pathological examination, measure the intracellular free calcium concentrations, hydroxyproline concentration, interstitial collagen volume fraction (CVF), perivascular collagen area/luminal area (PVCA/LA), the mRNA expression of SR Ca(2+)-ATPase, phospholamban and L-type calcium channel, and the protein levels of SR Ca(2+)-ATPase. The myocardial ultrastructure was analyzed by electron microscopy.
The speed, extent, and sustained time of blood pressure decrease were better in the combination group than in the other 2 treatment groups. Twelve and 24 weeks after treatment the levels of LVM/BW in the combination group were significantly lower than those of the control group, however, without significant differences among the 3 treatment groups. The values of LVSP, LVEDP, and tau 12 and 24 weeks after treatment in the 3 treatment groups were all significantly lower and the levels of -dP/dtmax significantly higher than those of the control group (all P < 0.01). The values of CVF in the myocardium and PCVA/VA of the heart wall arteriole 12 and 24 weeks after in the 3 treatment groups were significantly lower than those of the control group, and the CVF in the myocardium 12 weeks after in the combination group was significantly than that of the ramipril group. Microscopy showed that the degree of myocardial fibrosis in the 3 treatment groups were significantly milder than those of the control group, and the ultrastructure improvement improved along with the lapse of time in the sequence of combination group > losartan group > ramipril group. The concentrations of hydroxyproline in cardiac muscle cells of the 3 treatment 12 and 24 weeks after were significantly than those of the control group and decreased gradually time-dependently. The expression of Ca(2+)-ATPase mRNA 24 weeks after of the ramipril, losartan, and combination groups were 53.5%, 72.9%, and 76.7% higher than that of the control group, and the Ca(2+)-ATPase protein expression of the 3 treatment groups were 28.9%, 33.3%, and 49.3% higher than that of the control group. The expression of L-type Ca(2+) channel mRNA of the 3 treatment groups were 51.8%, 76.8%, and 98.2% than that of the control group.
Both losartan and ramipril reverse LVH and left ventricular diastolic dysfunction. A combination of these two drugs is more effective than single drug treatment for improvement of myocardial fibrosis and ultrastructure. All three-treatment groups can raise calcium-handling proteins mRNA and protein expressions, which may be the underlying molecular mechanisms for their therapeutic effects.
在血压处于同一水平的情况下,评估血管紧张素受体阻滞剂氯沙坦、血管紧张素转换酶抑制剂雷米普利及其联合用药对自发性高血压大鼠(SHR)左心室重构和舒张功能的影响。
将62只SHR和20只WKY大鼠随机分为5组:WKY对照组、SHR对照组、SHR-雷米普利组、SHR-氯沙坦组和SHR联合用药组。喂养12周后,每组随机选取6只大鼠进行血流动力学检查,然后处死进行进一步检查,其余大鼠在24周后进行相同检查。血流动力学检查包括尾动脉收缩压(SBP)、左心室收缩压(LVSP)、左心室舒张末期压力(LVEDP)、左心室压力最大上升速度(dP/dtmax)、左心室压力最大下降速度(-dP/dtmax)以及时间常数(tau)。然后取出心脏测量心脏重量,进行病理检查,测量细胞内游离钙浓度、羟脯氨酸浓度、间质胶原容积分数(CVF)、血管周围胶原面积/管腔面积(PVCA/LA)、肌浆网Ca(2+)-ATP酶、受磷蛋白和L型钙通道的mRNA表达以及SR Ca(2+)-ATP酶的蛋白水平。通过电子显微镜分析心肌超微结构。
联合用药组血压下降的速度、幅度和持续时间优于其他2个治疗组。治疗12周和24周后,联合用药组的左心室重量指数(LVM/BW)水平显著低于对照组,但3个治疗组之间无显著差异。3个治疗组治疗12周和24周后的LVSP、LVEDP和tau值均显著低于对照组,-dP/dtmax水平显著高于对照组(均P < 0.01)。3个治疗组治疗12周和24周后心肌中的CVF值以及心脏壁小动脉的PCVA/VA均显著低于对照组,联合用药组治疗12周后心肌中的CVF显著低于雷米普利组。显微镜检查显示,3个治疗组的心肌纤维化程度均显著轻于对照组,超微结构改善情况随时间推移依次为联合用药组>氯沙坦组>雷米普利组。3个治疗组治疗12周和24周后心肌细胞中的羟脯氨酸浓度均显著低于对照组,并随时间呈逐渐下降趋势。雷米普利组、氯沙坦组和联合用药组治疗24周后的Ca(2+)-ATP酶mRNA表达分别比对照组高53.5%、72.9%和76.7%,3个治疗组的Ca(2+)-ATP酶蛋白表达分别比对照组高28.9%、33.3%和49.3%。3个治疗组的L型Ca(2+)通道mRNA表达分别比对照组高51.8%、76.8%和98.2%。
氯沙坦和雷米普利均可逆转左心室肥厚和左心室舒张功能障碍。这两种药物联合使用在改善心肌纤维化和超微结构方面比单一药物治疗更有效。所有3个治疗组均可提高钙处理蛋白的mRNA和蛋白表达,这可能是其治疗作用的潜在分子机制。