Kawabata H, Ryomoto T, Ishikawa K
First Department of Internal Medicine, Kinki University School of Medicine, Osakasayama, Japan.
Hypertens Res. 2001 Jul;24(4):403-9. doi: 10.1291/hypres.24.403.
Although angiotensin converting enzyme (ACE) inhibitor and/or angiotensin II type 1 (AT1) receptor antagonist can protect the myocardium against ischemia-reperfusion injury, the mechanisms of the effect have not yet been characterized at the cellular level. We here examined the effect of the combination of an ACE inhibitor, temocaprilat, an AT1 receptor antagonist, CV-11974 and/or a nitric oxide synthase inhibitor, L-NAME, on the myocardial metabolism and contraction during ischemia and reperfusion by using phosphorus 31-nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts. After normothermic 20 min global ischemia, postischemic reperfusion of 30 min was carried out. Twenty-one hearts were divided into three experimental groups consisting of 7 hearts each: a Tem+CV group perfused with a combination of temocaprilat and CV-11974; a Tem+CV+L-NAME group perfused with a combination of temocaprilat and CV-11974 plus L-NAME, and a control group. During ischemia, both the Tem+CV group and Tem+CV+L-NAME group showed a significant inhibition of the decrease in adenosine triphosphate (ATP) compared with the control group (p<0.01); the increase in ATP was 50+/-3%, 42+/-4%, and 19+/-4% in the Tem+CV group, Tem+CV+L-NAME group, and control group, respectively. Both experimental groups also showed a significant inhibition of the increase in left ventricular end-diastolic pressure (LVEDP) compared with the control group (p<0.01). After postischemic reperfusion, the Tem+CV group and Tem+CV+L-NAME group again showed a significant improvement of ATP as compared with the control group (p<0.01); the increase in ATP was 73+/-3%, 64+/-3%, and 47+/-4% in the Tem+CV group, Tem+CV+L-NAME group, and control group, respectively, and a significant decrease of LVEDP as compared with the control group (p<0.01). There were no differences in ATP, or LVEDP during ischemia and reperfusion between the Tem+CV group and Tem+CV+ L-NAME group. In conclusion, the combination of temocaprilat and CV-11974 showed significant potential for improving myocardial energy metabolism and relaxation during both myocardial ischemia and reperfusion. This beneficial effect was not dependent on NO synthase.
尽管血管紧张素转换酶（ACE）抑制剂和/或血管紧张素II 1型（AT1）受体拮抗剂可保护心肌免受缺血再灌注损伤，但其作用机制在细胞水平上尚未明确。我们在此通过使用磷31核磁共振（31P-NMR）技术，研究了ACE抑制剂替莫卡普利、AT1受体拮抗剂CV-11974和/或一氧化氮合酶抑制剂L-NAME联合应用对兔Langendorff心脏缺血及再灌注期间心肌代谢和收缩功能的影响。在常温下进行20分钟全心缺血后，进行30分钟的缺血后再灌注。21只心脏被分为三个实验组，每组7只：替莫卡普利+CV组灌注替莫卡普利和CV-11974的组合；替莫卡普利+CV+L-NAME组灌注替莫卡普利、CV-11974和L-NAME的组合，以及一个对照组。在缺血期间，与对照组相比，替莫卡普利+CV组和替莫卡普利+CV+L-NAME组均显著抑制了三磷酸腺苷（ATP）的减少（p<0.01）；替莫卡普利+CV组、替莫卡普利+CV+L-NAME组和对照组的ATP增加量分别为50±3%、42±4%和19±4%。两个实验组与对照组相比，左心室舒张末期压力（LVEDP）的增加也受到显著抑制（p<0.01）。缺血后再灌注时，与对照组相比，替莫卡普利+CV组和替莫卡普利+CV+L-NAME组的ATP再次显著改善（p<0.01）；替莫卡普利+CV组、替莫卡普利+CV+L-NAME组和对照组的ATP增加量分别为73±3%、64±3%和47±4%，与对照组相比LVEDP显著降低（p<0.01）。替莫卡普利+CV组和替莫卡普利+CV+L-NAME组在缺血和再灌注期间的ATP或LVEDP没有差异。总之，替莫卡普利和CV-11974的组合在改善心肌缺血和再灌注期间的心肌能量代谢和舒张功能方面具有显著潜力。这种有益作用不依赖于一氧化氮合酶。
