Differential Effects of Quinaprilat and Enalaprilat on Endothelial Function of Conduit Arteries in Patients With Chronic Heart Failure
Background—Chronic heart failure (CHF) is associated with endothelial dysfunction, including impaired flow-dependent (endothelium-mediated) dilation (FDD). We have previously shown that ACE inhibition improves endothelium-mediated vasodilation in healthy volunteers. The present study was designed to determine whether ACE inhibition improves the impaired FDD in patients with CHF. Because their affinity to tissue ACE may influence the ability of ACE inhibitors to affect endothelial function, we compared the effects of quinaprilat (high affinity to tissue ACE) and enalaprilat (low affinity to tissue ACE) on FDD in patients with CHF.
Methods and Results—High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow in patients with CHF. The effects of intra-arterial infusion of quinaprilat 1.6 μg/min (n=15) and enalaprilat 5 μg/min (n=15) were determined at rest and during reactive hyperemia (causing endothelium-mediated dilation) before and after N-monomethyl-l-arginine (L-NMMA) to inhibit endothelial synthesis of nitric oxide. Quinaprilat improved FDD by >40% (10.2±0.6% versus 6.9±0.6%; P<0.01), whereas enalaprilat had no effect. In particular, the part of FDD mediated by nitric oxide (ie, inhibited by L-NMMA) was increased by >100% with quinaprilat (5.6±0.5% versus 2.5±0.5%; P<0.01). Enalaprilat had no effect on FDD even when it was infused twice in the same dose (5 μg/min) and up to 30 μg/min. The effect of sodium nitroprusside on radial artery diameter and blood flow was similar in patients treated with quinaprilat, enalaprilat, and placebo.
Conclusions—Quinaprilat improves FDD in patients with CHF as the result of increased availability of nitric oxide, whereas enalaprilat does not. This observation suggests that intrinsic differences exist between quinaprilat and enalaprilat that determine the ability to improve endothelium-mediated vasodilation, ie, their different affinity to tissue ACE.
Systemic vasoconstriction is a hallmark in patients with chronic heart failure (CHF) that leads to a vicious circle by increasing the afterload for the failing left ventricle. Although elevated sympathetic tone, increased endothelin levels, and activation of the renin-angiotensin system have been proposed to be involved in the reduced vasodilator capacity in heart failure,1 the important role of the endothelium in coordinating tissue perfusion has now been recognized.2 Several clinical studies have documented endothelial dysfunction of peripheral resistance arteries3 4 and impaired flow-dependent (endothelium-mediated) dilation (FDD) of conduit arteries in patients with CHF.5 6 An important functional consequence of endothelial dysfunction is the inability of a vessel to dilate in response to endothelium-derived NO after physiological stimuli, such as increases of blood flow, reflecting impaired FDD.6 The portion of FDD mediated by NO is reduced in patients with CHF compared with normal subjects.6 7 It has been hypothesized that endothelial dysfunc- tion in CHF is caused by a reduced availability of NO. An activation of ACE8 might represent one underlying mechanism that is involved in the reduced availability of NO in CHF. Because ACE is identical to kininase II, the enzyme that inactivates endogenous bradykinin, activation of ACE would be associated with an enhanced breakdown of endogenous bradykinin. Bradykinin is a potent vasodilator peptide that exerts its vasodilating properties through endothelial release of NO,9 prostacyclin,10 and hyperpolarizing factor.11 12 Activation of ACE in CHF8 associated with an increased degradation of endogenous bradykinin might therefore lead to reduced endothelial release of NO. Conversely, ACE inhibition represents a promising concept to improve endothelial function in patients with CHF, possibly by increasing the availability of NO. In the present study, we therefore determined the effects of intra-arterial infusions of ACE inhibitors on resting tone and FDD of the radial artery in patients with CHF in NYHA functional class III. To elucidate the contribution of NO to the postulated beneficial effect of ACE inhibition on FDD, we determined the effect of ACE inhibition on FDD during control conditions and after N-monomethyl-l-arginine (L-NMMA) to inhibit endothelial synthesis of NO.
Experimental studies have shown that distinct differences exist between ACE inhibitors with regard to their ability to inhibit tissue ACE.13 However, it remains to be established whether the affinity to tissue ACE plays an important role in vivo in humans. To investigate the role of vascular tissue ACE for endothelial function in humans, we compared the effects of quinaprilat, an ACE inhibitor with high affinity to tissue ACE, with those of enalaprilat, an ACE inhibitor with low affinity to tissue ACE,14 15 on endothelium-dependent vasodilation of the radial artery.
Forty patients with CHF in NYHA functional class III with radiological and echocardiographic signs of cardiomegaly were studied (protocol 1). Characteristics of CHF patients are shown in Table 1⇓. All patients were treated with digitalis and diuretics. Six of the 15 patients randomized to receive quinaprilat, 5 of the 15 patients randomized to receive enalaprilat, and 3 of the 10 patients randomized to receive placebo were treated with captopril but no other vasoactive drugs. Digoxin and captopril were stopped 24 hours and diuretics 12 hours before measurements. Patients receiving long-acting ACE inhibitors were not included in the protocol. Alcohol and caffeine were prohibited within 12 hours of the study. Patients with diabetes mellitus, hypercholesterolemia (LDL cholesterol >140 mg/dL), arterial hypertension, or significant hematologic, renal, or hepatic dysfunction were excluded by a careful history, physical examination, ECG, and laboratory analysis. All subjects were nonsmokers. Written informed consent was obtained for all subjects, and the protocol was approved by the local ethics committee.
Radial artery diameters and blood flow were measured with a high-resolution A-mode ultrasonic echo-tracking device (ASULAB; Reference 16 ) and an 8-MHz Doppler probe (Vasoscope III). This method is well established in our laboratory4 5 6 7 17 and has an excellent reproducibility and variability, as reported recently.7 FDD, expressed as percent change of radial artery diameter, was determined from peak diameter after release of wrist occlusion divided by baseline diameter before wrist occlusion. Arterial blood pressure and heart rate were measured on the contralateral arm with a commercially available automatic blood pressure cuff.
To inhibit bradykinin-induced prostaglandin release, aspirin 250 mg IV, a dose known to be effective in blocking vascular cyclooxygenase,18 was given 30 minutes before measurements. All reported measurements were performed after insertion of a polyethylene catheter into the left brachial artery (nondominant arm). In control conditions, saline was infused. Blood flow velocity was recorded continuously, and radial artery diameter was determined every 30 seconds until stable baseline conditions were obtained (≈30 minutes). All baseline measurements of radial artery diameter and blood flow were performed with the wrist cuff deflated at a point remote from a period of reactive hyperemia. The present article includes results of 4 different protocols; the exact sequence of maneuvers for each of the 4 protocols is shown in Figure 1⇓.
After baseline measurements of radial artery diameter and blood flow, first (protocol 1; Figure 1⇑) a wrist arterial occlusion was performed. After release of wrist occlusion, flow-dependent dilation in response to reactive hyperemic blood flow response was assessed at baseline. Next, L-NMMA (Calbiochem; 7 μmol/min for 5 minutes) was infused intra-arterially, followed by saline infusion during arterial occlusion and determination of FDD after release of wrist occlusion. This dose was based on our earlier observations that this dose of L-NMMA attenuated FDD by 64±6%.6 When radial artery diameter and blood flow had returned to baseline values, patients were randomized (ratio, 15:15:10) to receive intra-arterial infusion of quinaprilat 1.6 μg/min over 5 minutes, enalaprilat 5 μg/min over 5 minutes, or placebo (saline). Five minutes of intra-arterial infusion of quinaprilat, enalaprilat, or placebo was followed by saline infusion during arterial occlusion and determination of FDD after release of wrist occlusion. When radial artery diameter and blood flow had returned to baseline values, L-NMMA (7 μmol/min) was coinfused with quinaprilat, enalaprilat, or placebo over 5 minutes, followed by saline infusion during arterial occlusion and determination of FDD after release of wrist occlusion. The dose for quinaprilat and enalaprilat was based on a recent publication demonstrating that these dosages are equipotent in inhibiting the formation of angiotensin II from angiotensin I in the human forearm circulation.19 In addition, this dose of quinaprilat improves FDD in healthy volunteers.17 Finally, all subjects received an intra-arterial infusion of sodium nitroprusside (SNP; 10 μg/min over 5 minutes) to assess endothelium-independent vasodilatory capacity.
In 5 additional patients with CHF (Table 1⇑), the intraindividual response to enalaprilat and quinaprilat (protocol 2) was determined. First, FDD was determined during control conditions and repeated after enalaprilat. Then, saline was infused over a 1-hour washout period. FDD was determined again under control conditions and repeated after quinaprilat.
In 6 more patients with CHF (Table 1⇑), we determined the effect of repeated infusions of enalaprilat (protocol 3) to rule out the possibility that the positive effect of quinaprilat observed in protocol 2 was related to a crossover effect, ie, a cumulative effect of enalaprilat and quinaprilat. To this end, FDD was determined during control conditions and after enalaprilat. After a 1-hour washout period, FDD was determined again during control conditions and repeated after a second infusion of enalaprilat.
In 5 additional patients with CHF (Table 1⇑), the effect of increasing dosages of enalaprilat was determined (protocol 4) to investigate whether a higher dose of enalaprilat improves FDD of the radial artery. Therefore, FDD was determined during control conditions (saline) and repeated after infusion of enalaprilat at concentrations of 5, 10, 15, 20, and 30 μg/min (each over 5 minutes).
Patients with CHF included in protocols 2 through 4 had baseline characteristics similar to those of patients included in protocol 1 (Table 1⇑).
Blood flow and radial artery diameter data, reported for quinaprilat, enalaprilat, L-NMMA, placebo, and SNP, represent measurements during the last minute of each infusion. All measurements were recorded, and subsequently, vessel diameter and blood flow velocity were analyzed by 2 investigators who were unaware of the sequence of interventions and treatment assignment.
All data are expressed as mean±SEM. Comparisons of >2 measurements were done by 1-way ANOVA for repeated measures followed by a Student-Newman-Keuls test (comparisons within 1 group of patients and between the different groups). A value of P<0.05 was considered to be statistically significant.
After release of wrist occlusion, a significant increase in radial artery diameter was noted (Table 2⇓), representing FDD, defined as percent increase in vessel diameter. FDD during control conditions was similar in patients randomized to receive quinaprilat, enalaprilat, or placebo (Figure 2⇓). Effects of L-NMMA, quinaprilat, enalaprilat, and placebo on radial artery diameter are given in Table 2⇓ and Figure 2⇓. The effect of quinaprilat on FDD was similar in patients previously treated with captopril (n=6; control, 6.7±0.6%; quinaprilat, 10.1±0.7%) and without previous ACE inhibition (n=9; control, 6.9±0.5%; quinaprilat, 10.3±0.5%). The effect of enalaprilat on FDD was similar in patients previously treated with captopril (n=5; control, 6.5±0.6%; enalaprilat, 6.7±0.5%) and without previous ACE inhibition (n=10; control, 6.6±0.4%; enalaprilat, 6.6±0.5%), similar to the effect of placebo (with previous captopril: n=3; control, 6.6±0.6%; enalaprilat, 6.7±0.5%; without previous captopril: n=7; control, 6.8±0.5%; enalaprilat, 6.7±0.5%).
During control, the portion of FDD inhibited by L-NMMA (representing the portion of FDD mediated by NO) was reduced in all 3 groups of patients with CHF (quinaprilat group, 2.54±0.5%; enalaprilat group, 2.52±0.5%; placebo group, 2.61±0.6%). After administration of quinaprilat, but not after enalaprilat or placebo, the portion of FDD mediated by NO was significantly increased (5.61±0.6%; P<0.01 versus control; Figure 3⇓).
Intra-arterial SNP significantly increased radial artery diameter to a similar extent in all 3 groups of patients with CHF (quinaprilat group, 3.00±0.1 to 3.51±0.1 mm, 16.9±1.1%; enalaprilat group, 3.04±0.1 to 3.54±0.1 mm, 16.5±1.3%; placebo group, 3.02±0.1 to 3.54±0.1 mm, 17±2.2%; each P<0.01 versus before SNP).
Effects of L-NMMA, quinaprilat, enalaprilat, and placebo on forearm blood flow are shown in Table 3⇓.
Infusion of SNP increased forearm blood flow to a similar extent in all 3 groups of patients with CHF (quinaprilat group, 23±4 to 50±10 mL/min; enalaprilat group, 23±5 to 55±11 mL/min; placebo group, 25±7 to 51±10 mL/min; P<0.05 versus before SNP for each). Systemic blood pressure and heart rate did not change during the experimental protocol. There were no significant differences in vascular responses between patients with ischemic and idiopathic cardiomyopathy (data not shown).
At control 1, FDD was 6.9±0.6% (Figure 4⇓; from 3.01±0.1 to 3.22±0.1 mm; P<0.05); after enalaprilat, FDD was 6.9±0.7% (3.02±0.1 to 3.23±0.1 mm). After 1-hour washout (control 2), FDD was 7.0±0.7% (3.00±0.1 to 3.21±0.1 mm); after quinaprilat, however, FDD was increased to 11.6±0.8% (3.00±0.1 to 3.35±0.1 mm; P<0.05 versus control).
Radial artery blood flow under resting conditions and during reactive hyperemia was similar at control 1, enalaprilat, control 2, and quinaprilat (control 1, 25±5 to 86±15 mL/min; enalaprilat, 24±5 to 83±16 mL/min; control 2, 26±7 to 85±18 mL/min; and quinaprilat, 23±6 to 86±15 mL/min).
At control 1, FDD was 7.3±1.1% (Figure 4⇑; from 3.01±0.1 to 3.23±0.1 mm; P<0.05); after enalaprilat 5 μg/min, FDD was 7.3±1.2% (2.99±0.1 to 3.21±0.1 mm). After 1-hour washout (control 2), FDD was 7.1±1.5% (2.98±0.1 to 3.20±0.1 mm); after the second infusion of enalaprilat 5 μg/min, FDD was 7.4±1.0% (2.99±0.1 to 3.21±0.1 mm).
Radial artery blood flow at rest and during peak reactive hyperemia was similar at control 1, enalaprilat 1, control 2, and enalaprilat 2 (control 1, 20±4 to 81±11 mL/min; enalaprilat 1, 21±5 to 82±11 mL/min; control 2, 19±4 to 85±11 mL/min; and enalaprilat 2, 19±5 to 87±10 mL/min).
At control, FDD was 7.4±1.7% (Figure 4⇑; from 2.96±0.1 to 3.18±0.1 mm; P<0.05); after enalaprilat 5 μg/min, FDD was 6.8±1.4% (2.97±0.1 to 3.17±0.1 mm); after 10 μg/min, FDD was 7.9±1.1% (2.96±0.1 to 3.19±0.1 mm); after 15 μg/min, FDD was 7.4±1.2% (2.98±0.1 to 3.20±0.1 mm); after 20 μg/min, FDD was 7.7±1.6% (2.97±0.1 to 3.20±0.1 mm); and after 30 μg/min, FDD was 7.7±1.5% (2.95±0.1 to 3.19±0.2 mm).
Radial artery blood flow at rest and during reactive hyperemia was similar at control and after enalaprilat 5 to 30 μg/min (control, 20±5 to 90±17 mL/min; enalaprilat 5 μg/min, 21±5 to 92±11 mL/min; 10 μg/min, 24±4 to 85±11 mL/min; 15 μg/min, 26±5 to 94±11 mL/min; 20 μg/min, 25±5 to 90±13 mL/min; and 30 μg/min, 20±5 to 90±10 mL/min).
The salient finding of the present study is that the impaired FDD in patients with CHF is improved by the ACE inhibitor quinaprilat. However, FDD was not affected by enalaprilat. Because even high dosages of enalaprilat failed to improve endothelium-mediated vasodilation, our results suggest that an intrinsic characteristic, ie, high affinity to tissue ACE, is necessary for ACE inhibitors to improve endothelium-mediated vasodilation with short-term ACE inhibition. Furthermore, this study suggests that the beneficial effect of quinaprilat on FDD in patients with CHF is mediated by an enhanced availability of NO, because the portion of FDD that was mediated by NO was increased after quinaprilat.
We and others have demonstrated endothelial dysfunction of peripheral conduit and resistance arteries in patients with CHF.3 4 5 More recent data from our group suggest that the availability of NO during FDD is reduced in patients with CHF.6 Different mechanisms may be involved, such as reduced NO synthase gene expression,20 a deficit of the NO precursor l-arginine,21 or enhanced degradation of NO by oxygen free radicals.7 22 In the present study, we tested the hypothesis that activation of ACE (Reference 8 ) contributes to endothelial dysfunction in patients with CHF. Because ACE is identical to kininase II, which inactivates bradykinin, activation of ACE is expected to be associated with enhanced inactivation of bradykinin, leading to reduced bradykinin-mediated endothelial release of NO,9 prostacyclin,10 and endothelium-derived hyperpolarizing factor (EDHF).11 Conversely, ACE inhibition increases bradykinin plasma level in vivo23 and improves endothelium-mediated vasodilation in healthy volunteers by a bradykinin-mediated mechanism.17 These previous studies raised the possibility that ACE inhibition provides a valuable tool to improve the impaired endothelium-mediated vasodilation in patients with CHF. In the present study, therefore, we randomized 40 patients with CHF to receive quinaprilat, enalaprilat, or placebo to compare their effects on endothelium-mediated vasodilation. Although FDD during control conditions was similar in all 3 groups of patients, only quinaprilat improved the impaired FDD of the radial artery in patients with CHF by >40%, whereas enalaprilat and placebo had no effect on FDD. Quinaprilat improved FDD in patients with CHF in the present study to an extent similar to that in healthy volunteers with the same dose of quinaprilat.17 The finding that enalaprilat did not affect endothelium-mediated vasodilation was surprising; however, it is consistent with recent observations in patients with severe heart failure24 and essential hypertension,25 in whom enalaprilat failed to improve the impaired endothelium-mediated vasodilation in forearm resistance arteries. The result that quinaprilat improved endothelium-mediated vasodilation but enalaprilat had no effect raises the question of what underlying mechanism might explain this finding. To compare the effects of enalaprilat and quinaprilat, we used dosages known to be equipotent with regard to their ability to inhibit formation of angiotensin II from angiotensin I in the forearm circulation.19 Therefore, it appears to be unlikely that the lack of effect of enalaprilat on endothelium-mediated vasodilation can be explained by the dose of enalaprilat used in the present study. Moreover, enalaprilat did not improve endothelium-mediated vasodilation even when the dose was increased to the 20-fold dose of quinaprilat (protocol 4). To further prove a potential difference between quinaprilat and enalaprilat in terms of their impact on endothelium-dependent effects, we compared both substances in a further series of experiments intraindividually (protocol 2). The beneficial effect of quinaprilat on FDD cannot be explained by repeated infusion of an ACE inhibitor into 1 vascular bed, because repeated infusion of enalaprilat did not affect FDD (protocol 3). Taken together, it is unlikely that the observed difference between quinaprilat and enalaprilat can be explained by dose effects. In contrast, our results suggest that an intrinsic characteristic of quinaprilat is responsible for its effect on endothelium-mediated vasodilation. Experimental data suggest that differences exist between ACE inhibitors with regard to their affinity to tissue ACE, ie, their ability to inhibit plasma ACE and tissue ACE within the vascular wall.13 14 15 Experimental evidence suggests that quinaprilat has a high affinity to tissue ACE, whereas the affinity of enalaprilat to tissue ACE is low.13 14 15 The results of the present study therefore would be consistent with the concept that affinity to tissue ACE is important to affect endothelium-mediated vasodilation in humans. The present study cannot answer the question of whether the observed difference between quinaprilat and enalaprilat persists during chronic therapy. However, preliminary data from the Brachial Artery Normalization of Forearm Flow Function (BANFF) trial suggest that the observed difference between quinaprilat and enalaprilat persists during long-term therapy for 8 weeks.26
We have previously shown that the part of FDD mediated by NO is severely reduced in patients with CHF.6 In the present study, the portion of FDD mediated by NO was improved after quinaprilat, suggesting that quinaprilat improves endothelium-mediated vasodilation by an increased availability of NO. The present study was not designed to elucidate the involvement of bradykinin, ie, whether or not this effect is bradykinin-mediated. Recent data from our laboratory, however, obtained in healthy volunteers17 showed that the beneficial effect of quinaprilat on FDD is completely blocked after coinfusion with a bradykinin-receptor antagonist, suggesting that quinaprilat improves endothelium-mediated vasodilation by a bradykinin-mediated mechanism. It is unlikely that endothelial release of vasodilating prostaglandins can explain the increased availability of NO after quinaprilat in the present study, because all patients were pretreated with aspirin in a dose known to effectively block vascular cyclooxygenase.18 Most likely, quinaprilat increased FDD by enhanced endothelial release of NO and/or EDHF secondary to the increased availability of endogenous bradykinin. This interpretation is supported by experimental studies demonstrating that ACE inhibition potentiates endothelium-dependent vasodilation by increased release of NO and EDHF.11 However, there is also experimental evidence that ACE inhibitors might influence endothelial function not only by inhibition of bradykinin degradation but also secondary to accumulation of angiotensin I and its metabolite angiotensin-(1-7), which may cause bradykinin B2 receptor–linked release of kinins.27 However, it is unclear as yet whether this mechanism plays a role in humans.
Apparently, the beneficial effect of ACE inhibition did not play a role under resting conditions, because quinaprilat at the dose selected in the present study had no effect on radial artery diameter and blood flow. During flow-stimulated conditions, however, ie, during physical activity, quinaprilat may cause a marked improvement of FDD. It is important to note that the maximal reactive hyperemic blood flow response after release of wrist occlusion was not different at control or after quinaprilat, enalaprilat, placebo, L-NMMA, or coinfusion conditions. Therefore, the stimulus that caused endothelium-mediated dilation was similar during the different interventions.
Previous studies have shown that oral captopril exerts a decrease in peripheral vascular resistance in healthy volunteers28 and that quinaprilat increases total forearm blood flow, as determined by venous occlusion plethysmography.19 Therefore, it may be surprising that in the present study, quinaprilat and enalaprilat did not affect forearm blood flow during resting conditions and during reactive hyperemia after wrist occlusion. It should be noted, however, that we did not measure total forearm blood flow but rather blood flow in the radial artery, including the hand circulation. Because the hand circulation is related primarily to vasodilation in a skin vascular bed, it may not respond to ACE inhibition in the same way. However, the present study was specifically designed to evaluate FDD and reactive hyperemia serving as stimulus leading to endothelium-mediated changes in conduit artery diameter.
It seems unlikely that the beneficial effect of quinaprilat on FDD can be explained as an unspecific effect on vascular smooth muscle function rather than the endothelium, because in the present study, neither quinaprilat nor enalaprilat affected radial artery diameter and blood flow during resting conditions. Furthermore, the vasodilator response to SNP was similar in patients treated with quinaprilat, enalaprilat, and placebo. This is consistent with recent findings in healthy volunteers as well as patients with CHF, demonstrating that ACE inhibition did not change response to SNP in the forearm circulation.24 29
Limitations of the Study
The present study suggests that differences exist between ACE inhibitors with regard to their effect on endothelium-mediated vasodilation after short-term ACE inhibition. However, it remains to be determined whether the observed difference persists during long-term therapy. In addition, the clinical impact of improved endothelial function remains to be established, because ACE inhibitors like enalapril improved outcome in large clinical trials.30 A further possible limitation of the present study is that the last dose of captopril was given 24 hours before the study. Therefore, it is likely that an extraordinary amount of angiotensin I was present because of an ACE inhibitor–mediated increase in renin. However, quinaprilat improved FDD to a similar extent in patients with and without previous therapy with captopril. Enalaprilat did not affect FDD in patients with and without previous therapy with captopril. Therefore, the observed difference between quinaprilat and enalaprilat on FDD cannot be explained by an ACE inhibitor–mediated increase in renin.
In conclusion, the present study demonstrates that endothelial dysfunction in patients with CHF can be improved by the ACE inhibitor quinaprilat but not by enalaprilat. Our results extend previous findings reporting beneficial effects of acute administration of ACE inhibitors on endothelium-mediated vasodilation in healthy volunteers. Importantly, the present study indicates that the beneficial effect of quinaprilat is related to increased availability of NO. In addition, the present study suggests that differences exist among ACE inhibitors with regard to their ability to improve endothelial function. Whether this beneficial effect persists during long-term treatment and is translated into clinical benefit needs to be confirmed by further studies.
This study was supported in part by the Deutsche Forschungsgemeinschaft (Dr 148/7-2). Dr Arakawa was supported by a grant from the Japan-Europe Scientist Exchange Program from the CIBA-Geigy Foundation.
- Received June 22, 1998.
- Revision received September 8, 1998.
- Accepted September 16, 1998.
- Copyright © 1998 by American Heart Association
Henderson AH. St Cyres lecture. Endothelium in control. Br Heart J. 1991;65:116–125.
Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-dependent dilation is attenuated in patients with heart failure. Circulation. 1991;84:1589–1596.
Hayoz D, Drexler H, Münzel T, Hornig B, Zeiher A, Just H, Brunner HR, Zelis R. Flow-mediated arteriolar dilation is abnormal in congestive heart failure. Circulation. 1993;87(suppl VII):VII-92–VII-96.
Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation. 1996;93:210–214.
Hornig B, Arakawa N, Kohler C, Drexler H. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation. 1998;97:363–368.
Studer R, Reinecke H, Müller B, Holtz J, Just H, Drexler H. Increased angiotensin-I converting enzyme gene expression in the failing human heart. J Clin Invest. 1994;94:301–310.
Mombouli JV, Illiano S, Nagao T, Scott-Burden T, Vanhoutte PM. Potentiation of endothelium-dependent relaxations to bradykinin by angiotensin-I converting enzyme inhibitors in canine coronary arteries involve both endothelium-derived relaxing and hyperpolarizing factors. Circ Res. 1992;71:137–144.
Kinoshita A, Urata H, Bumpus M, Husain A. Measurement of angiotensin I converting enzyme inhibition in the heart. Circ Res. 1993;73:51–60.
Johnston CI, Jandeleit K, Mooser V, Katapothis A, Perich R, Paxton D, Murohara Y, Jackson B. Angiotensin-converting enzyme and its inhibition in the heart and blood vessels. J Cardiovasc Pharmacol. 1992;20(suppl B):S6–S11.
Johnston CI, Fabris B, Yamada H, Mendelsohn FAO, Cubela R, Sivell D, Jackson B. Comparative studies of tissue inhibition by angiotensin converting enzyme inhibitors. J Hypertens. 1989;7(suppl 5):S11–S16.
Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation. 1997;95:1115–1118.
Haefeli WE, Linder L, Lüscher TF. Quinaprilat induces arterial vasodilation mediated by nitric oxide in humans. Hypertension. 1997;30:912–917.
Smith CJ, Sun D, Hoegler C, Roth BS, Zhang X, Zhao G, Xu X, Kobari Y, Pritchard K, Sessa WC, Hintze TH. Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. Circ Res. 1996;78:58–64.
Hirooka Y, Imaizumi T, Tagawa T, Shiramoto M, Endo T, Ando S, Takeshita A. Effects of l-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation. 1994;90:658–668.
Belch JJF, Bridges AB, Scott N, Chopra M. Oxygen free radicals and congestive heart failure. Br Heart J. 1991;65:245–248.
Craeger MA, Roddy M. Effect of captopril and enalapril on endothelial function in hypertensive patients. Hypertension. 1994;24:499–505.
Anderson TJ, Overhiser RW, Haber H, Charbonneau F. A comparative study of four antihypertensive agents on endothelial function in patients with coronary artery disease. J Am Coll Cardiol. 1998;31(suppl A):1147–1154. Abstract.
Kiowski W, Linder L, Kleinbloesem C, Van Brommelen P, Bühler FR. Blood pressure control by the renin-angiotensin system in normotensive subjects: assessment by angiotensin converting enzyme and renin inhibition. Circulation. 1992;85:1–8.
Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, Benedict C, Rousseau M, Bourassa M, Pitt B. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fraction. Lancet. 1992;340:1173–1178.We hypothesized that activation of ACE is involved in endothelial dysfunction in patients with chronic heart failure. Using high-resolution ultrasound, we measured the effects of quinaprilat, enalaprilat, and L-NMMA (NO inhibitor) on radial artery diameter and blood flow in 40 patients with CHF at rest and during reactive hyperemia. Quinaprilat improved flow-dependent dilation by 40%; enalaprilat had no effect. In particular, the part of FDD mediated by NO was improved after quinaprilat by >100%. Therefore, we conclude that quinaprilat improves endothelial function in patients with CHF due to an increased availability of NO.