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European Journal of Heart Failure 2005 7(1):37-42; doi:10.1016/j.ejheart.2004.08.001
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© 2004 European Society of Cardiology

Comparison of selective ETA and ETB receptor antagonists in patients with chronic heart failure

Peter J. Cowburna,*, John G.F. Clelandb, Theresa A. McDonaghc, John D. McArthurd, Henry J. Dargiee and James J. Mortone

a Wessex Cardiothoracic Centre, Southampton General Hospital Mailpoint 46, Tremona Road, Southampton, SO16 6YD, UK
b Department of Cardiology, Castle Hill Hospital, University of Hull Kingston upon Hull HU5 7RX, UK
c Royal Brampton Hospital Sydney Street, London, SW3 6NP, UK
d Department of Cardiology, Western Infirmary Glasgow G11 6NT, UK
e Medical Research Council Clinical Research Initiative in Heart Failure University of Glasgow, Glasgow G12 8QQ, UK

* Corresponding author. Tel.: +44 2380 777222; fax: +44 2380 796352. E-mail address: pjcowburn{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The vasoconstrictor action of endothelin-1 (ET-1) is mediated through ETA and ETB receptor subtypes on vascular smooth muscle. ETB receptors are also present on the vascular endothelium where they mediate vasodilation. Animal studies suggest that the ETB receptor also acts as a clearance receptor for endothelin.

Aims: To investigate the effects of a selective ETA and a selective ETB receptor antagonist alone and in combination on haemodynamics and circulating concentrations of ET-1 in patients with chronic heart failure.

Results: Infusion of BQ-123 (n=10), a selective ETA receptor antagonist, led to systemic vasodilation and did not change plasma ET-1 concentrations (1.38±0.82 to 1.38±0.91 fmol/ml, ns). Infusion of BQ-788 (n=8) led to systemic vasoconstriction with a rise in plasma ET-1 (1.84±1.06 to 2.73±0.99 fmol/ml, p<0.01). The addition of BQ-123 to BQ-788 led to systemic and pulmonary vasodilation with no further increase in plasma ET-1 concentrations (2.80±1.14 to 2.90±1.20 fmol/ml, ns).

Conclusion: The rise in plasma ET-1 concentrations in response to selective blockade of ETB receptors and the associated adverse haemodynamic effects suggest that ETB receptors have a role in the clearance of ET-1 in man and that their blockade may not be advantageous for patients with heart failure.

Key Words: Endothelins • Heart failure • Pulmonary circulation

Received August 4, 2004; Accepted August 18, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by the vascular endothelium [1], which acts locally as a paracrine factor and probably also as a circulating hormone in the regulation of arterial and venous tone [2–5]. Plasma concentrations of ET-1 are elevated in patients with moderate to severe chronic heart failure [6–9], correlate with the symptomatic and haemodynamic severity of heart failure [8,9] and independently predict prognosis on multivariate analysis[10]. Consequently, there is considerable interest in the therapeutic potential of endothelin receptor antagonists in heart failure [11].

The vasoconstrictor action of ET-1 is mediated through two high affinity endothelin receptor subtypes on smooth muscle, denoted ETA and ETB. ETB receptors are also present on the vascular endothelium where they mediate vasodilation via nitric oxide and /or prostaglandins [12,13]. There is growing evidence of altered endothelin receptor function in heart failure [14], and the net effect of endothelial and smooth muscle ETB receptor activation could result in either vasoconstriction or vasodilation. Animal data also suggest that ETB receptors act as a clearance mechanism for circulating ET-1 [15,16].

Administration of both non-selective [17,18], and ETA selective antagonists [19–21] has improved haemodynamic indices in patients with heart failure. The relative merits of selective ETA or non-selective ETA/ETB receptor antagonists for patients with heart failure depend on the functional importance of ETB receptors. Enhanced vasoconstriction to ETB selective agonists has been described in patients with heart failure [22,23]. Conversely, BQ-788, an ETB selective antagonist, has been reported to cause forearm vasoconstriction in patients with heart failure [24], and to increase plasma concentrations of ET-1 and peripheral vascular resistance in healthy volunteers [25]. We investigated the effects of ETA selective, ETB selective and combined ETA/ETB receptor antagonism on circulating concentrations of ET-1 and central haemodynamics in patients with chronic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
Studies were approved by the local ethics committee and conformed to the principles outlined in the Declaration of Helsinki. All patients gave written, informed consent, had stable chronic heart failure (NYHA Class II to III) secondary to left ventricular systolic dysfunction (left ventricular ejection fraction <40%) and were taking diuretics and an ACE inhibitor or an angiotensin II receptor antagonist. Ten patients took part in the BQ-123 study (63±3 years) and eight patients took part in the BQ-788/BQ-123 study (60±4 years). Four patients took part in both studies, a minimum of 3 months apart. Patients took their usual cardiac medications including diuretics 6 h prior to the study. Patients with primary pulmonary disease, severe coronary disease, primary valvular heart disease, atrial fibrillation, insulin-dependent diabetes, uncontrolled hypertension and chronic renal failure (creatinine >220 µmol/ml) were excluded.

2.2. Study protocol
Each study began with a saline infusion for a minimum of 30 min to establish baseline haemodynamics. In the first study, BQ-123 (Clinalfa, Switzerland), an ETA selective antagonist [26], was infused at 200 nmol/min (100 nmol/min in first two patients) for 45 min. In the second study, BQ-788 (Clinalfa), an ETB selective antagonist [27], was infused at 100 nmol/min (50 nmol/min in the first patient) for 45 min. BQ-123 (200 nmol/min) was then co-infused with BQ-788 for a further 45 min. Femoral artery blood samples were taken immediately prior to the end of each infusion period. Haemodynamic measurements were taken at 15-min intervals throughout the infusion studies.

2.3. Endothelin assays
Blood samples were taken from the femoral artery and were collected into chilled tubes containing 4% EDTA. Samples were kept on ice and were then centrifuged at 4 °C. Separated plasma samples were immediately stored at –20 °C. ET-1 was assayed directly using an enzyme immunoassay (Biomedica). The kits incorporate an immunoaffinity purified polyclonal capture antibody and a monoclonal detection antibody, highly specific for endothelin (1–21). Samples were assayed in duplicate and averaged. Endothelin (1–28) assay characteristics: measuring range 0–10 fmol/ml; cross-reactivity-ET-1: 100%, ET-2: 100%, ET-3: <5%, big endothelin (1–38): <1%, big endothelin(22–38): <1%.

2.4. Statistical analysis
The primary end-points of the studies were the haemodynamic changes from baseline to the end of the infusion of each ET receptor antagonist (BQ-123 or BQ-788 depending on the study). All values are reported as mean±S.E.M. Haemodynamic changes from baseline to the end of each infusion were examined using repeated measures ANOVA. Values were considered significantly different if p<0.05. Post hoc comparisons of individual time points were analysed using Student's paired t-test (two tailed) using the Bonferroni correction. Changes in plasma ET-1 concentration were also analysed using Student's paired t-test (two-tailed).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Haemodynamic effects
Infusion of BQ-123, the ETA selective antagonist, led to beneficial short-term haemodynamic effects as previously reported [19]. The peak effect was seen after 45 min of BQ-123 infusion, with a fall in mean arterial pressure (86±5 to 79±4 mm Hg, p<0.05), mean pulmonary artery pressure (22±3 to 19±3 mm Hg, p<0.05), mean pulmonary capillary wedge pressure (12±2 to 10±2 mm Hg, p=0.01) and systemic vascular resistance (1478±91 to 1301±70 dyn s cm–5, p<0.001), and a rise in cardiac index (2.39±0.15 to 2.51±0.13 l/min/m2, p<0.05). Changes in mean right atrial pressure (6±1 to 5±1 mm Hg, p=0.06), pulmonary vascular resistance (178±24 to 153±13 dyn s cm–5, ns) and heart rate (70±5 to 71±6 beats/min, ns) did not achieve statistical significance.

Infusion of BQ-788, the ETB selective antagonist, led to adverse short-term haemodynamic effects. The peak effect was seen after 45 min, with a rise in mean arterial pressure (89±5 to 97±5 mm Hg, p=0.001), mean right atrial pressure (7±1 to 8±1 mm Hg, p<0.01) and systemic vascular resistance (1398±149 to 1665±175 dyn s cm–5, p<0.0001), and a fall in cardiac index (2.60±0.18 to 2.38±0.18 l/min/m2 p=0.001). There were non-significant trends towards a rise in mean pulmonary artery pressure (20±3 to 22±4 mm Hg), mean pulmonary capillary wedge pressure (11±2 to 13±3 mm Hg) and pulmonary vascular resistance (144±21 to 172±26 dyn s cm–5). Heart rate did not change during BQ-788 infusion (74±6 to 73±7 beats/min, ns).

The addition of BQ-123 to BQ-788 infusion (seven patients), i.e. combined ETA/ETB receptor antagonism, led to a reversal of the vasoconstriction seen with BQ-788 infusion. The peak effect was once again seen after 45 min; mean arterial pressure (97±6 to 88±5 mm Hg, p<0.0001), systemic vascular resistance (1748±177 to 1341±105 dyn s cm–5, p<0.01) and pulmonary vascular resistance (177±29 to 122±16 dyn s cm–5, p<0.05) fell, whilst cardiac index rose (2.32±0.20 to 2.68±0.16 l/min/m2, p=0.001). There were non-significant trends towards a fall in mean pulmonary artery pressure (23±4 to 19±3 mm Hg) and mean pulmonary capillary wedge pressure (14±3 to 12±2 mm Hg); mean right atrial pressure (7±1 to 7±1 mm Hg, ns) and heart rate (70±6 and 72±5 beats/min, ns) were unchanged.

Although there were trends towards net vasodilation with the combination of BQ-123 and BQ-788 (compared with baseline pre-BQ-788 infusion values), changes were not generally significant (n=7): mean arterial pressure (91±5 to 88±5 mm Hg, ns), mean right atrial pressure (7±1 to 7±1 mm Hg, ns), mean pulmonary artery pressure (20±3 to 19±3 mm Hg, p<0.05), mean pulmonary capillary wedge pressure (12±2 to 11±2 mm Hg, ns), systemic vascular resistance (1476±137 to 1341±105 dyn s cm–5, ns), pulmonary vascular resistance (148±24 to 122±16 dyn s cm–5, ns), cardiac index (2.52±0.19 to 2.68±0.16 l/min/m2, ns) and heart rate (70±6 to 72±5 beats/min). One patient did not receive BQ-123 in addition to BQ-788 because his baseline SVR was low at 805, and we were concerned that further vasodilation might lead to hypotension, as was seen with a patient in the BQ-123 study with a low baseline SVR. Fig. 1 compares the peak haemodynamic responses between agents as described above.


Figure 1
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  		Fig. 1 Comparison of the haemodynamic effects of selective ETA and ETB receptor antagonists and the combination of both ETA selective and ETB selective antagonists: BQ-123 is an ETA selective antagonist and BQ-788 is an ETB selective antagonist. HR=heart rate, MAP=mean arterial pressure, RAP=right atrial pressure, MPAP=mean pulmonary artery pressure, PCWP=pulmonary capillary wedge pressure, CI=cardiac index, SVR=systemic vascular resistance, PVR=pulmonary vascular resistance.

 
3.2. Plasma ET-1 concentrations
Infusion of BQ-123, the ETA selective antagonist, did not change plasma ET-1 concentrations (1.38±0.82 to 1.38±0.91 fmol/ml, ns) (Fig. 2). Infusion of BQ-788, the ETB selective antagonist, led to a rise in plasma ET-1 (1.84±1.06 to 2.73±0.99 fmol/ml, p<0.01) (Fig. 3) while plasma ET-1 concentrations on the combination of BQ-123 and BQ-788 (seven patients) were similar to those with BQ-788 alone (2.90±1.20 vs. 2.80±1.14 fmol/ml, ns).


Figure 2
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  		Fig. 2 Plasma concentrations of endothelin-1 during infusion of BQ-123, an ETA selective antagonist (nine patients). One patient with very high baseline plasma endothelin-1 concentrations is not represented in the graph (8.71 rising to 9.50 fmol/ml with BQ-123).

 


Figure 3
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  		Fig. 3 Plasma concentrations of endothelin-1 during infusion of BQ-788, an ETB selective antagonist (7 patients). One patient with very high baseline plasma endothelin-1 concentrations is not represented in the graph (9.14 rising to 9.26 fmol/ml with BQ-788).

 
3.3. Side effects
One patient developed profound hypotension and bradycardia subsequent to infusion of BQ-123 alone. Leg elevation and colloid infusion led to a rapid recovery. One patient became breathless with BQ-788 infusion with a marked increase in pulmonary capillary wedge pressure. Haemodynamic changes and symptoms were reversed by co-infusing BQ-123 with BQ-788 (diuretic was given in addition). Another patient had a marked rise in pulmonary capillary wedge pressure with BQ-788 infusion but remained asymptomatic; the infusion was stopped early and the changes were reversed by infusion of BQ-123 alone. There were no long-term sequelae. We informed our ethics committee of the adverse effects seen with BQ-788 and decided not to expose further patients to this agent.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study demonstrates that, in patients with heart failure, selective ETA receptor blockade results in systemic vasodilation without affecting plasma ET-1 concentrations, whereas selective ETB receptor blockade causes systemic vasoconstriction with an associated rise in plasma ET-1 concentrations. The addition of an ETA selective antagonist to established ETB receptor blockade led to pulmonary and systemic vasodilation without further altering plasma ET-1 concentrations. These data suggest that the ETB receptor has a role in the clearance of ET-1 and that blockade of the ETB receptor may not be beneficial for patients with heart failure.

The finding that BQ-788, an ETB selective antagonist, causes vasoconstriction in patients with heart failure concurs with previous reports of the effects of selective ETB receptor antagonists on the forearm circulation of normal subjects [28] and patients [24] and also with systemic ETB blockade in healthy volunteers [25]. ETB selective agonists, as well as antagonists, cause vasoconstriction in patients with heart failure [14,22,23]. This appears contradictory. Both ETB receptor agonists and antagonists could displace ET-1 from receptors or reduce ETB receptor-mediated clearance if receptor occupancy is high enough, leading to an increase in plasma concentrations of ET-1 and ETA receptor-mediated vasoconstriction. In an earlier study, however, we did not identify ETB receptor agonist-induced increases in plasma ET-1 [23].

We have previously reported that ET-1, when infused to achieve pathophysiological concentrations of ET-1, caused systemic haemodynamic effects, in patients with left ventricular systolic dysfunction [5]. In that study, plasma ET-1 increased from 0.17±0.17 to 1.13±0.4 fmol/ml (first generation assay, Biomedica). Mean arterial pressure increased by 7% and systemic vascular resistance increased by 20%. There was no significant change in pulmonary artery pressure or pulmonary vascular resistance [5]. In the current study, BQ-788 infusion led to an increase in plasma ET-1 from 1.84±1.06 to 2.73±0.99 fmol/ml (second generation assay, Biomedica) associated with increases in mean arterial pressure of 9% and systemic vascular resistance of 19%. While we saw trends to a rise in pulmonary pressures, these were not statistically significant. Blocking the ETA receptor with BQ-123 reversed these effects. Thus, it seems likely that the vasoconstriction seen with ETB selective antagonism is due, at least in part, to rising plasma ET-1 concentrations.

4.1. Endothelin clearance
Plasma ET-1 concentrations rose with ETB blockade, but remained unchanged with ETA blockade. This suggests that the ETB receptor acts as a clearance receptor for ET-1. We did not measure ET-1 extraction, however, as in the animal studies [15,16]. Another possible explanation for our findings might be that BQ-788 led to decreased renal excretion of ET-1, as ETB selective antagonists have been shown to reduce renal plasma flow in an animal model of heart failure [29]. However, non-selective antagonists increased renal plasma flow in the same animal model [30], and if plasma concentrations of ET-1 reflected renal plasma flow, we would have expected plasma ET-1 concentrations to fall when BQ-123 was co-infused with BQ-788. Instead, we saw that plasma concentrations of ET-1 remained elevated, despite the systemic vasodilation achieved with combined ETA/ETB blockade.

4.2. Selective or non-selective antagonists for HF?
The results of clinical trials with ET receptor antagonists in patients with heart failure have been disappointing so far [31]. With rare exceptions [20,32], plasma concentrations of ET-1 [18,21,33,34] have risen when ET antagonists have been administered to patients with heart failure, implying blockade of the ETB receptor. ET receptor antagonists are not, in general, highly selective nor do they have equal affinity for ETA and ETB receptors. Most ET receptor antagonists when used in low enough doses will be ETA selective and when used in high enough doses will be non-selective. Before ET receptor antagonists are discarded for the management of heart failure, further trials of both ETA selective and non-selective antagonists should be undertaken, at lower doses than previously studied and in selected groups of patients with heart failure, such as those with pulmonary hypertension [35]. Selecting a dose of an effective endothelin receptor antagonist that does not elevate plasma concentrations of ET-1 could prove important.

In conclusion, ETB receptor antagonists have detrimental haemodynamic effects in patients with CHF. This probably reflects reduced clearance of ET-1 leading to stimulation of the ETA receptor.


   Acknowledgements
 
Dr. Peter Cowburn and Professor John Cleland were supported by the British Heart Foundation. We thank our patients and our technical and nursing staff for their help with this study. We would also like to thank Dr. Eric Gardiner, University of Hull, for statistical advice.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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N F Kelland and D J Webb
Clinical trials of endothelin antagonists in heart failure: publication is good for the public health
Heart, January 1, 2007; 93(1): 2 - 4.
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 Exp. Biol. Med.Home page
B. Battistini, N. Berthiaume, N. F. Kelland, D. J. Webb, and D. E. Kohan
Profile of Past and Current Clinical Trials Involving Endothelin Receptor Antagonists: The Novel "-Sentan" Class of Drug.
Experimental Biology and Medicine, June 1, 2006; 231(6): 653 - 695.
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 Exp. Biol. Med.Home page
N. F. Kelland and D. J. Webb
Clinical Trials of Endothelin Antagonists in Heart Failure: A Question of Dose?
Experimental Biology and Medicine, June 1, 2006; 231(6): 696 - 699.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
D. F. Pauly
Cardiac Function and Heart Failure
J. Am. Coll. Cardiol., June 7, 2005; 45(11_Suppl_B): B24 - B29.
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