(Circulation. 2001;103:799.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Comparative Effect of ACE Inhibition and Angiotensin II Type 1 Receptor Antagonism on Bioavailability of Nitric Oxide in Patients With Coronary Artery Disease
Role of Superoxide Dismutase
From the Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Correspondence to Burkhard Hornig, MD, Medizinische Hochschule Hannover, Abteilung Kardiologie und Angiologie, Carl Neuberg Straße 1, 30625 Hannover, Germany. E-mail hornig.burkhard{at}mh-hannover.de
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Abstract |
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Background—Flow-dependent, endothelium-mediated vasodilation (FDD) and activity of extracellular superoxide dismutase (EC-SOD), the major antioxidative enzyme of the arterial wall, are severely impaired in patients with coronary artery disease (CAD). We hypothesized that both ACE inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT1-A) increase bioavailability of nitric oxide (NO) by reducing oxidative stress in the vessel wall, possibly by increasing EC-SOD activity.
Methods and Results—Thirty-five patients with CAD were randomized to 4 weeks of ACEI (ramipril 10 mg/d) or AT1-A (losartan 100 mg/d). FDD of the radial artery was determined by high-resolution ultrasound before and after intra-arterial N-monomethyl-L-arginine (L-NMMA) to inhibit NO synthase and before and after intra-arterial vitamin C to determine the portion of FDD inhibited by oxygen free radicals. EC-SOD activity was determined after release from endothelium by heparin bolus injection. FDD was improved after ramipril and losartan (each group P<0.01), and in particular, the portion of FDD mediated by NO, ie, inhibited by L-NMMA, was increased by >75% (each group P<0.01). Vitamin C improved FDD initially, an effect that was lost after ramipril or losartan. After therapy, EC-SOD activity was increased by >200% in both groups (ACEI, 14.4±1.1 versus 3.8±0.9 and AT1-A, 13.5±1.0 versus 3.9±0.9 U · mL-1 · min-1; each P<0.01).
Conclusions—Four weeks of therapy with ramipril or losartan improves endothelial function to similar extents in patients with CAD by increasing the bioavailability of NO. Our results suggest that beneficial long-term effects of interference with the renin-angiotensin system may be related to reduction of oxidative stress within the arterial wall, mediated in part by increased EC-SOD activity.
Key Words: inhibitors • angiotensin • endothelium • coronary disease • superoxide dismutase
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Introduction |
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In patients with coronary artery disease (CAD), endothelial dysfunction contributes to the abnormal vasomotor response to exercise, exposure to cold, or mental stress and may trigger myocardial ischemia.1 In addition, the long-term follow-up of patients with endothelial dysfunction suggests that reduced bioavailability of nitric oxide (NO) may even have prognostic implications and contribute to progression of coronary atherosclerosis, because impaired endothelium-mediated vasomotion is associated with future cardiovascular events.2 Therefore, restoring endothelial function represents an attractive novel therapeutic target in patients with CAD. The Trial on Reversing Endothelial Dysfunction (TREND) has shown that ACE inhibitors (ACEIs) improve coronary endothelium-dependent vasomotor function in patients with CAD,3 a mechanism that may well contribute to the beneficial effects of ACE inhibition on cardiovascular mortality.4 Angiotensin II type 1 (AT1)–receptor antagonists are popular drugs frequently prescribed for treatment of hypertension or heart failure,5 and experimental data suggest that AT1-receptor antagonists have the potential to improve endothelium-mediated vasomotion.6 7 The comparative effects of ACEI and AT1-receptor antagonists on endothelial function in patients with CAD, however, are controversial.8 9
There is evidence that increased inactivation of NO by superoxide anions contributes to impaired endothelial function in patients with CAD.10 Experimental data suggest that AT1-receptor antagonists improve endothelial function by reducing NADH oxidase–mediated superoxide anion formation.7 So far, however, it is unclear whether AT1-receptor antagonists affect the activity of vascular antioxidative enzyme systems, such as extracellular superoxide dismutase (EC-SOD). We recently showed that activity of vascular EC-SOD, the major antioxidative enzyme system of the human arterial wall, is severely reduced in patients with CAD and is closely related to NO-mediated vasodilation,11 supporting the concept that reduced activity of EC-SOD contributes to increased oxidative stress in patients with CAD, leading to reduced bioavailability of NO. Fukai and colleagues12 demonstrated that the bioavailability of NO modulates the activity of vascular EC-SOD, raising the question of whether therapeutic interventions that increase the bioavailability of NO increase EC-SOD activity. Short-term intra-arterial infusion of an ACEI has the potential to increase the bioavailability of NO during flow-dependent, endothelium-mediated vasodilation (FDD).13 In the present study, we tested the hypothesis that 4 weeks of oral therapy with the ACEI ramipril or the AT1-receptor antagonist losartan increases the bioavailability of NO and the activity of EC-SOD and improves endothelium-mediated vasodilation in patients with CAD.
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Methods |
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Thirty-five patients with angiographically documented CAD (
1 diameter stenosis 60%) were studied. All patients were
clinically stable whites without present indications for
interventional or surgical revascularization. All patients were on
long-term therapy with aspirin, and with the exception of 1 patient in
each group, all were on long-term therapy with 
-blockers.
Aspirin and -blockers were used on the day of measurement as they
were every day. Calcium antagonists, diuretics, and sustained-release
or long-acting preparations of nitrates were not used by the patients.
Short-acting nitrates were withheld and alcohol and caffeine were
prohibited for 12 hours before the study. Because we were interested
in evaluating the long-term effect of ramipril and losartan rather than
the short-term effect of an oral dose after long-term therapy, we
elected to study our patients >12 hours after the last dose in the
morning of the following day, beginning between 9 and 10
AM. A breakfast including
clear liquids (no juice) and cereals was allowed before the
measurements. Characteristics of the patients are shown in
Table 1
. Patients with uncontrolled hypertension
(Riva-Rocci sphygmomanometer >140/90 mm Hg at rest despite
therapy), diabetes mellitus, current tobacco use, congestive heart
failure, significant valvular heart disease, or severe renal or hepatic
disease were excluded from the study by careful history, physical
examination, ECG, and laboratory analysis. Patients who had previously
received ACEIs, AT1-receptor antagonists, or
antioxidant vitamin supplements were not included in the protocol.
Written informed consent was obtained for all subjects, and the
protocol was approved by the local ethics committee.
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Protocol
Patients were randomized to 4 weeks of treatment with
the maximally approved dose of ramipril (5 mg
BID4 ) or losartan (50
mg BID). At baseline and after 4 weeks of therapy, FDD of the radial
artery was determined. FDD was measured before and after intra-arterial
infusion of the NO synthase inhibitor
N-monomethyl-L-arginine
(L-NMMA) to determine the NO-mediated portion of FDD, ie, the
bioavailability of NO. In addition, FDD was determined before and after
intra-arterial infusion of the antioxidant vitamin C to determine the
portion of FDD inhibited by oxygen free radicals. Furthermore,
endothelium-bound EC-SOD (eEC-SOD) activity was measured before and
after 4 weeks of treatment.
Measurement of FDD
Radial artery diameter was measured by
high-resolution ultrasound
(Asulab).14 This method is
well established in our
laboratory,11 13 15 16
has an excellent reproducibility and variability, and was used as
described recently.17 Blood
flow velocity was recorded continuously, and radial artery diameter was
determined every 30 seconds until stable baseline conditions were
obtained (
30 minutes). Then a wrist arterial occlusion (8 minutes)
was performed, and FDD in response to reactive hyperemic blood flow was
assessed at baseline and after intra-arterial infusion of L-NMMA
(Clinalfa; 7 µmol/min; 5
minutes).17 When radial
artery diameter and blood flow had returned to baseline values, FDD was
determined again after intra-arterial infusion of vitamin C (25 mg/min;
10 minutes), followed by determination of FDD after coinfusion of
vitamin C and L-NMMA.17
Finally, all subjects received an intra-arterial infusion of sodium
nitroprusside (SNP; 10 µg/min; 5 minutes) to assess
endothelium-independent vasodilatory capacity. Six patients with CAD
were randomized to receive intra-arterial infusion of placebo before
vitamin C. Blood flow and diameter data reported for L-NMMA, vitamin C,
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 unaware of the
sequence of interventions and treatment
assignment.
Determination of eEC-SOD Activity In
Vivo
EC-SOD is specifically released from endothelium into
plasma by heparin bolus injection, allowing determination of eEC-SOD
activity in humans in
vivo.11 18 19
In brief, to measure plasma SOD activity at baseline, 2 arterial
(brachial artery) and 2 venous (antecubital vein) blood samples were
drawn. Then 5000 U of heparin was injected into the brachial artery,
and blood samples were drawn from the antecubital vein of the same arm
(1, 3, 5, 7, and 10 minutes after heparin injection). eEC-SOD activity
(U · mL-1 · min-1)
was calculated as area under the curve of the increase of plasma SOD
activity within 10 minutes after heparin injection. The time interval
of 10 minutes was used because maximum increase of plasma SOD activity
was approached within this
time.11 The coefficient of
variation for determination of eEC-SOD activity was 7.6%. For blood
sampling, EDTA-containing vacuum tubes were used to avoid the cellular
leakage of Cu,Zn-SOD from vascular and skeletal muscle cells observed
after use of a tourniquet.20
Tubes were immediately centrifuged
(2000g, 15 minutes, 4°C), and
plasma was stored at -80°C. Activity of SOD was measured at pH 8.2
by a modified nitrite
method.21 Superoxide
generated by hypoxanthine and xanthine oxidase was changed to nitrite
ion by hydroxylamine. Nitrite ion was measured by color densitometry at
550 nm using a coloring reagent. The amount of SOD necessary to inhibit
the rate of nitrite ion generation by 50% was defined as 1 U of SOD
activity, according to McCord and
Fridovich.22 Calibrations
were performed with known amounts of purified bovine SOD. To
distinguish between cyanide-sensitive isoenzymes (Cu,Zn-SOD and EC-SOD)
and the resistant one (MnSOD), 2 mmol/L cyanide was used. For specific
analysis of EC-SOD activity in plasma, chromatography on Con
A-Sepharose (Pharmacia Biotech) was performed as described
previously.23 Unlike
Cu,Zn-SOD and Mn-SOD, the glycoprotein EC-SOD binds to the lectin
concanavalin A. Cu,Zn-SOD activity was calculated as cyanide-sensitive
SOD activity minus EC-SOD activity. Reagents were from
Sigma-Aldrich.
Statistical Analysis
All data are expressed as mean±SEM. Comparisons of
>2 measurements were done by 1-way ANOVA for repeated measures
followed by Student-Newman-Keuls test (comparisons within 1 group of
patients and between the different groups of patients). A value of
P<0.05 was considered to be
statistically significant.
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Results |
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Flow-Dependent, Endothelium-Mediated Vasodilation
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. Before therapy, FDD during control conditions was
similar in patients randomized to receive ramipril or losartan
(Table 2,
Figure 1). The effects of 4 weeks of treatment with ramipril
or losartan on radial artery diameter at baseline and during FDD are
given in
Table 2. FDD was significantly increased after 4 weeks of
treatment with ramipril or losartan
(Figure 1, Table 2). There was no significant difference between the
effects of ramipril and losartan on FDD. The portion of FDD mediated by
NO (represented by the portion of FDD inhibited by L-NMMA) was
significantly increased after 4 weeks of treatment with ramipril
(6.3±0.6% versus 2.6±0.6%;
P<0.01) or losartan
(5.5±0.6% versus 1.8±0.6%;
P<0.01), with no significant
difference between the 2 drugs. Intra-arterial infusion of vitamin C
improved FDD at baseline, but not after 4 weeks of treatment with
ramipril and losartan
(Figure 2;
Table 2). Intra-arterial SNP increased radial artery
diameter to a similar extent before and after treatment with losartan
or ramipril (before/after ramipril, 3.02±0.1 to 3.50±0.1/3.04±0.1 to
3.53±0.1 mm; before/after losartan, 3.04±0.1 to 3.57±0.1/3.00±0.1
to 3.59±0.1 mm; each P<0.01
versus before SNP).
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The effects of L-NMMA and vitamin C on radial artery blood
flow before and after treatment with losartan or ramipril are shown in
Table 3.
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Systemic blood pressure and heart rate did not change during the experimental protocol. There was no significant difference of systemic blood pressure after 4 weeks of treatment with losartan or ramipril (data not shown).
eEC-SOD Activity
eEC-SOD activity was increased by >200% after
treatment with losartan and ramipril (before/after losartan, 3.9±0.9
versus 13.5±1.0; before/after ramipril, 3.8±0.9 versus 14.4±1.1
U · mL-1 · min-1;
P<0.01 versus before
treatment;
Figure 3). There was no significant difference between the
effects of losartan and ramipril on eEC-SOD activity. There was a
positive relationship between increase of NO bioavailability during FDD
and increase of EC-SOD activity after 4 weeks of treatment (ramipril,
r=0.80; losartan,
r=0.76; each
P<0.01;
Figure 4, top). In addition, there was a positive
relationship between increase of EC-SOD activity after 4 weeks and
reduction of the short-term effect of intra-arterial vitamin C on FDD
(= effect of vitamin C on FDD before therapy minus effect of vitamin C
on FDD after 4 weeks of therapy; ramipril,
r=0.82; losartan,
r=0.78; each
P<0.01;
Figure 4, bottom). Thus, there was a marked reduction of the
effect of vitamin C on FDD in patients with a large increase of EC-SOD
activity after 4 weeks of therapy with ramipril or
losartan.
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Discussion |
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The major findings of the present study are as follows. (1) Four weeks of therapy with the ACEI ramipril or with the AT1-receptor antagonist losartan improves endothelium-dependent vasodilation to a similar extent in patients with CAD. (2) The beneficial effect of ramipril and losartan on endothelium-dependent vasodilation is mediated by an increased bioavailability of NO, because the portion of FDD mediated by NO was increased after treatment with ramipril and losartan. (3) The antioxidant vitamin C improved FDD at baseline but not after treatment with ramipril and losartan, suggesting that reduction of oxidative stress in the vessel wall contributes to the beneficial effect of ramipril and losartan on endothelial function. (4) The activity of eEC-SOD, the major antioxidative enzyme system of the human arterial wall, was increased by >200% after treatment with ramipril and losartan. This effect of ramipril and losartan on eEC-SOD activity may represent one of the underlying mechanisms responsible for the observed antioxidative effect of losartan and ramipril.
The HOPE study, which involved more than 9000 patients with preserved left ventricular function, showed that ACE inhibition results in a marked reduction of cardiovascular events largely independent of the effect on systemic blood pressure.4 The beneficial effect of ACE inhibition emerged after 6 months of therapy, raising the possibility that functional aspects of the vascular wall, including endothelial function, may be involved. Because it is unclear whether AT1-receptor antagonists have vascular effects similar to those of ACEIs, the present study compared the effect of the target dose of ramipril in the HOPE study with the maximal recommended doses of the AT1-receptor antagonist losartan on endothelium-dependent vasodilation in patients with CAD. We found that ACE inhibition and AT1 antagonism improved endothelium-dependent vasodilation to a similar extent in patients with CAD by increasing the bioavailability of NO. The results cannot be explained by an antihypertensive effect of ramipril or losartan, because blood pressure was unchanged after treatment. Therefore, a specific effect of ramipril and losartan on the function of the arterial wall must account for the increased bioavailability of NO during FDD after 4 weeks of therapy. There is increasing evidence that inactivation of NO by superoxide anions contributes to impaired endothelium-dependent vasodilation in patients with CAD,10 24 25 raising the question of whether the beneficial long-term effect of ACEIs on endothelial function3 and cardiovascular mortality and morbidity4 is mediated in part by antioxidative properties of the drug. Angiotensin II stimulates superoxide anion generation in vascular smooth muscle cells.26 We therefore hypothesized that both ACEIs and AT1-receptor antagonists, by preventing the vascular actions of angiotensin II, increase the bioavailability of NO by reducing superoxide anion generation within the vessel wall. To estimate the contribution of superoxide anion–mediated inactivation of NO in vivo, we determined the effect of the antioxidant vitamin C on endothelium-dependent vasodilation before and after treatment with ramipril and losartan.10 17 Before treatment with ramipril or losartan, vitamin C improved NO-mediated vasodilation in all patients, an effect that was lost after 4 weeks of both therapy regimens. This suggests that both drugs have antioxidative properties during long-term therapy.
EC-SOD has recently been reported to be a major antioxidant enzyme system of the human arterial vessel wall27 28 located strategically between endothelium and vascular smooth muscle cells in the compartment of the vessel wall in which NO is expected to be inactivated by superoxide anions. Inhibition of vascular SOD activity resulted in impaired endothelium-dependent vasodilation in bovine coronary arteries, suggesting that SOD levels are critical for the ability of NO to modulate vascular tone.29 We recently showed that vascular EC-SOD activity is substantially reduced in patients with CAD and positively related to endothelium-dependent vasodilation.11 Furthermore, vascular EC-SOD activity was inversely related to the effect of the antioxidant vitamin C on FDD, consistent with the notion that reduced vascular EC-SOD activity contributes to impairment of endothelium-mediated vasodilation in patients with CAD. In the present study, we observed a marked increase of eEC-SOD activity after 4 weeks of therapy with ramipril and losartan. In addition, we found a positive correlation between the increase of EC-SOD activity and the increase of NO bioavailability after 4 weeks of therapy in both therapy groups. This suggests that restoration of EC-SOD activity is associated with improvement of endothelial function in patients with CAD; it does not, however, establish a cause-and-effect relationship. Furthermore, we found a positive correlation between increase of EC-SOD activity and reduction of therapeutic effect of vitamin C on FDD, suggesting that increased EC-SOD activity is associated with reduced oxidative stress in vivo. Our results are therefore consistent with the notion that improved activity of EC-SOD contributes to the antioxidative effects of ramipril and losartan in addition to the reduction of angiotensin II–induced radical formation, as suggested by recent experimental work.7 An alternative explanation for the improved EC-SOD activity after therapy with ramipril and losartan is that both drugs increase the bioavailability of NO, possibly by activation of the bradykinin-NO cascade,16 30 which in turn may enhance the expression and activity of EC-SOD. This concept would be consistent with data of Fukai et al12 demonstrating that EC-SOD activity is severely reduced in eNOS-deficient mice but increased in response to enhanced bioavailability of NO.
It may be surprising that we did not observe a significant difference between the effect of ACE inhibition and AT1-receptor blockade on endothelium-mediated vasodilation in patients with CAD, as was observed recently.8 This may be explained by the lower dose of losartan used in the Brachial Artery Normalization of Forearm Function (BANFF) study (50 mg/d) than in our study (100 mg/d). Furthermore, in the BANFF study, endothelium-mediated vasodilation of the brachial artery was determined, whereas the radial artery was used in our protocol. Because it is known that flow-mediated vasodilation is inversely related to the vessel size, it may be easier to detect changes of endothelium-mediated vasodilation after therapy by use of our method. Because measurements after therapy were performed only at 1 point in time (4 weeks), it cannot be concluded from the present study that both agents have similar effects during longer therapy, because the 2 drugs may have different time courses in terms of their vascular effects.
We have previously shown that bradykinin is involved in the vascular effects of ACE inhibition in healthy subjects,16 which may be secondary to reduced bradykinin breakdown or interference with sequestration of the B2 kinin receptor.31 These results raised the possibility that ACE inhibition might have a superior effect on endothelium-dependent vasodilation compared with AT1-receptor antagonists. There is now increasing experimental evidence,30 32 33 however, that AT1-receptor blockade may lead to bradykinin-dependent release of NO from the endothelium, effects mediated by increased AT2-receptor stimulation.
Study Limitations
The study was not blinded, which represents a possible
limitation. To deal with this potential bias, measurements were
performed by investigators unaware of randomization status (B.H., U.L.,
C.K.). In addition, all measurements were recorded, and subsequently,
vessel diameter and blood flow velocity were analyzed by 2
investigators unaware of the sequence of interventions or treatment
assignment (B.H., U.L.).
There is evidence that losartan increases uric acid excretion in normal control subjects34 and patients with hypertension.35 Because uric acid may exert oxidative stress, this effect of losartan might contribute to the antioxidative effects observed in our study. Losartan does not lower uric acid plasma concentrations,35 however, which may be more relevant for oxidative stress within the vascular wall. Thus, although we cannot exclude the possibility that increased uric acid excretion was a contributing factor, it is very unlikely that the uricosuric effect of losartan can explain the effects of losartan on the endothelium-mediated vasodilation and activity of EC-SOD activity observed in the present study.
In conclusion, our present work suggests that the ACEI ramipril and the AT1-receptor antagonist losartan have comparable effects on endothelial function after 4 weeks of therapy, ie, both drugs increase bioavailability of NO, improve NO-mediated vasodilation, and increase EC-SOD activity to a similar extent in patients with CAD. These effects are mediated at least in part by a reduction of oxidative stress within the vessel wall, because the antioxidant vitamin C improves endothelium-mediated vasodilation before but not after therapy with ramipril and losartan. Increased EC-SOD activity may well represent 1 mechanism contributing to the antioxidative properties of ACEIs and AT1-receptor antagonists in patients with CAD.
Received May 31, 2000; revision received October 4, 2000; accepted October 4, 2000.
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