Kitakaze M, Minamino T, Node K, Komamura K, Shinozaki Y, Mori H, Kosaka H, Inoue M, Hori M, Kamada T
First Department of Medicine, Osaka University School of Medicine, Japan.
Circulation. 1995 Aug 15;92(4):950-61. doi: 10.1161/01.cir.92.4.950.
Angiotensin-converting enzyme (ACE) produces angiotensin II, causing vasoconstriction of coronary arteries and reduction of coronary blood flow. The present study was undertaken to test the hypothesis that an ACE inhibitor increases coronary blood flow and improves myocardial metabolic and contractile functions of ischemic myocardium.
In 65 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the left carotid artery. When cilazaprilat (3 micrograms/kg per minute) was infused into the bypass tube for 10 minutes after reduction of coronary blood flow due to partial occlusion of the bypass tube, coronary blood flow increased from 30 +/- 1 to 43 +/- 2 mL/100 g per minute despite there being no changes in coronary perfusion pressure (43 +/- 1 mm Hg). The ratio of myocardial endocardial flow to epicardial flow increased during an infusion of cilazaprilat. Both fractional shortening and lactate extraction ratio of the perfused area were increased (fractional shortening: 4.1 +/- 0.6% to 8.9 +/- 0.6%, P < .001; lactate extraction ratio: -55.7 +/- 3.3% to -36.7 +/- 3.9%, P < .001). During an infusion of cilazaprilat, the bradykinin concentration of coronary venous blood was markedly increased. The increased coronary blood flow due to cilazaprilat was attenuated by HOE-140 (an inhibitor of bradykinin receptors; coronary blood flow: 35 +/- 2 mL/100 g per minute), and by N omega-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase; coronary blood flow: 34 +/- 2 mL/100 g per minute). Intracoronary administration of bradykinin mimicked the beneficial effects of cilazaprilat. Cyclic GMP content of the coronary artery was increased by cilazaprilat compared with the untreated condition in the ischemic myocardium. In the denervated hearts, the increased coronary blood flow due to cilazaprilat was not attenuated. On the other hand, CV11974, an inhibitor of angiotensin II receptors, slightly increased coronary blood flow to 34 +/- 2 from 30 +/- 1 mL/100 g per minute.
We conclude that an inhibitor of ACE can increase coronary blood flow and ameliorate myocardial ischemia, primarily due to accumulation of bradykinin and production of nitric oxide from the ischemic myocardium. Inhibition of angiotensin II production due to inhibition of ACE partially contributes to coronary vasodilation in the ischemic myocardium.
血管紧张素转换酶（ACE）产生血管紧张素II，导致冠状动脉血管收缩并减少冠状动脉血流。本研究旨在验证ACE抑制剂可增加冠状动脉血流并改善缺血心肌的心肌代谢和收缩功能这一假说。
在65只开胸犬中，经体外旁路管从左颈动脉灌注左前降支冠状动脉。当因旁路管部分闭塞使冠状动脉血流减少后，向旁路管内输注西拉普利拉（3微克/千克·分钟）10分钟，尽管冠状动脉灌注压无变化（43±1毫米汞柱），冠状动脉血流仍从30±1毫升/100克·分钟增加至43±2毫升/100克·分钟。输注西拉普利拉期间，心肌心内膜血流与心外膜血流的比值增加。灌注区域的缩短分数和乳酸摄取率均增加（缩短分数：4.1±0.6%至8.9±0.6%，P<0.001；乳酸摄取率：-55.7±3.3%至-36.7±3.9%，P<0.001）。输注西拉普利拉期间，冠状静脉血中的缓激肽浓度显著增加。西拉普利拉所致的冠状动脉血流增加被HOE-140（缓激肽受体抑制剂；冠状动脉血流：35±2毫升/100克·分钟）和Nω-硝基-L-精氨酸甲酯（一氧化氮合酶抑制剂；冠状动脉血流：34±2毫升/100克·分钟）减弱。冠状动脉内给予缓激肽可模拟西拉普利拉的有益作用。与缺血心肌未处理状态相比，西拉普利拉可增加冠状动脉的环磷酸鸟苷含量。在去神经支配的心脏中，西拉普利拉所致的冠状动脉血流增加未被减弱。另一方面，血管紧张素II受体抑制剂CV11974使冠状动脉血流从30±1毫升/100克·分钟轻度增加至34±2毫升/100克·分钟。
我们得出结论，ACE抑制剂可增加冠状动脉血流并改善心肌缺血，主要是由于缓激肽的蓄积以及缺血心肌产生一氧化氮。因抑制ACE而抑制血管紧张素II的产生在一定程度上有助于缺血心肌的冠状动脉血管舒张。
