(Hypertension. 2001;37:40.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Vascular Effects of ACE Inhibition Independent of the Renin-Angiotensin System in Hypertensive Renovascular Disease
A Randomized, Double-Blind, Crossover Trial
From the Department of Nephrology and Hypertension (J.M.A. van A., J.J.B., H.A.K.), University Medical Center Utrecht, Utrecht, the Netherlands; and Department of Vascular Medicine (J.M.A. van A., M.L.H., R.E. van E., T.J.R., E.S.G.S.), University Medical Center Utrecht, Utrecht, the Netherlands.
Correspondence to Dr E.S.G. Stroes, Department of Vascular Medicine, F03.226, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. E-mail E.Stroes{at}digd.azu.nl
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Abstract |
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Abstract—To evaluate whether ACE inhibition and angiotensin II type 1 blockade exert beneficial effects on NO availability independent of their blood pressure–lowering effect, we used a double-blind crossover design to study vascular function in 18 patients with hypertensive renovascular disease during 6 weeks of therapy with enalapril (Ena) and valsartan (Val) compared with non–renin-angiotensin system–mediated treatment with the
1-blocker doxazosin (Dox). Control
measurements were performed in 13 age-matched volunteers. Forearm blood
flow was assessed with venous occlusion plethysmography, and
serotonin and nitroprusside were used as
endothelium-dependent and -independent vasodilators,
respectively. Blood pressure was similar during all treatment periods.
Serotonin-induced vasodilation was decreased in patients
during Dox treatment (n=12) compared with control subjects (n=13)
(increase 42±20% versus 107±65%, P<0.05). Crossover
from Dox to Val (n=6) had no effect on serotonin response
(increase 50±14%), but crossover to Ena (n=6) caused a significant
improvement (increase 79±39%, P<0.05 versus Dox). In
an assessment of all patients, serotonin-induced
vasodilation during Ena (n=12, increase 75±31%) was increased
compared with both Val and Dox (43±14% and 42±20%, respectively;
both P<0.05 versus Ena). The nitroprusside response
remained unaltered during all treatment periods. In conclusion, ACE
inhibition improves the impaired endothelium-dependent
vascular function in patients with hypertensive renovascular disease.
This effect is unrelated to blood pressure–lowering or
angiotensin II–mediated effects.
Key Words: endothelium • angiotensin-converting enzyme inhibitors • angiotensin • receptors, angiotensin • nitric oxide • hypertension, renovascular
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Introduction |
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During the past decade, the assessment of endothelial function has been incorporated in cardiovascular prevention trials as a potential intermediate end point for cardiovascular disease.1 2 Currently, data are accumulating to show that endothelial dysfunction has prognostic value for the occurrence of future cardiovascular disease.3 4 5 The latter observation, taken together with the large burden of evidence showing that NO is a pivotal player in the antiatherogenic effects of the endothelium,6 7 underscores the relevance of improving endothelial function as a potential therapeutic target.
The renin-angiotensin system interacts with endothelial function and, in particular, with NO availability in several ways. First, angiotensin II (Ang II) not only induces a potent vasoconstrictor response but also stimulates NAD(P)H:oxidase–dependent oxygen radical release.8 9 10 Both of these actions are mediated through the Ang II type 1 receptor.8 11 Oxygen radicals react with NO at a diffusion limited rate and thus contribute to impaired NO availability.12 13 Second, the Ang II type 2 receptor has been suggested to induce NO release on activation by Ang II.14 Third, ACE not only mediates conversion from Ang I to Ang II but is also responsible for the degradation of bradykinin.15 16 Bradykinin has direct stimulatory effects on NO synthase, resulting in increased NO release. Thus, theoretically, both Ang II type 1 receptor antagonists and ACE inhibitors may have beneficial effects on endothelial function. Thus far, several studies have shown an improvement in endothelial function by ACE inhibition in atherosclerotic,17 18 diabetic,19 20 and hypertensive21 subjects. In contrast, the effect of Ang II type 1 receptor antagonists on endothelial function remains to be established.
To evaluate the extent to which the various pathways (ie, Ang II,
bradykinin, and/or blood pressure lowering per se) contribute to
changes in NO availability in vivo, we evaluated vascular function in
patients with hypertensive renovascular disease and healthy age-matched
control subjects. Patients were studied during blood pressure–lowering
therapy with ACE inhibition, Ang II type 1 receptor blockade, and
1-blockade, respectively.
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Methods |
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Subjects
Eighteen patients (5 women and 13 men, mean age 63±8 years) with atherosclerotic renovascular disease participated in this study. Thirteen healthy, age-matched control subjects (5 women and 8 men, mean age 59±9 years) without signs of macrovascular disease, use of vasoactive drugs, or both were assessed simultaneously. All subjects refrained from tobacco, alcohol, and caffeine-containing drinks for
12 hours before measurements were performed. All subjects
gave written informed consent. The study was approved by the University
Medical Center Utrecht Ethical Committee for Studies in
Humans. The procedures followed were in accordance with
institutional guidelines.
Study Design
Vascular function in control subjects was evaluated once at
baseline. The patients were subdivided into 3 groups of 6 patients
each. The first 6 patients were randomized to receive doxazosin (8 mg)
for 6 weeks, followed by enalapril (40 mg) for 6 weeks, or vice versa.
The second 6 patients received doxazosin (8 mg) for 6 weeks, followed
by valsartan (160 mg) for 6 weeks, or vice versa. The final 6 patients
received enalapril (40 mg) for 6 weeks, followed by valsartan (160 mg),
or vice versa. If blood pressure remained above 150 mm Hg
systolic or 85 mm Hg diastolic, furosemide
was added to the medication. Of 12 patients, 8 during doxazosin
therapy, 5 during enalapril therapy, and 6 during valsartan therapy
received furosemide. All antihypertensive medication other than
doxazosin and furosemide were discontinued 1 week before study
inclusion. Vascular function in the forearm of the patients was studied
after each treatment period. The physician who performed the forearm
studies was unaware of the medication used.
Study Protocol
All studies were performed in a quiet room maintained at a
controlled temperature between 22°C and 24.5°C. The subjects were
supine with both forearms resting slightly above heart level. A
20-gauge needle was inserted into the brachial artery after local
anesthesia. Forearm blood flow (FBF) was measured
simultaneously in both arms with venous occlusion
plethysmography as described previously.22 Baseline
measurements were started 30 minutes after cannulation of the
brachial artery, when FBF had stabilized.
For an assessment of endothelium-dependent vasodilatation, serotonin (Sigma Chemical Co) was infused into the brachial artery in increasing doses of 0, 0.2, 0.6, 1.8, and 6.0 ng/100 mL forearm volume (FAV)/min for 5 min/dose. These dosages have previously been shown to cause specific NO-mediated vasodilation.23 For an assessment of endothelium-independent vasodilation, sodium nitroprusside (Merck) was administered intra-arterially at incremental doses of 0, 6, 60, 180, and 600 ng · 100 mL FAV-1 · min-1 for 5 min/dose. The order of these 2 infusion blocks was randomized. Blood samples taken before FBF measurements were tested for creatinine, glucose, total cholesterol, HDL cholesterol, and triglyceride levels.
Analysis
FBF was expressed as mL · 100 mL forearm
tissue-1 · min-1.
Results are expressed as mean±SD. Baseline characteristics of patients
and control subjects were compared with use of an unpaired t
test. Average values of FBF in both arms were obtained for the last 5
or 6 consecutive recordings of each measurement period. Changes
in percent increase/decrease in FBF during serotonin and
nitroprusside infusion were evaluated with repeated measures ANOVA for
the 3 crossover groups (3x n=6). For a comparison of all enalapril
therapy measurements (n=12), all valsartan measurements (n=12) and all
doxazosin measurements (n=12), as well as for a comparison of the
responses in patients versus control subjects, nonrepeated measures
ANOVA was used. If variance ratios reached statistical significance,
differences between the means were analyzed with the
Student-Newman-Keuls test for P<0.05.
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Results |
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The characteristics of patients and control subjects are shown in Table 1. In control subjects, serotonin induced a 107±65% increase in FBF (absolute FBF in the infused arm from 2.5±0.8 to 4.8±2.0; Figure 1). On sodium nitroprusside infusion, FBF increased from 100% to 412±97% (2.6±0.8 to 10.4±3.8; Figure 1). During non–renin-angiotensin system (RAS)–mediated antihypertensive treatment (ie, doxazosin) serotonin-induced, endothelium-dependent vasodilation was significantly impaired in patients versus control subjects (P<0.05; Figure 1), whereas endothelium-independent vasodilation was not significantly different (Figure 1). In both control subjects and patients, FBF in the control arm did not change significantly during the infusion blocks.
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Doxazosin-Enalapril Crossover
Serotonin-induced vasodilation increased significantly
in patients during enalapril compared with during doxazosin. During
doxazosin treatment, serotonin induced a 38±19% increase
in FBF (absolute FBF in the infused arm increased from 2.8±0.6 to
3.9±0.9), whereas during enalapril, the increase was 79±39%
(2.6±0.6 to 4.6±1.5) (P<0.05, doxazosin versus enalapril;
Figure 2).
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On sodium nitroprusside infusion, the FBF increased from 100% to 419±112% (3.1±1.1 to 12.3±2) during doxazosin and from 100% to 436±145% (2.9±0.6 to 12.5±3.4) during enalapril (NS, Figure 3). The mean arterial pressure was 104±16 mm Hg during doxazosin treatment and 97±7 mm Hg during enalapril treatment.
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Doxazosin-Valsartan Crossover
Serotonin-induced vasodilation in patients during
doxazosin treatment was not significantly different from
serotonin-induced vasodilation during valsartan. During
doxazosin treatment, serotonin induced a 45±23% increase
in FBF (absolute FBF in the infused arm from 2.5±1.2 to 3.9±2),
whereas during valsartan, the increase was 50±14% (2.9±0.6 to
4.1±0.7) (NS, Figure 2). On sodium nitroprusside infusion, the
FBF increased from 100% to 415±120% (2.9±1.3 to 11.7±3.5) during
doxazosin and from 100% to 434±123% (2.7±0.9 to 11.4±4.1) during
valsartan (NS, Figure 3). The mean arterial pressure
was 101±10 mm Hg during doxazosin treatment and 103±15
mm Hg during valsartan treatment.
Enalapril-Valsartan Crossover
Serotonin-induced vasodilation in patients during
enalapril treatment was not significantly different from
serotonin-induced vasodilation with valsartan. FBF
increased from 100% to 172±25% (absolute FBF in the infused arm from
3.2±1.1 to 5.6±2.2) during enalapril and from 100% to 136±10%
(3.3±1 to 4.4±1.4) during valsartan (NS, Figure 2). During
sodium nitroprusside infusion, the FBF changed from 100% to 432±121%
(2.9±0.8 to 11.9±3.7) with enalapril and from 100% to
422±131% (3.3±1.1 to 12±3.6) with valsartan (Figure 3). The mean arterial pressure was 96±21
mm Hg during enalapril treatment and 97±16 mm Hg during
valsartan treatment.
On analysis of all treatment periods with serotonin in the patient group, serotonin-induced vasodilation during enalapril (n=12) was significantly increased compared with the response during both doxazosin (n=12) and valsartan (n=12). FBF increased from 100% to 175±31% (2.7±1.0 to 4.7±1.9) with enalapril, from 100% to 142±20% with doxazosin (2.7±0.9 to 3.9±1.5), and from 100% to 143±14% with valsartan (3.1±0.8 to 4.3±1.1) (P<0.05 enalapril versus doxazosin and enalapril versus valsartan; Figure 4). Serum creatinine levels did not change significantly during medication switches.
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Discussion |
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In the present study, we demonstrate that patients with atherosclerotic renovascular disease have an impaired endothelium-dependent vasodilator response compared with age-matched control subjects, whereas endothelium-independent vasomotion remains unaltered. During ACE inhibition, endothelium-dependent vasodilation is significantly enhanced in comparison with both Ang II type 1 receptor blockade and
1-blockade in
these patients. Endothelial dysfunction has been shown to be an early event in the development of atherogenesis2 6 that clearly precedes the development of morphological vessel wall alterations.24 More recently, several groups have independently shown that endothelial dysfunction has a clear prospective value for future cardiovascular disease.3 4 5 In the present study, our patients are characterized by a clear impairment in endothelium-dependent vasodilator response compared with age-matched control subjects. Several factors may have contributed to this dysfunction, including the generalized atherosclerotic state, advanced age, hypertension, and dyslipidemia. We evaluated the effect of RAS inhibition for 2 reasons: (1) several direct interactions between activated RAS and impaired NO availability have been reported8 9 10 11 14 15 16 and (2) patients with renovascular hypertension are generally characterized by an activated RAS.25
Ang II Type I Receptor Antagonism
In the present study, RAS inhibition with an Ang II type I
receptor antagonist had no effect on agonist-stimulated
endothelium-dependent vasomotion compared with
non–RAS-mediated blood pressure lowering with doxazosin. These data
show that Ang II is not a major determinant for impaired NO
availability in these patients. The absence of vascular effects during
Ang II type 1 receptor blockade, where increased Ang II levels have
been shown to contribute to increased Ang II type 2 receptor–mediated
NO-release,14 also lend no support to Ang II type 2
receptor–mediated NO release in resistance vessels in these
patients.
The absence of an improvement in vascular function by Ang II type I receptor inhibition is in accordance with the BANFF trial,26 in which the Ang II type I receptor losartan had no effect on endothelium-dependent vasomotion. Accordingly, 2 months of therapy with the Ang II type I receptor blocker candesartan had no effect on acetylcholine-induced vasodilation in patients with essential hypertension.27 In contrast, recent data have suggested a positive effect of Ang II type 1 receptor blockade.28 29 However, in 1 study, a short-term, local intra-arterial infusion of an Ang II type 1 receptor was administered,28 whereas in another study, the effects were observed in diabetic patients without overt macrovascular disease.29 Hence, these data cannot be compared with our results.
Of note, in a previous study,30 insufficient dosing of the Ang II receptor antagonist has been suggested to potentially explain the lack of vascular effects. In the present study, however, we have used a highly potent, noncompetitive Ang II type 1 receptor antagonist, at a dose near the top of the dose-response curve,31 32 33 making insufficient dosing of the receptor blocker less likely.
ACE Inhibition
In the present study, RAS inhibition with an ACE
inhibitor resulted in a significant improvement in
serotonin-stimulated endothelium-dependent
vasomotion compared with blood pressure lowering with doxazosin
therapy. This finding is in agreement with earlier studies in diabetic
patients,19 20 34 in patients with coronary artery
disease,17 18 35 in hypertensive patients,21
and in healthy volunteers.16 36 This selective improvement
in endothelium-dependent vasomotion cannot be related
to inhibition of Ang II formation, because Ang II receptor antagonism
had no effect on endothelium-dependent vasomotion.
Also, it cannot be explained by the blood pressure–lowering effect of
ACE inhibition, because again both -blockade and
angiotensin receptor antagonism had no effect on
serotonin-induced vasodilation.
Attention has focused on the dual action of ACE inhibition, which, in addition to mediating the conversion of Ang I to Ang II, is responsible for the inactivation of bradykinin, the latter being a potent activator of endothelial NO synthase.37 In this respect, it has been demonstrated in vivo that both the hypotensive15 and the vascular16 35 38 effects of ACE inhibition are at least in part mediated by bradykinin. However, the improved endothelium-dependent vasomotion during ACE inhibition in our study cannot be attributed to a bradykinin effect for 2 reasons: First, we infused serotonin as NO agonist. Serotonin acts directly through the 5-hydroxytryptamine1d receptor and thus acts independent of bradykinin.23 Moreover, degradation of serotonin is independent of kininase activity.39 Second, serotonin-induced vasodilation is completely blocked by NO inhibition,23 40 whereas (microvascular) vasodilation in the forearm by bradykinin cannot be inhibited by NO inhibition.41
What mechanisms could then be held responsible for the enhanced
endothelium dependent vasodilation to
acetylcholine17 18 19 20 and serotonin during ACE
inhibition? In view of the former discussion, it most likely involves
increased NO release, which is supported by recent findings in patients
with essential hypertension, where ACE inhibition caused a significant
increase in plasma NO metabolites.42 In line, recent data
have shown that ACE inhibition results in a sustained, 
2-fold
increase in endothelial NO synthase expression in
endothelial cells,37 43 which is
accompanied by an enhanced production of NO after
agonist-induced stimulation. Further studies are needed to elucidate
whether changes in NO production in vivo are responsible for
the different vascular effects during ACE inhibition and/or Ang II type
I receptor inhibition in these patients.
Study Limitations
In the present study, we show a beneficial effect of ACE
inhibition on NO availability. Besides the interaction of the RAS with
NO-mediated vasodilatation, Ang II also has clear interactions with
several "proatherogenic" pathways, including stimulation of
transforming growth factor-ß, a key factor in the transition from
initial tissue injury to tissue fibrosis,44 and
stimulation of endothelin-1 release, which exerts strong
vasoconstrictor and proliferative effects.45 46 In this
respect, the "selective" improvement in vascular function during
ACE inhibition has to be interpreted with caution as a surrogate end
point for future cardiovascular disease, because the
effects of changes in other proatherogenic, vessel-damaging pathways
by, for example, Ang II type 1 receptor antagonists may
also be of importance for cardiovascular "damage
control."
Clinical Implications
In the present study, we show that ACE inhibition has
selective beneficial effects on endothelial dysfunction
in a high-risk population with generalized
atherosclerosis, hypertension, and older age. It is
interesting to note that recent data from the HOPE trial have
emphasized that the blood pressure–lowering effect of ACE
inhibitors can be held responsible for only 30% of the
total cardiovascular benefit, seen after relatively
short-term ACE inhibitor therapy in patients at an
increased cardiovascular risk.47 As such,
it is a challenge to determine the extent to which improvement in
endothelial function by ACE inhibition contributes to
improved cardiovascular outcome for
cardiovascularly compromised patients and the extent to
which endothelial function testing can contribute to
further optimization of cardiovascular preventive
strategies for the individual patient.
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Acknowledgments |
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Dr Stroes is a fellow of the Dutch Heart Foundation (D97.023). Dr van Ampting is supported by a grant from the Dutch Kidney Foundation (C95.1516).
Received March 8, 2000; first decision April 12, 2000; accepted June 20, 2000.
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