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Journal of the American College of 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 Abnormal Flow-Mediated Epicardial Vasomotion in Coronary Is Improved by -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 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 (Ϫ5 Ϯ 1%) dilated (3 Ϯ 2%) with pacing in the presence of enalaprilat (p ϭ 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 Ϯ 1% dilation (p Ͻ 0.001). Cardiac pacing-induced reduction in coronary of 27 Ϯ 4% (p Ͻ 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 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 , , 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 ϭ angiotensin-converting enzyme was performed with the ARTREK software (ImageComm ϭ BK bradykinin Systems, Inc.). A total of 50 segments were analyzed; 3 NO ϭ nitric oxide segments of epicardial 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 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 (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 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 Ϯ 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 ϭ mild coronary atherosclerosis or its risk factors, and B) any 62.5 ng/min (n 19) for 3 min, followed by 2-min ␮ ϭ ␮ ϭ 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 . METHODS Intracoronary sodium nitroprusside was given at 40 ␮g/min for 3 min, and intracoronary adenosine at 2.2 mg/min for Patients. We studied 19 patients with angiographically 2 min. Ͻ normal, or near normal ( 30% narrowing) coronary arter- After a 15-min interval, an infusion of BK (62.5 ng/min) ies, undergoing diagnostic for inves- was given and pacing was repeated during the infusion. tigation of or abnormal noninvasive tests. Pa- Following a 10-min recovery period, baseline measurements tients with 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 ␮g/min for 10 min. In a in the previous two weeks were excluded. The mean age was previous study, this intravascular concentration of enala- Ϯ 50 10 years; there were 15 (79%) men. Eight patients prilat adequately blocked the constrictor response to Ͼ were hypertensive ( 140/90 mm Hg), hy- angiotensin I (22). While continuing the infusion, pacing Ͼ 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 ϭ 17) was co-infused for 2 min, and 40 cologic antidiabetic therapy). Seven patients were either ␮g/min sodium nitroprusside was given for 3 min (n ϭ current smokers or had smoked in the previous 2 years; 13 Ͼ 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 Ϯ 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 Ͻ0.05 was considered of statistical the coronary artery and blood flow velocity was measured significance. Correlation analysis was performed using Pear- using a 0.018 inch wire equipped with a Doppler crystal at son’s correlation coefficient. 798 Prasad et al. JACC Vol. 33, No. 3, 1999 ACE Inhibition and Coronary Flow-Mediated Vasodilation March 1, 1999:796–804

Figure 1. Effects of bradykinin (left) and sodium nitroprusside (right) before (control, ●) and after enalaprilat (⅙) on epicardial diameter. (Data represent mean Ϯ SEM).

RESULTS not further potentiate the 9.6 Ϯ 1% dilation observed in the dilating segments (Fig. 2). Thus, ACE inhibition selectively Effect of enalaprilat on endothelium-dependent and improved epicardial dilation in segments with abnormal -independent epicardial coronary artery responses. Rest- pacing-mediated vasomotion. ing mean coronary epicardial diameter remained unchanged 10 minutes after infusion of enalaprilat; 2.1 Ϯ 0.1 versus Effect of BK and sodium nitroprusside on epicardial 2.0 Ϯ 0.1 mm (p ϭ ns), suggesting that ACE did not segments with abnormal vasomotion during pacing. Bra- regulate resting epicardial vessel tone. There was also no dykinin (62.5 ng/min) produced no vasodilation (0 Ϯ 2%) alteration in mean arterial blood pressure (105 Ϯ 2to106Ϯ in the segments that constricted abnormally with pacing, 2 mm Hg) and (79 Ϯ 2to81Ϯ 3 bpm). compared with a 4.9 Ϯ 2% (p ϭ 0.003) dilation in segments Epicardial diameter increased progressively with the that dilated normally during pacing (Fig. 3). In contrast, 62.5 ng/min, 1 ␮g/min, and 4 ␮g/min doses of BK by vasodilation with sodium nitroprusside was similar in the 1.5 Ϯ 1%, 8.3 Ϯ 1% and 11.4 Ϯ 1%, respectively (p Ͻ constricting and dilating segments; 19 Ϯ 3% and 20 Ϯ 3%, 0.001, ANOVA). When the 62.5 ng/min dose of BK was respectively, p ϭ 0.9. Enalaprilat enhanced BK-mediated coinfused with enalaprilat, the response was enhanced to epicardial vasodilation in both constricting and dilating a 5.6 Ϯ 1% (p Ͻ 0.001) increase in epicardial diameter segments (11.6 Ϯ 3%, p Ͻ 0.001 and 10.7 Ϯ 3%, respec- (Fig. 1). In contrast, dilation of epicardial coronary tively, p ϭ 0.04, Fig. 3). Thus, segments of epicardial arteries with sodium nitroprusside was similar before and after coronary arteries with abnormal pacing-mediated vasomo- enalaprilat (p ϭ 0.2) (Fig. 1). Thus, enalaprilat significantly tion demonstrated abnormal reactivity to endothelium- potentiated BK- but not sodium nitroprusside-mediated epi- dependent, but not endothelium-independent vasodilators, cardial vasodilation. and ACE inhibition improved BK-mediated dilation in both groups. Effect of enalaprilat on pacing-induced coronary epicar- dial changes. During control pacing, epicardial coronary Effects of low-dose BK on pacing-induced epicardial artery diameter increased by a mean 3.7 Ϯ 1% (p ϭ 0.06) in vasomotion. To investigate whether the improvement of the 50 segments analyzed in 19 patients. After enalaprilat, epicardial constriction during pacing by enalaprilat was there was no significant further increase in pacing-mediated secondary to increased local BK levels, we studied the effects epicardial vasodilation (5.8 Ϯ 2%, p ϭ 0.4, compared with on pacing-induced epicardial vasomotion of low-dose BK at control). Further analysis was performed in the 20 segments a concentration that did not alter resting diameter in the from 12 patients that constricted (abnormal response) and constricting segments. Segments that initially constricted by the 30 segments from 16 patients that dilated (normal 5.1 Ϯ 1% during pacing, dilated by 5.9 Ϯ 1% (p Ͻ 0.001) response) with pacing (Fig. 2). A mean 5.1 Ϯ 1% constric- during pacing with BK (62.5 ng/ml, Fig. 4). Segments of tion observed during control pacing improved to a 6.1 Ϯ 2% epicardial coronary arteries that initially dilated with pacing dilation when pacing was repeated in the presence of also dilated with BK and there was no further change during enalaprilat (p ϭ 0.002, Fig. 2). In contrast, enalaprilat did pacing with BK (Fig. 4). Thus, BK selectively improved JACC Vol. 33, No. 3, 1999 Prasad et al. 799 March 1, 1999:796–804 ACE Inhibition and Coronary Flow-Mediated Vasodilation

Figure 2. The effects of cardiac pacing before and after enalaprilat on coronary epicardial segments that initially constricted (left, n ϭ 20) or dilated (right, n ϭ 30) with cardiac pacing. There was no significant difference (p ϭ 0.5) between the mean baseline diameters of constricting segments (2.1 Ϯ 0.1 mm) compared to dilating segments (2.0 Ϯ 0.1 mm). Data represent mean Ϯ SEM. abnormal pacing-induced vasomotion in segments with 1 ␮g/min and 4 ␮g/min doses; mean blood flow increased endothelial dysfunction, mimicking the action of enalapri- by 14 Ϯ 3%, 79 Ϯ 9% and 162 Ϯ 18%, respectively, and lat. vascular resistance decreased by 10 Ϯ 2%, 41 Ϯ 4% and Ϯ Ͻ Effect of enalaprilat on coronary microvascular function. 58 4%, respectively, (p 0.001, ANOVA, both). Resting mean coronary blood flow and vascular resistance Enalaprilat enhanced the response of BK (62.5 ng/min) to Ϯ ϭ Ϯ ϭ remained unchanged 10 min after infusion of enalaprilat; a40 13% (p 0.08) increase in flow and a 25 5% (p Ϫ 39 Ϯ 4 ml/min and 3.3 Ϯ 0.4 mm Hg⅐ml 1⅐min before, 0.02) reduction in vascular resistance, indicating inhibition Ϫ Ϯ versus 39 Ϯ 4 ml/min and 3.2 Ϯ 0.3 mm Hg⅐ml 1⅐min of coronary ACE with enalaprilat. In contrast, the 137 after, respectively (p ϭ ns for all), suggesting that ACE did 19% increase in coronary blood flow and 62 Ϯ 2% reduction not regulate resting coronary microvascular tone. Bradyki- in vascular resistance with sodium nitroprusside remained nin produced graded increases in coronary blood flow and unaltered after enalaprilat (146 Ϯ 19% [p ϭ 0.5] and 61 Ϯ reduction in vascular resistance; at the 62.5 ng/min, 3% [p ϭ 0.6]) change, respectively.

Figure 3. The effects of bradykinin (left) and sodium nitroprusside (right) on coronary epicardial segments that constricted or dilated with cardiac pacing. The potentiation of bradykinin by enalaprilat is demonstrated in hatched bars. Data represent mean Ϯ SEM. 800 Prasad et al. JACC Vol. 33, No. 3, 1999 ACE Inhibition and Coronary Flow-Mediated Vasodilation March 1, 1999:796–804

Figure 4. The effects of cardiac pacing before and after 62.5 ng/min of intracoronary bradykinin on coronary epicardial segments which constricted (left) or dilated (right) with control pacing. Data represent mean Ϯ SEM.

During initial cardiac pacing, coronary blood flow in- study, we observed that acute ACE inhibition improves creased by 54 Ϯ 10% and vascular resistance decreased by acetylcholine-mediated, endothelium-dependent dilation 27 Ϯ 4%. In the presence of enalaprilat, these indices were and that this is in part achieved by increased NO bioavail- not significantly different at 47 Ϯ 9% (p ϭ 0.5) and 27 Ϯ ability (27). In this study, we evaluated the effects of ACE 5% (p ϭ 0.9), respectively. There was also no correlation inhibition and BK on coronary vasomotion during stress. between the magnitude of reduction in vascular resistance Our data show that: 1) ACE inhibition improves endothe- with control pacing and the change observed when pacing lial dysfunction and abolishes abnormal epicardial coronary was repeated in the presence of enalaprilat (r ϭ 0.2, p ϭ artery constriction during cardiac pacing, 2) low-dose BK NS). Thus, ACE inhibition did not influence pacing- also abolishes coronary constriction during pacing, and 3) mediated metabolic coronary microvascular dilation in pa- ACE inhibition did not influence microvascular dilation tients with depressed responses. Furthermore, pacing- during stress. induced microvascular vasodilation was similar in patients with epicardial vessel constriction and those with dilation Improvement in flow-mediated epicardial vasomotion by during pacing (52 Ϯ 10% vs. 55 Ϯ 11% [p ϭ ns] increase in ACE inhibition. As previously reported, cardiac pacing flow with pacing). Finally, flow reserve with adenosine was produced a heterogenous epicardial coronary arterial re- similar in both groups (345 Ϯ 44% vs 324 Ϯ 24% increase sponse where some segments dilated and others either in flow in patients with epicardial dilation and constriction, constricted or remained unchanged. Often constriction and respectively). dilation in different segments of epicardial coronary arteries occurred in the same patients. This heterogenous response of epicardial coronary arteries to endothelium-dependent DISCUSSION stimuli has been observed previously (28,29) and highlights the patchy nature of vascular endothelial dysfunction in Coronary epicardial and microvascular dilation accompanies coronary conductance vessels of patients with atherosclerosis increases in myocardial oxygen demand. Whereas epicardial or its risk factors. dilation is primarily believed to be due to endothelium- In order to evaluate endothelial function of segments that dependent release of NO (1,21,23,24), the causes for mi- constricted or dilated during pacing, we assessed the effects crovascular dilation are multifactorial in origin (25,26). of BK, an endothelium-dependent vasodilator, and sodium Endothelial dysfunction associated with diminished NO nitroprusside, an endothelium-independent agonist. Seg- activity in patients with atherosclerosis, or those with ments that constricted with pacing did not dilate with BK, normal coronary arteries and risk factors for atherosclerosis, whereas those that reacted normally to pacing by dilating results in absence of flow-mediated dilation (1). In epicar- also dilated with BK. In contrast, both dilating and con- dial coronary arteries of these patients, increased shear stricting segments relaxed equally with sodium nitroprus- precipitated by exercise, pacing or mental stress causes side, indicating that endothelial, but not smooth muscle paradoxical coronary constriction, probably as a result of function, was abnormal in segments which constricted with unopposed myogenic constriction (2,3,5,11). In a previous pacing. This is in keeping with animal studies where JACC Vol. 33, No. 3, 1999 Prasad et al. 801 March 1, 1999:796–804 ACE Inhibition and Coronary Flow-Mediated Vasodilation endothelial damage following balloon injury to the canine Mechanism underlying the improvement in flow- coronary arteries resulted in marked during mediated epicardial vasomotion by ACE inhibition: role exercise (30). Similarly, in , an attenuated vasodila- of BK. There are at least two important mechanisms tor response to acetylcholine in patients with endothelial whereby ACE inhibition may improve endothelial NO dysfunction is associated with a depressed dilator response activity. By reducing vascular angiotensin II production, it to pacing (31). can increase bioavailability of NO as angiotensin II is a The effect of enalaprilat was specific for the endothelium- powerful stimulus for NADH/NADPH oxidase-dependent dependent vasodilator, BK, and was greater in segments vascular superoxide anion generation (17,18). Increased that initially did not dilate with BK (endothelial dysfunc- vascular oxidant level inactivates endothelial NO, a mech- tion) compared to those that dilated (normal endothelial anism that appears to be instrumental in precipitating function). Thus, after ACE inhibition, both segments endothelial dysfunction in hypercholesterolemia, atheroscle- dilated to a comparable degree. Similar changes were rosis, hypertension and diabetes (37–40). The second pos- observed with ACE inhibition during cardiac pacing. The sible mechanism underlying the beneficial effects of ACE beneficial effect of ACE inhibition was restricted to seg- inhibition is by elevation of vascular BK levels that will ments with endothelial dysfunction, where pacing after directly stimulate the NO pathway. enalaprilat abolished epicardial constriction. In contrast, Although the precise mechanism whereby the endothe- segments which initially dilated normally with pacing re- lium senses and transduces the stimulus of flow and shear mained unchanged after enalaprilat. However, there was no stress is unknown, the possibility that BK may play a key difference in the magnitude of increase in flow and, hence, role in mediating tonic basal and flow-stimulated release of shear stress between the two groups to account for the NO was suggested by recent studies. Epicardial constriction observed difference in epicardial arterial response. These and inhibition of flow-mediated epicardial dilation in the findings are in agreement with a previous study where acute human coronary circulation was observed during inhibition infusion of the ACE inhibitor, perindoprilat, improved cold of endogenous BK activity with icatibant, a specific B2 presser-mediated epicardial coronary constriction (32). receptor antagonist (12). In our study, we investigated whether the observed improvement in flow-mediated con- striction by ACE inhibition was a result of increased BK Improvement in coronary endothelial function by ACE activity by repeating pacing during a low-dose infusion of inhibition. As reported previously, acute ACE inhibition BK that in itself did not change epicardial diameter in the with enalaprilat did not alter basal coronary vascular tone segments with dysfunction. Pacing-induced constriction (22,32,33). However, it is not possible to conclude from this was abolished by low-dose BK, whereas segments that observation that local generation of angiotensin II by initially dilated with pacing, and, hence, had normal endo- vascular ACE or enalaprilat-mediated increased endoge- thelial function, had no effect. These observations allow us nous BK availability do not contribute to resting tone. Since to speculate that coronary endothelial dysfunction results in resting coronary vascular tone is tightly autoregulated, it is diminished endogenous kinin activity during stress, which possible that reduced angiotensin II-mediated constriction can be overcome by either exogenous BK or by ACE and BK-mediated dilation is offset by changes in other inhibition, and that the beneficial effect of ACE inhibitors endogenous dilators and constrictors. is, at least partly, due to enhanced BK activity. This is In the present study, enalaprilat potentiated epicardial further supported by a recent study in normal volunteers and microvascular dilation in response to BK, but not to which demonstrated that B2 receptor inhibition abolishes sodium nitroprusside, suggesting that it can selectively the potentiation of flow-mediated dilation of the radial improve endothelium-dependent but not -independent va- artery by quinaprilat (41). sodilation. Potentiation of BK responses also confirms that The observation that BK and ACE inhibition does not acute administration of enalaprilat achieved adequate inhi- affect epicardial diameter in constricting segments at rest, bition of coronary ACE. Because BK is metabolized by yet improves flow-mediated dilation with pacing, needs kininase II or endothelial ACE, improvement of the BK explanation. One explanation is that there is up-regulation response by enalaprilat would be expected and would not of vascular ACE in these segments as described in animal necessarily indicate global improvement in endothelial func- models of atherosclerosis and in humans (42,43). Thus, low tion. However, in a previous study, we have also demon- dose BK is metabolized rapidly resulting in no baseline strated improved acetylcholine responses with enalaprilat, effect; however, during increasing shear, there is likely to be an effect that was due to increased NO bioactivity (27), a increased availability of BK as a result of its shear-mediated finding confirmed by the TREND investigators using oral production. This increased endogenous production in the quinapril (34). Data from studies in the human forearm setting of either ACE inhibition or low-dose BK infusion is circulation of patients with mild (35) and the able to reverse the flow-mediated constriction. In the femoral circulation of patients with atherosclerosis (36) dilating segments, there is no up regulation of ACE and, confirms a similar action of ACE inhibition on peripheral thus, no limitation in BK production during stress. Thus, vascular endothelial dysfunction. enhancement does not occur. Alternatively, basal and shear- 802 Prasad et al. JACC Vol. 33, No. 3, 1999 ACE Inhibition and Coronary Flow-Mediated Vasodilation March 1, 1999:796–804 mediated NO production by the BK pathway may have clinical use. Our study did not include vessels with Ͼ50% different thresholds and are affected differentially by athero- stenosis and thus we cannot conclude from our data whether sclerosis and its risk factors, a possibility that is worthy of ACE inhibition would also improve flow-mediated vaso- further study. motion in vessels with more severe atherosclerosis. Results from trials in progress examining the effect of ACE inhib- Angiotensin-converting enzyme inhibition and micro- itors in myocardial ischemia will help clarify this issue (46). vascular coronary dilation during stress. Cardiac pacing Our study was also not designed to evaluate whether an significantly reduced coronary vascular resistance, but this increase in NO activity is responsible for the beneficial effect was not altered by enalaprilat in either patients with, or of ACE inhibition on flow-mediated dilation, but the those without, depressed pacing-induced microvascular di- finding that improvement in acetylcholine- and BK- lation. Our data indicates that, unlike epicardial vasomo- mediated coronary and peripheral dilation is due to in- tion, microvascular metabolic dilation is not potentiated by creased NO activity in our previous studies suggests that this ACE inhibition in patients with atherosclerosis or its risk is the most likely explanation for the observed changes factors. This was observed despite improvement in BK- (27,36). Due to limited number of patients studied, we are mediated microvascular responses in these patients, and, unable to investigate whether the beneficial effects of ACE therefore, deserves explanation. inhibitors are more likely to occur in patients with one or That metabolic coronary microvascular dilation is, at least other of the specific risk factors for atherosclerosis. This partly, dependent on endothelium-derived NO activity has issue needs to be tested in specific subsets of patients. been demonstrated by us in a previous study (1). L-NG, monomethyl arginine, an inhibitor of NO synthesis, partly Conclusions. Abnormal epicardial flow-mediated vasomo- inhibited pacing-induced increase in coronary blood flow in tion is associated with endothelial dysfunction in patients patients with normal endothelial function, but this contri- with atherosclerosis and its risk factors. Angiotensin- bution of NO was reduced in those with endothelial converting enzyme inhibition selectively improves dysfunction. In contrast to its partial effects on the mi- endothelium-dependent, but not -independent dilation. crovessels, NO synthase inhibition completely inhibited Furthermore, ACE inhibition abolishes abnormal flow- pacing-mediated epicardial coronary dilation, indicating mediated epicardial vasomotion in patients with endothelial that conductance vessel dilation is almost entirely, and dysfunction, but it does not influence microvascular dilation microvascular dilation only partially dependent on endothe- during pacing in patients with diffuse but nonstenotic lial NO (44). Coronary microvascular dilation during pacing epicardial coronary artery disease. This improvement in in addition to NO is also mediated by release of local epicardial constriction with ACE inhibition is likely to be metabolites including adenosine, prostaglandins, carbon mediated, in part, by an increase in endogenous BK activity. dioxide, hypoxia and is partly due to circulating cat- Improvement in abnormal coronary vasomotion during echolamines and withdrawal of sympathetic tone (44). stress with ACE inhibitors may result in amelioration of Additionally, these multiple mechanisms may compensate myocardial ischemia in patients with coronary artery disease. for any deficiency in NO activity in patients with endothe- Their long-term effects in enhancing vascular NO activity lial dysfunction because of the known autoregulatory capac- provides a pathophysiologic basis for the observed anti- ity of the coronary microcirculation (25,26,44). Further- thrombotic effect of ACE inhibitors and point to a potential more, cardiac pacing is not a maximal shear stress- role of these agents in arresting the progression of athero- producing stimulus, as coronary blood flow on average only sclerosis. increases by 50% with cardiac pacing. It is possible that during conditions where blood flow increases are near the Acknowledgments maximum vasodilatory capacity of the human coronary We thank Gloria Zalos, R.N., William H. Schenke, B.S., microvessels, the importance of an intact NO pathway will Rita Mincemoyer, R.N. for their technical assistance. become evident. Thus, unlike BK or acetylcholine-mediated dilation, which is predominantly endothelium-dependent, Reprint requests and correspondence: Dr. Arshed A. Quyyumi, pacing-induced microvascular dilation is only in a small part Cardiology Branch, NHLBI, National Institutes of Health, Bldg. NO-dependent. Since ACE inhibition selectively improves 10, Rm. 7B15, 10 Center Dr. MSC 1650, Bethesda, Maryland endothelium-dependent vasodilation, these differences may 20892-1650. E-mail: [email protected]. explain the lack of potentiation of microvascular dilation in the present study compared to previous studies in which augmentation of endothelium-dependent acetylcholine- REFERENCES mediated microvascular dilation has been observed (27,45). Limitations. In this study we did not use a BK receptor 1. Quyyumi AA, Dakak N, Andrews NP, et al. Contribution of nitric oxide to metabolic coronary vasodilation in the human antagonist to investigate the contribution of kinins in the heart. Circulation 1995;92:320–6. action of ACE inhibitors. Though this would have been the 2. Gage JE, Hess OM, Murakami T, et al. 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