血管紧张素 II 受体阻滞剂（坎地沙坦）与血管紧张素转换酶抑制剂（喹那普利）对扩张型心肌病大鼠的比较效应。

Comparative effects of angiotensin II receptor blockade (candesartan) with angiotensin-converting enzyme inhibitor (quinapril) in rats with dilated cardiomyopathy.

作者信息

Watanabe Kenichi, Juan Wen, Narasimman Gurusamy, Ma Meilei, Inoue Mikio, Saito Yuki, Wahed Mir I I, Nakazawa Mikio, Hasegawa Go, Naito Makoto, Tachikawa Hitoshi, Tanabe Naohito, Kodama Makoto, Aizawa Yoshifusa, Yamamoto Tadashi, Yamaguchi Kenichi, Takahashi Toshihiro

机构信息

Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata City, Japan.

出版信息

J Cardiovasc Pharmacol. 2003 Jan;41 Suppl 1:S93-7.

PMID:12693379

Abstract

Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure, but their inhibitory actions on angiotensin I-induced increases in blood pressure in heart failure are not clear. Angiotensin I blocking and cardioprotective properties of the angiotensin II receptor blocker candesartan and the angiotensin-converting enzyme inhibitor quinapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Low-dose candesartan (0.5 mg/kg) showed the same angiotensin I blocking action as high-dose quinapril (20 mg/kg) in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (43/58, 74%) were divided into three groups and given quinapril at 20 mg/kg per day (group Q, n = 14), candesartan at 0.5 mg/kg per day (group C, n = 14) or vehicle alone (group V, n = 15). After oral administration for 1 month, four of 15 (27%) rats in group V and two of 14 (14%) in group C died. None of the animals in group Q died. Although angiotensin II levels of the blood and the left ventricle in group V [367 +/- 26 and 437 +/- 18% versus normal rats (group N)] were significantly higher than those in group N (both p < 0.01), they were reduced in group Q (88 +/- 32 and 169 +/- 53%, both p < 0.01). The left ventricular end-diastolic pressure and the area of myocardial fibrosis were lower, and the first derivative +/-dP/dt was higher in group Q (7.0 +/- 1.7 mmHg, 9 +/- 3% and +3451+/- 170/-3182 +/- 186 mmHg/s, respectively) than in group V (16.7 +/- 1.3 mmHg, 36 +/- 6% and +2601 +/- 235/-2156 +/- 257 mmHg/s, respectively) and in group C (11.2 +/- 2.0 mmHg, 26 +/- 4% and +3063 +/- 164/-2734 +/- 174 mmHg/s, respectively). Although levels of expression of transforming growth factor beta1 and collagen III mRNA in groupV (367 +/- 26 and 437 +/- 18% versus group N) were significantly higher than those in group N (both p < 0.01), they were reduced in group Q (88 +/- 32 and 169 +/- 53%, both p < 0.01). These results suggested that although low-dose candesartan can block increases in blood pressure with circulating angiotensin I to the same extent as high-dose quinapril, it does not confer sufficient protection against injury from the renin-angiotensin system in heart failure.

摘要

血管紧张素II受体阻滞剂和血管紧张素转换酶抑制剂已被证明可降低心力衰竭患者的发病率和死亡率，但其对心力衰竭患者中血管紧张素I诱导的血压升高的抑制作用尚不清楚。在自身免疫性心肌炎后扩张型心肌病大鼠模型中，研究了血管紧张素II受体阻滞剂坎地沙坦和血管紧张素转换酶抑制剂喹那普利的血管紧张素I阻断和心脏保护特性。低剂量坎地沙坦（0.5mg/kg）在心力衰竭大鼠中显示出与高剂量喹那普利（20mg/kg）相同的血管紧张素I阻断作用。免疫后28天，存活的Lewis大鼠（43/58，74%）分为三组，分别给予每天20mg/kg的喹那普利（Q组，n = 14）、每天0.5mg/kg的坎地沙坦（C组，n = 14）或单独给予赋形剂（V组，n = 15）。口服给药1个月后，V组15只大鼠中有4只（27%）死亡，C组14只大鼠中有2只（14%）死亡。Q组无动物死亡。虽然V组血液和左心室中的血管紧张素II水平[与正常大鼠（N组）相比为367±26和437±18%]显著高于N组（均p < 0.01），但在Q组中降低（分别为88±32和169±53%，均p < 0.01）。Q组的左心室舒张末期压力和心肌纤维化面积较低，而一阶导数±dP/dt较高（分别为7.0±1.7mmHg、9±3%和+3451±170/-3182±186mmHg/s），高于V组（分别为16.7±1.3mmHg、36±6%和+2601±235/-2156±257mmHg/s）和C组（分别为11.2±2.0mmHg、26±4%和+3063±164/-2734±174mmHg/s）。虽然V组中转化生长因子β1和胶原蛋白III mRNA的表达水平（与N组相比为367±26和437±18%）显著高于N组（均p < 0.01），但在Q组中降低（分别为88±32和169±53%，均p < 0.01）。这些结果表明，虽然低剂量坎地沙坦可以在与高剂量喹那普利相同的程度上阻断循环血管紧张素I引起的血压升高，但它对心力衰竭中肾素-血管紧张素系统损伤的保护作用不足。