View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 33, No. 3, 1999 © 1999 by the American College of Cardiology ISSN 0735-1097/99/$20.00 Published by Elsevier Science Inc. PII S0735-1097(98)00611-1 Vascular Biology Abnormal Flow-Mediated Epicardial Vasomotion in Human Coronary Arteries Is Improved by Angiotensin-Converting Enzyme Inhibition A Potential Role of Bradykinin Abhiram Prasad, MB, MRCP, Syed Husain, MD, Arshed A. Quyyumi, MD, MRCP, FACC Bethesda, Maryland OBJECTIVES This study was performed to determine whether angiotensin converting enzyme (ACE) inhibition improves endothelium-dependent flow-mediated vasodilation in patients with atherosclerosis or its risk factors and whether this is mediated by enhanced bradykinin activity. BACKGROUND Abnormal coronary vasomotion due to endothelial dysfunction contributes to myocardial ischemia in patients with atherosclerosis, and its reversal may have an antiischemic action. Previous studies have shown that ACE inhibition improves coronary endothelial responses to acetylcholine, but whether this is accompanied by improved responses to shear stress remains unknown. METHODS In 19 patients with mild atherosclerosis, metabolic vasodilation was assessed during cardiac pacing. Pacing was repeated during separate intracoronary infusions of low-dose bradykinin (BK) and enalaprilat. Endothelium-dependent and -independent vasodilation was estimated with intracoronary BK and sodium nitroprusside respectively. RESULTS Enalaprilat did not alter either resting coronary vascular tone or dilation with sodium nitroprusside, but potentiated BK-mediated dilation. Epicardial segments that constricted abnormally with pacing (25 6 1%) dilated (3 6 2%) with pacing in the presence of enalaprilat (p 5 0.002). Similarly, BK at a concentration (62.5 ng/min) that did not alter resting diameter in the constricting segments also improved the abnormal response to a 6 6 1% dilation (p , 0.001). Cardiac pacing-induced reduction in coronary vascular resistance of 27 6 4% (p , 0.001) remained unchanged after enalaprilat. CONCLUSIONS Thus ACE inhibition: A) selectively improved endothelium-dependent but not -independent dilation, and B) abolished abnormal flow-mediated epicardial vasomotion in patients with endothelial dysfunction, in part, by increasing endogenous BK activity. (J Am Coll Cardiol 1999;33:796–804) © 1999 by the American College of Cardiology Exercise and cardiac pacing dilate human coronary epicar- microvascular dilator responses and paradoxical constriction dial arteries and microvessels in normal individuals, and the of epicardial arteries with exercise and cardiac pacing which resulting augmentation in blood flow serves to meet the may contribute to the pathogenesis of myocardial ischemia increased myocardial oxygen requirements (1–5). The vas- in these patients (1–3,5,11). Endothelial cell dysfunction cular endothelium is pivotal in regulating this vasomotion associated with reduced NO activity is believed to be the by the release of a variety of relaxing and constricting factors major underlying cause for this abnormal vasomotion, and, (6–8). One important endothelium-derived relaxing factor thus, interventions which ameliorate endothelial dysfunc- is nitric oxide (NO) or an adduct of NO (9,10) that tion and increase NO bioavailability are likely to improve contributes almost entirely to epicardial and, to a lesser coronary vasomotion and reduce myocardial ischemia in extent, microvascular dilation during metabolic stress. Ath- patients with coronary atherosclerosis. erosclerosis and its risk factors are associated with depressed A potential therapeutic target for improving endothelial dysfunction appears to be the inhibition of the angiotensin converting enzyme (ACE/kininase II). This enzyme, From the Cardiology Branch, National Heart, Lung, and Blood Institute, National present in large quantities on the surface of endothelial cells, Institutes of Health, Bethesda, Maryland 20892-1650. Manuscript received January 14, 1998; revised manuscript received October 9, is a key component of the circulating and vascular 1998, accepted November 16, 1998. kallikrein-kinin and the renin-angiotensin systems. One of JACC Vol. 33, No. 3, 1999 Prasad et al. 797 March 1, 1999:796–804 ACE Inhibition and Coronary Flow-Mediated Vasodilation its tip (Cardiometrics Flowire, Cardiometrics, Inc., Moun- Abbreviations and Acronyms tain View, California) (19,20). Quantitative angiography ACE 5 angiotensin-converting enzyme was performed with the ARTREK software (ImageComm 5 BK bradykinin Systems, Inc.). A total of 50 segments were analyzed; 3 NO 5 nitric oxide segments of epicardial coronary arteries could be measured in 13 patients, 2 segments in 5 patients, 1 segment in 1 patient. Coronary blood flow and resistance were calculated as described previously (1,21). All drugs were infused its functions is to degrade bradykinin (BK), a locally directly into the left main coronary artery via the guide synthesized polypeptide that is known to regulate resting catheter at infusion rates ranging between 1 to 2 ml/min. tone and flow-mediated vasodilation in the normal human Infusion rates were halved for studies performed in the right coronary circulation (12), possibly through the release of coronary artery. NO (13,14), prostacyclin (15) and endothelium-derived After a five-minute infusion of dextrose 5% at 1 ml/min, hyperpolarizing factor (16). Thus, inhibition of ACE would baseline coronary blood flow velocity was measured and increase BK activity and potentially improve endothelial coronary angiography performed. Rapid atrial pacing was function, especially if BK activity is depressed in atheroscle- performed in 17 patients at heart rates ranging between 130 rosis. In addition to its effects on BK metabolism, ACE also to 150 bpm. Pacing from the right ventricle was performed promotes the synthesis of angiotensin II from angiotensin I, at 150 bpm in the remaining two patients who developed which among several actions, also stimulates vascular super- atrioventricular Wenckebach at rates below 115 bpm. Thus oxide generation (17,18). Thus, ACE inhibition may rectify 6 endothelial dysfunction by reducing angiotensin II synthesis the mean cardiac pacing rate was 144 7 bpm. and thus attenuating vascular oxidant stress. In this study, Endothelium-dependent vasodilation was estimated in we investigated whether: A) ACE inhibition improves shear all patients by performing a dose-response curve with stress-induced (physiological) vasodilation in patients with incremental infusions of intracoronary BK starting at 5 mild coronary atherosclerosis or its risk factors, and B) any 62.5 ng/min (n 19) for 3 min, followed by 2-min m 5 m 5 observed improvement in vasomotion is mediated by in- infusions of 1 g/min (n 17) and 4 g/min (n 19). creased BK activity. Five minutes after performing the dose-response curve with BK, endothelium-independent function was estimated with sodium nitroprusside and flow reserve with adenosine. METHODS Intracoronary sodium nitroprusside was given at 40 mg/min for 3 min, and intracoronary adenosine at 2.2 mg/min for Patients. We studied 19 patients with angiographically 2 min. , normal, or near normal ( 30% narrowing) coronary arter- After a 15-min interval, an infusion of BK (62.5 ng/min) ies, undergoing diagnostic cardiac catheterization for inves- was given and pacing was repeated during the infusion. tigation of chest pain or abnormal noninvasive tests. Pa- Following a 10-min recovery period, baseline measurements tients with myocardial infarction in the previous month, were made. Intracoronary enalaprilat, a potent ACE inhib- valvular heart disease or those treated with ACE inhibitors itor, was then infused at 20 mg/min for 10 min. In a in the previous two weeks were excluded. The mean age was previous study, this intravascular concentration of enala- 6 50 10 years; there were 15 (79%) men. Eight patients prilat adequately blocked the constrictor response to . were hypertensive (blood pressure 140/90 mm Hg), hy- angiotensin I (22). While continuing the infusion, pacing . percholesterolemia (total cholesterol 200 mg/dl) was was repeated at the control rate in all the patients, BK present in 14 patients and 2 had diabetes (both on pharma- (62.5 ng/min, n 5 17) was co-infused for 2 min, and 40 cologic antidiabetic therapy). Seven patients were either mg/min sodium nitroprusside was given for 3 min (n 5 current smokers or had smoked in the previous 2 years; 13 . 11). Blood flow velocity was measured and coronary patients were exposed to 1, and 6 patients to 1 risk factors. angiography was performed after each intervention. Angiographic atherosclerosis was present in 11 patients. Cardiac medications were withdrawn for at least 48 h, and Statistical analysis. Data are expressed as mean 6 SEM. aspirin a week before the study. The study was approved by Differences between means were compared by paired or the National Heart, Lung, and Blood Investigational Re- unpaired Student t test, as appropriate. The effect of view Board and informed written consent was obtained multiple doses of BK were analyzed using the two-way from all patients. analysis of variance (ANOVA). Appropriate interaction Protocol. After completion of diagnostic coronary arte- (dose X drug) tests were employed. All P values are riography, a six-French guide catheter was introduced into two-tailed, and a value ,0.05 was considered