Amlodipine releases nitric oxide from canine coronary microvessels: an unexpected mechanism of action of a calcium channel-blocking agent.
Amlodipine releases nitric oxide from canine coronary microvessels: an unexpected mechanism of action of a calcium channel-blocking agent.
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DOI：
10.1161/01.cir.97.6.576
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发表时间：
1998-02
期刊：
影响因子：
37.8
通讯作者：
Xiaoping Zhang;T. Hintze
中科院分区：
文献类型：
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作者：
Xiaoping Zhang;T. Hintze
背景最近的研究表明，氨氯地平可以降低心力衰竭患者，特别是扩张型心肌病患者的死亡率。一般来说，释放一氧化氮的药物，如有机硝酸盐和血管紧张素转换酶抑制剂，已被证明在治疗心力衰竭方面有实质性的好处。方法与结果我们推测氨氯地平的部分有益作用可能与NO的释放或作用有关。从正常犬心脏分离冠脉微血管，并与增加剂量的钙通道阻滞剂硝苯地平、地尔硫卓和氨氯地平或血管紧张素转换酶抑制剂依那普利拉和雷米普利孵育。硝苯地平和地尔硫卓在所研究的任何剂量下都不能增加亚硝酸盐的产生。与之形成鲜明对比的是，氨氯地平使亚硝酸盐的产量从74+/-5增加到130+/-8 pmol/mg(增加85+/-21%，10(-5)mol/L，P<；0.05)，其幅度与两种血管紧张素转换酶抑制剂中的任何一种相似。氨氯地平还增加了大冠状动脉和主动脉中亚硝酸盐的生成。N(Omega)-硝基-L-精氨酸甲酯、HOE-140和二氯异香豆素基本上阻断了亚硝酸盐产生的增加，表明(1)亚硝酸盐的产生反映了NO的形成，(2)亚硝酸盐的产生依赖于激动素受体的刺激，以及(3)亚硝酸盐的产生最有可能是局部激动素的形成。结论与硝苯地平和地尔硫卓不同，氨氯地平从血管释放NO。
BACKGROUND Recent studies suggest that amlodipine may reduce mortality in patients with heart failure, especially those with dilated cardiomyopathy. In general, drugs that release NO, such as organic nitrates and ACE inhibitors, have been shown to be of substantial benefit in the treatment of heart failure. METHODS AND RESULTS We hypothesized that a portion of the beneficial actions of amlodipine may involve the release or action of NO. Coronary microvessels were isolated from the heart of normal dogs and incubated with increasing doses of the calcium channel blockers nifedipine, diltiazem, and amlodipine or the ACE inhibitors enalaprilat and ramiprilat. Neither nifedipine nor diltiazem increased nitrite production at any dose studied. In marked contrast, amlodipine caused a dose-dependent increase in nitrite production from 74+/-5 to 130+/-8 pmol/mg (by 85+/-21%,10(-5) mol/L, P<.05) that was similar in magnitude to that of either of the ACE inhibitors. Amlodipine also increased nitrite production in large coronary arteries and in aorta. N(omega)-Nitro-L-arginine methyl ester, HOE-140, and dichloroisocoumarin essentially abolished the increase in nitrite production, indicating that (1) nitrite production reflected NO formation, (2) nitrite production was dependent on stimulation of the kinin2 receptor, and (3) nitrite production is most likely secondary to the formation of local kinins. CONCLUSIONS Thus, unlike nifedipine and diltiazem, amlodipine releases NO from blood vessels.