Mital S, Loke K E, Slater J P, Addonizio L, Gersony W M, Hintze T H
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Am J Cardiol. 1999 Jun 17;83(12A):92H-98H. doi: 10.1016/s0002-9149(99)00269-6.
The production of endogenous nitric oxide, which regulates myocardial oxygen consumption, is decreased in heart failure. As with angiotensin-converting enzyme (ACE) inhibitors, amlodipine, a calcium antagonist, increases kinin-mediated nitric oxide production in coronary microvessels. We investigated the possibility of synergy between ACE inhibitors and amlodipine in regulating myocardial oxygen consumption. Left ventricular myocardium was isolated from 6 healthy dog hearts and 5 human hearts with end-stage heart failure at the time of orthotopic heart transplantation. Myocardial oxygen consumption was measured before and after administration of bradykinin, S-nitroso N-acetyl penicillamine (SNAP, a nitric oxide donor), ramiprilat (an ACE inhibitor), amlodipine, and the combination of a sub-threshold dose of ramiprilat (10(-8) md/L) + amlodipine. These experiments were repeated with L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthesis), dichloroisocoumarin (an inhibitor of kinin synthesis), and HOE 140 (a B2 kinin-receptor antagonist). Baseline myocardial oxygen consumption in canine hearts was 182 +/- 21 nmol/g/min. Bradykinin and SNAP caused dose-dependent reductions in myocardial oxygen consumption (p <0.05). Ramiprilat and amlodipine caused a 10 +/- 3.2% and 11 +/- 0.8% reduction in myocardial oxygen consumption, respectively, when used alone (p <0.05). In the presence of a subthreshold dose of ramiprilat, amlodipine caused a larger (15 +/- 1.7%) reduction in myocardial oxygen consumption compared with either drug used alone (p <0.05). In human hearts, baseline myocardial oxygen consumption was 248 +/- 57 nmol/g/min. Amlodipine caused a larger reduction in myocardial oxygen consumption when used with ramiprilat (22 +/- 3.2%) as compared with amlodipine alone (15 +/- 2.6%). The effect of both drugs was attenuated by L-NAME, dichloroisocoumarin, and HOE 140 (p <0.05). In conclusion, ACE inhibitors and amlodipine act synergistically to regulate myocardial oxygen consumption by modulating kinin-mediated nitric oxide release, and this combination of drugs may be useful in the treatment of heart failure.
内源性一氧化氮的生成在心力衰竭时会减少，而内源性一氧化氮可调节心肌耗氧量。与血管紧张素转换酶（ACE）抑制剂一样，钙拮抗剂氨氯地平可增加冠状动脉微血管中缓激肽介导的一氧化氮生成。我们研究了ACE抑制剂与氨氯地平在调节心肌耗氧量方面协同作用的可能性。从6只健康犬心脏以及5例原位心脏移植时处于终末期心力衰竭的人心脏中分离出左心室心肌。在给予缓激肽、S-亚硝基-N-乙酰青霉胺（SNAP，一种一氧化氮供体）、雷米普利拉（一种ACE抑制剂）、氨氯地平以及亚阈值剂量的雷米普利拉（10⁻⁸ mol/L）+氨氯地平组合前后，测量心肌耗氧量。使用L-硝基-精氨酸甲酯（L-NAME，一种一氧化氮合成抑制剂）、二氯异香豆素（一种缓激肽合成抑制剂）和HOE 140（一种B2缓激肽受体拮抗剂）重复这些实验。犬心脏的基础心肌耗氧量为182±21 nmol/g/min。缓激肽和SNAP导致心肌耗氧量呈剂量依赖性降低（p<0.05）。单独使用时，雷米普利拉和氨氯地平分别使心肌耗氧量降低10±3.2%和11±0.8%（p<0.05）。在存在亚阈值剂量雷米普利拉的情况下，与单独使用任何一种药物相比，氨氯地平使心肌耗氧量降低幅度更大（15±1.7%）（p<0.05）。在人心脏中，基础心肌耗氧量为248±57 nmol/g/min。与单独使用氨氯地平（15±2.6%）相比，氨氯地平与雷米普利拉联合使用时使心肌耗氧量降低幅度更大（22±3.2%）。L-NAME、二氯异香豆素和HOE 140减弱了两种药物的作用（p<0.05）。总之，ACE抑制剂和氨氯地平通过调节缓激肽介导的一氧化氮释放协同调节心肌耗氧量，这种药物组合可能对心力衰竭治疗有用。
