Additive beneficial effects of the combination of a calcium channel blocker and an angiotensin blocker on a hypertensive rat-heart failure model
Additive beneficial effects of the combination of a calcium channel blocker and an angiotensin blocker on a hypertensive rat-heart failure model
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DOI：
10.1291/hypres.27.771
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发表时间：
2004-10-01
影响因子：
5.4
通讯作者：
Iwao, H
中科院分区：
文献类型：
--
作者：
Kim-Mitsuyama, S;Izumi, Y;Iwao, H
本研究观察了钙通道阻滞剂氮卓尼地平(1 mg/kg/d)、血管紧张素转换酶(ACE)抑制剂替莫普利(10 mg/kg/d)、血管紧张素111型(AT1)受体阻滞剂(ARB)、奥美沙坦(5 mg/kg/d)及其合用对Dahl盐敏感大鼠(DS)心力衰竭后收缩功能的影响。DS大鼠从7周龄开始喂食高盐饮食(8%氯化钠)，并逐渐发展为高血压。与替莫普利或奥美沙坦单药治疗相比，阿齐尼地平单药治疗对DS大鼠的降压作用更明显，但对心肌肥厚、心肌纤维化、脑钠尿肽、转化生长因子-β1、I型胶原、III型胶原和单核细胞趋化蛋白-1mRNA的表达(Northern印迹分析估计)和心脏舒张期功能障碍(超声心动图估计)的影响相似。这些结果表明，血管紧张素转换酶和血管紧张素转换酶AT1受体以及高血压参与了DS大鼠心脏收缩功能保留的心力衰竭的发生。阿泽尼地平与奥美沙坦或替莫普利合用对DS大鼠无相加降压作用，对心肌肥厚或基因表达也无相加作用。然而，联合用药对DS大鼠存活率的延长作用比阿泽尼地平(P<；0.01)或替莫普利(P<；0.05)更明显，而且联合治疗的这种相加的有益作用与更大程度地减少心肌纤维化、尿白蛋白排泄和血肌酐有关。因此，我们的结果表明，钙通道阻滞剂与血管紧张素转换酶抑制剂或血管紧张素转换酶抑制剂联合使用，对收缩功能保持不变的高血压性心力衰竭大鼠具有额外的预防作用。因此，联合应用这些药物似乎是预防高血压性心力衰竭的有效治疗策略。
The present study was undertaken to examine the effects of a calcium channel blocker, azelnidipine (1 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, temocapril (10 mg/kg/day), an angiotensin 11 type 1 (AT1) receptor blocker (ARB), olmesartan (5 mg/kg/day), and their combination on Dahl salt-sensitive rats (DS rats) developing heart failure with preserved systolic function. DS rats were fed a high-salt diet (8% NaCl) from 7 weeks of age and progressively developed hypertension. Although monotherapy with azeinidipine lowered the blood pressure of DS rats to a greater extent than monotherapy with temocapril or olmesartan, the three drugs had similar effects on cardiac hypertrophy, cardiac fibrosis, the expressions of brain natriuretic peptide, transforming growth factor-beta1, collagen I, collagen III and monocyle chemoattractant protein-1 mRNA (as estimated by Northern blot analysis), and cardiac diastolic dysfunction (as estimated by echocardiography). These results show that ACE and AT1 receptor, as well as hypertension, are involved in the development of heart failure with preserved systolic function in DS rats. The combination of azelnidipine with olmesartan or temocapril produced no additive hypotensive effect in DS rats and no additive effect on cardiac hypertrophy or gene expressions. However, the combination therapy prolonged the survival rate of DS rats more than azelnidipine (p < 0.01) or temocapril alone (p < 0.05), and this additive beneficial effect by the combination therapy was associated with a greater reduction of cardiac fibrosis, urinary albumin excretion and serum creatinine. Our results thus showed that the combination of a calcium channel blocker with an ARB or an ACE inhibitor had additive preventive effects on a rat model of hypertensive heart failure with preserved systolic function. Thus, combination therapy with these agents seems to be a useful therapeutic strategy for the prevention of hypertensive heart failure.