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European Journal of Heart Failure 2004 6(2):151-159; doi:10.1016/j.ejheart.2003.10.009
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© 2003 European Society of Cardiology

Endothelial dysfunction in congestive heart failure: ACE inhibition vs. angiotensin II antagonism

Andreas Schäfera, Daniela Fraccarolloa, Piet Tasb, Isabel Schmidta, Georg Ertla and Johann Bauersachsa,*

a Medizinische Klinik der Julius-Maximilians-Universität Würzburg Josef Schneider Str. 2, D-97080 Würzburg, Germany
b Klinik für Anaesthesiologie der Julius-Maximilians-Universität Würzburg D-97080 Würzburg, Germany

* Corresponding author. Tel.: +49-931-201-1; fax: +49-931-201-36302. E-mail address: bauersachs_j{at}medizin.uni-wuerzburg.de


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Endothelial dysfunction of the vasculature contributes to the elevated peripheral resistance and reduced myocardial perfusion in congestive heart failure (CHF). The present study systematically investigated the effect of angiotensin II (AT1)- receptor blockade on vascular superoxide (O2–) production and endothelial dysfunction.

Methods and results: Vasodilator responses and O2– production were determined in aortic rings from Wistar rats with experimental CHF 10 weeks after extensive myocardial infarction and compared with sham-operated animals (Sham). Rats were either treated with placebo (P), with the AT1-receptor antagonist Irbesartan (50 mg kg–1 day–1) or with the ACE inhibitor Trandolapril (0.3 mg kg–1 day–1). In CHF-P, endothelium-dependent, acetylcholine-induced relaxation was significantly attenuated compared with Sham-P. Chronic treatment with Trandolapril or Irbesartan significantly improved endothelium-dependent relaxation. Aortic O2– formation was markedly increased in CHF, and was not significantly affected by Trandolapril treatment, while it was reduced by Irbesartan. eNOS expression was reduced in CHF and normalised by both treatments.

Conclusion: Endothelial vasomotor function in CHF rats was normalised by long-term treatment with an ACE inhibitor or an AT1-antagonist. Reduced aortic eNOS expression was normalised by both treatments, whereas aortic superoxide formation was only reduced by the AT1-antagonist Irbesartan.

Key Words: Endothelium • Angiotensin • Myocardial infarction • Free radicals

Received June 13, 2003; Revised August 17, 2003; Accepted October 23, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Reduced endothelium-dependent vasodilator capacity of coronary, large conductance and peripheral arteries contributes to reduced myocardial perfusion, increased peripheral vascular resistance and cardiac workload in patients with chronic heart failure (CHF) [1–3] and experimental models of cardiac dysfunction [4,5]. The endothelium is an important therapeutic target [6], since the normalisation of endothelial function increases myocardial perfusion and reduces vascular resistance and cardiac workload [7]. A major contributor to endothelial dysfunction in CHF appears to be a decreased bioavailability of endothelium-derived nitric oxide (NO) either arising from reduced expression of endothelial NO synthase (eNOS) [8] or resulting from increased vascular release of superoxide anions (O2–) [9–11]. Since O2– rapidly scavenges NO within the vascular wall, a reduction of bioactive NO might occur even despite an increased NO-generation [12,13]. This is further supported by restoration of the impaired flow-induced NO-mediated dilation by acute treatment with high doses of vitamin C [14]. In addition, antioxidant treatment improves the attenuated coronary flow reserve in patients with heart failure [15] and agonist-induced endothelium-dependent relaxation [10].

Angiotensin II has emerged as the most important stimulus for vascular O2– formation in the vascular wall [9]. In patients with CHF, treatment with ACE inhibitors favourably alters hemodynamics, improves symptoms, reduces overall mortality, and enhances NO-dependent dilatation [16–18]. The classical steps in the activated renin–angiotensin–aldosterone system are (1) the conversion of angiotensin I to angiotensin II by ACE, (2) direct actions of angiotensin II, and (3) aldosterone-mediated actions due to local or systemic formation of the mineralocorticoid. Inhibition of ACE only partially blocks radical formation whereas aldosterone receptor blockade completely inhibits oxidative stress [19]. In the current study we investigated whether angiotensin II receptor blockade would have an effect superior to ACE inhibition as ACE inhibitor-insensitive local production of angiotensin II in cardiovascular tissues has long been described [20]. Recent studies suggest that even supramaximal doses of ACE inhibitors are not able to inhibit angiotensin I-induced vasoconstriction in human arteries, while angiotensin II antagonists do and thereby indicate the potential role of ACE-independent angiotensin II formation [21]. Therefore, we simultaneously determined endothelium-dependent dilator responses as well as O2– formation and eNOS expression in the aorta of rats with CHF either treated with an ACE inhibitor or an angiotensin II antagonist, as it is still unclear whether angiotensin II antagonism is more effective in improving endothelial dysfunction than ACE inhibitors and this has not yet been investigated in an experimental model of CHF.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.1. Myocardial infarction, hemodynamic measurements
Left coronary artery ligations were performed in adult male Wistar rats (250–300 g) as previously described [22]. Briefly, under ether anaesthesia, the thorax was opened, the heart exteriorised and a ligature placed around the proximal left coronary artery. Sham-operated rats were treated similarly except that the operative procedure did not produce a detectable infarction. On the tenth postoperative day, surviving rats were randomly allocated to placebo (Placebo), or either the ACE inhibitor Trandolapril (TR) or the angiotensin II antagonist Irbesartan (IR) given with drinking water. TR was used at a dose of 0.3 mg kg–1 day–1, which is the most commonly used dose for this drug in rats with heart failure [19,23,24]. This dose has previously been described to increase plasma-renin-activity as is expected after inhibition of ACE [25]. IR was given at 50 mg kg–1 day–1 as previously described in this model [26,27]. Hemodynamic studies were performed 10 weeks after coronary artery ligation as described before [22]. Therefore, rats were anaesthetised with barbiturate (Narcoren®, Rhone Merieux, Laupheim, Germany). A saline filled catheter was advanced from the right carotid artery into the left ventricle and connected to a Millar-micrometer and Statham-transducer. Left ventricular end-diastolic pressure was recorded under light barbiturate anaesthesia, under which the animals were asleep and did not react to pain, but were breathing spontaneously. Afterwards, the transducer was withdrawn to the ascending part of the thoracic aorta and blood pressure was recorded. The treatments had been withheld for 24 h before hemodynamic studies were performed in order to avoid acute treatment effects.

2.2. Sample collection and determination of infarct size
After hemodynamic measurement, the heart was removed and the left ventricle was then cut into three transverse sections: apex, middle ring (3 mm), and base. From the middle ring, 5 µm-sections were cut at 100-µm intervals and stained with picrosirius red. The boundary length of the infarcted and non-infarcted surfaces of the endocardium and the epicardium were traced with a planimeter digital image analyser and infarct size (fraction of the infarcted left ventricle) was expressed as a percentage of length and only rats with extensive infarcts (>45%) were included in the vascular reactivity studies.

2.3. Vascular reactivity studies
The descending thoracic aorta was dissected following removal of the heart, cleaned of connective tissue and cut into three sections as described before [28]. Aortic rings (3 mm in length) were mounted in an organ bath (Föhr-Medical-Instruments, Seeheim, Germany) for isometric force measurement. The rings were equilibrated for 30 min under a resting tension of 2 g in oxygenated (95% O2; 5% CO2) Krebs–Henseleit solution (pH 7.4, 37 °C) of the following composition (mmol/l): NaCl 118, KCl 4.7, MgSO4 1.2, CaCl2 1.6, K2HPO4 1.2, NaHCO3 25, glucose 12, and the cyclo-oxygenase inhibitor diclofenac (1 µmol/l). Rings were repeatedly contracted by KCl (50–100 mmol/l) until reproducible responses were obtained. Thereafter, the rings were preconstricted with phenylephrine (0.3–1 µmol/l) to comparable constriction levels and the relaxant response to cumulative doses of acetylcholine and sodium nitroprusside was assessed.

2.4. Measurement of superoxide anion formation
Vascular O2– formation was measured using lucigenin-enhanced chemiluminescence [28]. The light reaction between O2– and lucigenin (5 µmol/l [29]) was detected in a luminometer (Wallac, Freiburg, Germany) during incubation of rings in a HEPES-modified Krebs buffer (pH 7.40). The specific chemiluminescence-signal was expressed as counts per minute per mg dry weight of tissue [cpm/mg].

The oxidative fluorescent dye hydroethidine (HE) was used to evaluate in situ production of superoxide. HE is freely permeable to cells and in the presence of O2– is oxidised to ethidium bromide (EtBr), where it is trapped by intercalating with the DNA [30]. EtBr is excited at 488 nm with an emission spectrum of 610 nm. In cell-free assays, addition of hydrogen peroxide to HE does not significantly increase EtBr fluorescence [31].

Unfixed frozen ring segments were cut into 30-µm thick sections and placed on a glass slide. HE (2 µmol/l) was topically applied to each tissue section and coverslipped. Slides were incubated in a light-protected humidified chamber at 37 °C for 30 min. Images were obtained with a Bio-Rad MRC-1024 laser scanning confocal microscope equipped with a krypton/argon laser. Aortic rings from CHF animals and control tissues were processed and imaged in parallel. Laser settings were identical for acquisition of images from CHF and control specimens. Fluorescence was detected with a 585-nm long-pass filter.

2.5. Western blot analysis
Aorta samples were homogenised in ice-cold RIPA buffer (NaCl 150 mmol/l, Tris–Cl 50 mmol/l, EDTA 5 mmol/l, Nonidet P-40 1% v/v, deoxycholate 0.5% w/v, NaF 10 mmol/l, sodium pyrophosphate 10 mmol/l, phenylmethylsulfonyl fluoride 100 mmol/l, aprotinin 2 µg/ml, and leupeptin 2 µg/ml). Proteins were determined by Bradford assay. Aorta extracts (30 µg protein per lane) were mixed with sample loading buffer and under reducing conditions separated on 10% SDS-polyacrylamide gel. Proteins were electrotransferred overnight at 4 °C onto PVDF membrane (Immun-Blot®, Bio-Rad). The bands were detected using chemiluminescence assay (ECL+Plus, Amersham). For detection of eNOS, we used a mouse monoclonal antibody (N-30020, Transduction-Laboratories, Affiniti, Exeter, England) diluted 1:1.000.

2.6. Materials
All biochemicals were obtained in the highest purity available from Sigma (Deisenhofen, Germany). Irbesartan and Trandolapril were provided by Sanofi-Synthelabo (Berlin, Germany) and by Knoll AG (Ludwigshafen, Germany), respectively.

2.7. Statistics
Relaxant responses were given as percentage relaxation relative to the preconstriction level. Values are expressed as mean±S.E.M. of n experiments with segments from different arteries. Statistical analysis was performed by repeated-measures two-way analysis of variance (ANOVA).

O2– formation and eNOS protein expression are expressed as mean±S.E.M. and were analysed using ordinary ANOVA followed by Tukey–Kramer multiple comparisons test. P values<0.05 were considered statistically significant. All parameters were normally distributed.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Global parameters
Global parameters of CHF rats and sham-operated animals are shown in Table 1. Infarct sizes were comparable among the different experimental groups. Arterial blood pressures were significantly lower in rats with CHF, whereas left ventricular end-diastolic pressure (LVEDP) was elevated. The lack in improvement of LVEDP by Trandolapril despite its positive modulation of left-ventricular fibrosis has been observed before [25].


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  		Table 1 Global parameters

 
3.2. Vasodilator responses in aortic rings
In phenylephrine-preconstricted aortic rings, acetylcholine elicited a concentration-dependent relaxation which was blunted in aortae from rats with CHF after extensive MI (Fig. 1a and Table 2). Chronic treatment with Trandolapril or Irbesartan significantly improved endothelium-dependent relaxation (Fig. 1a and Table 2). Although Irbesartan tended to be more effective, there was no significant difference between the two treatments.


Figure 1
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  		Fig. 1 Endothelium-dependent, acetylcholine-induced (a) and endothelium-independent, sodium nitroprusside (SNP)-induced relaxations (c) of phenylephrine-preconstricted aortic rings from rats with heart failure 10 weeks after myocardial infarction compared with sham-operated animals ({circ}). Rats were either treated with placebo (bullet), the ACE inhibitor Trandolapril ({blacktriangledown}, 0.3 mg kg–1day–1) or the angiotensin II antagonist Irbesartan ({blacksquare}, 50 mg kg–1day–1). The absolute preconstriction following administration of phenylephrine prior to the relaxations is shown in the bar graphs ((b) acetylcholine-induced and (d) SNP-induced relaxations). Results are expressed as the mean±S.E.M. from 8–10 separate animals. *P<0.05, **P<0.01 vs. placebo.

 


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  		Table 2 Vasomotor function

 
The EC50 for endothelium-independent relaxations induced by sodium nitroprusside was increased in rats with heart failure and only significantly improved in the group treated with Irbesartan (Table 2). Maximum relaxations were not different among all groups of rats (Fig. 1c and Table 2).

3.3. Production of superoxide anions in aortic segments
The production of O2– generated by aortic rings was assessed by lucigenin-enhanced chemiluminescence. O2– formation was significantly increased in aortae from rats with CHF (Fig. 2). To assess the relationship between endothelial-dependent relaxation and O2– formation we correlated the maximum relaxant response with the amount of O2– measured in aortic rings from the same placebo-treated animals (Fig. 2b).


Figure 2
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  		Fig. 2 (a) O2– production (lucigenin 5 µmol/l) in aortic rings from CHF rats 10 weeks after MI, compared with sham-operated animals (Sham). Rats were either treated with placebo (Placebo), the ACE inhibitor Trandolapril (TR, 0.3 mg kg–1day–1) or the angiotensin II antagonist Irbesartan (IR, 50 mg kg–1day–1). Mean±S.E.M. from 8–10 separate experiments. **=P<0.01 vs. Placebo and Trandolapril. (b) Correlation between acetylcholine-induced relaxation and superoxide-anion formation in isolated aortic rings from placebo-treated animals in this study (r=0.49, P=0.03).

 
While long-term treatment with Trandolapril did not significantly modify aortic O2– generation in CHF, Irbesartan treatment markedly reduced radical formation (Fig. 2a).

In parallel, staining of aortic rings with the superoxide sensitive fluorescent dye hydroethidine showed an increased O2– formation in the vessel wall, which was attenuated in animals treated with Irbesartan (Fig. 3).


Figure 3
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  		Fig. 3 O2– formation in aortic rings from CHF rats 10 weeks after MI, compared with sham-operated animals (Sham). Rats were either treated with placebo (Placebo), the ACE inhibitor Trandolapril (TR, 0.3 mg kg–1 day–1) or the angiotensin II antagonist Irbesartan (IR, 50 mg kg–1 day–1). Vessels were labelled with the superoxide sensitive fluorescent dye hydroethidine, which produces a fluorescence when oxidised to ethidium bromide by superoxide. Data are representative for n=4 experiments.

 
3.4. eNOS expression in the aorta
To elucidate whether the attenuation of endothelium-dependent relaxation is the result of an alteration in eNOS expression, eNOS protein was determined in aortic segments from rats with heart failure and sham-operated animals by Western-blot. As shown in Fig. 4, eNOS protein-levels were found to be significantly decreased in aortae from rats with CHF as compared with sham-operated animals. Treatment with either Trandolapril or Irbesartan normalised eNOS expression.


Figure 4
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  		Fig. 4 Comparison of eNOS-expression in aortae from rats with CHF 10 weeks after MI compared with sham-operated animals. Representative Western-blot (a) and densitometric analysis showing aortic eNOS-protein levels (b, for experimental groups see Fig. 2). Values are means±S.E.M. from four separate animals.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
In the present study, endothelium-dependent relaxation in rats with CHF was significantly improved by long-term treatment with either the ACE inhibitor Trandolapril or the angiotensin II antagonist Irbesartan. Reduced aortic eNOS expression was normalised by both treatments, whereas aortic O2– formation was only reduced by angiotensin II antagonism.

4.1. Expression and function of eNOS in CHF
Heart failure is associated with an endothelial dysfunction of coronary arteries as well as large conductance and peripheral arteries [1,32,33] and the mechanism underlying the reduction of agonist-stimulated dilator responses in heart failure has been proposed to be a defective production of endothelium-derived nitric oxide (NO). In several models of heart failure, a reduction of endothelial NO-release was associated with an attenuated expression of eNOS [34,35]. Our results provide insights into the mechanisms of the alteration of endothelial function in heart failure after myocardial infarction, which represents the most important cause for cardiac failure in patients. In severe CHF, impaired left ventricular systolic function results in reduced cardiac output and subsequently reduced blood flow in conductance and peripheral arteries. Therefore, on the luminal side of the endothelium less shear stress is exerted, which is one of the physiologically most important regulators of eNOS gene expression in vivo (as reviewed in Ref. [36]). While decreased shear stress might explain reduced eNOS expression in CHF rats on placebo, direct effects of ACE inhibition and angiotensin II antagonism on vascular eNOS expression are more likely to beneficially influence eNOS expression in the treatment groups. As recently reviewed [36] ACE inhibitors [37,38] as well as angiotensin II antagonists [39] increase vascular eNOS expression in the vasculature of healthy animals. Similarly to our previous findings, ACE inhibition increased vascular eNOS expression [19] as it has also been reported before in humans with coronary artery disease [40].

Furthermore, ACE inhibition also influences the remaining signalling of angiotensins by an augmented formation of the heptapeptide angiotensin (1–7) [41]. Accumulating evidence suggests that the vasodilator angiotensin (1–7) may oppose the vasoconstrictor and growth-promoting actions of angiotensin II either directly or by stimulation of kinin, prostaglandin and NO release [42,43]. Recently, angiotensin (1–7) infusion during the chronic phase of MI prevented the development of endothelial dysfunction in rat aorta [44]. In eNOS–/– mice the cardioprotective effects of ACE inhibition as well as angiotensin II antagonism were almost abolished, suggesting that NO is an important mediator in cardioprotective effects of these substances [45].

Increased levels of angiotensin II are related to a decreased activity of the soluble guanylyl cyclase [46] and would explain the higher EC50 for SNP in the CHF animals, which was only significantly modified by Irbesartan but not Trandolapril. Recently, the ACE inhibitor captopril failed to suppress angiotensin I-induced contraction in human arteries in vitro even despite the use of supramaximal concentrations, while it was almost completely prevented by Irbesartan [21]. This further supports the hypothesis that local ACE-independent mechanisms of angiotensin II formation are activated in CHF and may partially contribute to the failure of ACE inhibitors to chronically suppress angiotensin II [47].

4.2. Oxidative stress in heart failure and vascular O2– formation
An imbalance between NO and O2– production with enhanced inactivation of NO has been associated with endothelial dysfunction and appears to be a common feature of many cardiovascular diseases [13,28,48]. As demonstrated before [9] and confirmed in the present study, vascular O2– production is significantly increased in CHF and limits the bioavailability of NO providing direct experimental evidence for an enhanced release of reactive oxygen species from the vasculature in CHF. As plasma renin activity and tissue angiotensin converting enzyme activity are markedly elevated in heart failure [49] an increased formation of angiotensin II may lead to an enhanced vascular O2– formation through the expression of an NAD(P)H-dependent oxidase in aortic smooth muscle cells [48,50]. Indeed, the observed up-regulation of NADH-dependent O2– formation in aortae from rats with chronic myocardial infarction suggests that this mechanism may be operative in ischemic heart failure [9].

In congestive heart failure different therapies reducing reactive oxygen species including inhibition of the renin–angiotensin-system [16], endothelin antagonism [6,23], antioxidants [10,14] and mineralocorticoid receptor blockers [19] have shown an improvement of NO bioavailability and vascular endothelial function. One possible reason for the failure of ACE inhibition to reduce vascular O2– generation in this study may be increased ACE-independent formation of angiotensin II. Another hypothetical explanation is related to the structure of the ACE inhibitor: it has been suggested that only ACE inhibitors with a sulfhydryl group such as captopril and zofenapril have radical scavenging properties [51,52]. This would explain the observed lack of effect of Trandolapril, which does not possess a sulfhydryl group. However, other investigators have reported that the antioxidative properties of ACE inhibitors are not necessarily determined by the presence or absence of the sulfhydryl group [53,54]. ACE inhibitors as well as angiotensin II-receptor antagonists increase endothelium-dependent NO-mediated relaxations most likely by reducing oxidative stress within the arterial wall [55] strengthening the hypothesis of enhanced O2– production being responsible for the decrease in NO bioavailability [56].

Furthermore, chronic treatment with ACE inhibitors in CHF patients improves symptoms and prognosis as proven in large clinical studies [57,58]. Although in patients with CHF, the addition of an angiotensin II antagonist to ACE inhibition did not further reduce mortality, in patients not on ACE inhibition, angiotensin II antagonism improved morbidity and mortality very effectively [59] and markedly reduced overall neurohumoral activation [60]. As improved endothelial function in CHF correlates with improved symptoms and exercise capacity [61], it is tempting to speculate that the beneficial effect of angiotensin II antagonism observed in the present study may contribute to the positive effects of angiotensin II antagonism in patients with CHF.

4.3. Study limitations
Whenever two drug regimens are compared, a major issue is the use of equipotent dosages. We found in our model with extensive myocardial infarction, that both the ACE inhibitor as well as the AT antagonist did not further reduce blood pressure thus making it impossible to use the blood pressure drop as an index of potency of the drugs. When comparing the effect of the two drugs in previous studies, it appears that in rats with moderate infarctions [19,23–27], both regimen are equally effective suggesting that the dosages are quite equipotent, although a direct comparison was not made. As the two drugs in the applied dosages had similar effects on LVEDP in rats with moderate to large infarctions [24,27], the different effects on LVEDP in the present study in rats with extensive myocardial infarction are unlikely to result from under-dosage of Trandolapril. One may speculate, that the slightly better endothelial function as well as a potentially more effective reduction of myocardial superoxide formation by Irbesartan contribute to the reduction in LVEDP.

In summary, endothelial vasomotor function in CHF rats was normalised by long-term treatment with an ACE inhibitor or an angiotensin II antagonist. Reduced aortic eNOS expression was normalised by both treatments, whereas aortic superoxide formation was only reduced by the angiotensin II antagonist Irbesartan.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
The authors wish to thank Anna Dembny, Christian Chen and Christian May for technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 355, B 10).


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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