(Circulation. 2000;101:142.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Contrasting Inotropic Effects of Endogenous Endothelin in the Normal and Failing Human Heart
Studies With an Intracoronary ETA Receptor Antagonist
From the Department of Cardiology (P.A.M., R.G.-M., B.D.P.), University of Wales College of Medicine, Heath Park, Cardiff, UK, and GKT School of Medicine (A.M.S.), King’s College London, London, UK.
Correspondence to Professor Ajay M. Shah, Department of Cardiology, GKT School of Medicine, King’s College London, Bessemer Rd, London SE5 9PJ, United Kingdom. E-mail ajay.shah{at}kcl.ac.uk
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Abstract |
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Background—Endothelin-1 (ET-1) is a potent positive inotrope in vitro, but its physiological effects on intrinsic myocardial contractile function in humans in vivo are unknown. Plasma ET-1 levels are elevated in heart failure, and ET-1 may be involved in the pathophysiology of this condition. However, its effects on contractile function of the failing human heart are also unknown.
Methods and Results—A specific ETA receptor antagonist, BQ123, was infused (40 nmol/min, 16 minutes) into the left coronary artery in 8 patients with atypical chest pain (normal left ventricular [LV] function and coronary arteries) and 8 patients with nonischemic dilated cardiomyopathy (DCM) who were undergoing diagnostic catheterization. In normal subjects, BQ123 rapidly induced a significant reduction in LV dP/dtmax (-270±71 mm Hg/s after 16 minutes; P<0.05) and in LV dP/dt at a developed pressure of 40 mm Hg (LV dP/dt40) (-179±54 mm Hg/s; P<0.05). In DCM patients, however, BQ123 caused no reductions in LV dP/dtmax (62±49 mm Hg/s after 16 minutes) or LV dP/dt40 (83±51 mm Hg/s;P<0.05 compared with normal subjects). BQ123 had no effect on heart rate, LV relaxation, LV end-diastolic pressure, right atrial pressure, or pulmonary pressure in either patient group.
Conclusions—Endogenous ET-1 has a tonic positive inotropic effect in normal subjects, independent of effects on the peripheral vasculature and unmasked by inhibition of ETA receptors. However, the effect of short-term ETA blockade in DCM patients was opposite to that in normal subjects, which suggests that ET-1 may cause negative inotropic effects in the failing heart.
Key Words: endothelin • cardiomyopathy • contractility
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Endothelin-1 (ET-1)1 has potent in vitro positive inotropic effects on normal myocardium of several species, including humans.2 The effects of ET-1 in the whole heart are more difficult to interpret. Exogenous ET-1 may potentially exert opposing direct positive inotropic effects and indirect negative inotropic effects, secondary to the potent coronary vasoconstriction induced by the peptide and to the increased cardiac load that results from peripheral vasoconstriction. The use of ET receptor antagonists to inhibit the effects of "basal" ET-1 release may be a better approach for addressing this question. Both ETA and ETB receptors are expressed on cardiac myocytes, although in adult human myocardium, only ETA receptors are reported to be functionally important.3 We previously reported that a specific ETA receptor antagonist, BQ123, induced earlier and faster myocardial relaxation in isolated ferret papillary muscle preparations4 and isolated perfused ejecting guinea pig hearts.5 Likewise, McClellan et al6 reported that BQ123 induced a negative inotropic effect in isolated rat cardiac trabeculae. These in vitro studies suggested that basal release of ET-1 may have positive inotropic effects and may delay myocardial relaxation. Using an analogous approach in normal humans, Webb and colleagues reported that ET antagonists infused either locally into the forearm7 or systemically8 decreased vascular resistance and reduced blood pressure. Thus, endogenous ET-1 appears to have a role in maintaining basal vascular tone and blood pressure in healthy humans. However, the role of endogenous ET-1 in regulating intrinsic cardiac contractile function in healthy humans is unknown.
Recent experimental and clinical studies indicate a role for ET-1 in the pathophysiology of heart failure. Elevated production of ET-1 is thought to contribute to systemic and pulmonary vasoconstriction, as well as to cardiac hypertrophy, fibrosis, and remodeling.9 10 11 12 13 Plasma ET-1 levels are elevated in patients with congestive heart failure (CHF) and correlate positively with New York Heart Association functional class.14 15 16 In animal studies, ET antagonists reduced mortality from heart failure.17 Experimental data also suggest that ET-1 may have a blunted positive inotropic effect or even a negative inotropic effect in failing myocardium, which could contribute to impairment of left ventricular (LV) function.13 18 19 20 21 However, the effect of endogenous ET-1 on intrinsic contractile function of the failing human heart, independent of changes in systemic loading, remains unknown.
In this study, we compared the short-term effects of endogenous ET-1 on intrinsic cardiac contractile function in normal subjects and in patients with dilated cardiomyopathy (DCM). To assess the effects of endogenous ET-1 independent of changes in systemic loading, we studied the response to intracoronary infusion of a locally acting dose of the specific ETA receptor antagonist BQ123.
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Methods |
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The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the Institutional Research and Ethics Committee. All subjects provided written informed consent.
Patient Characteristics
The first group comprised 8 patients (2 men, mean age 47.3±5.4
years) undergoing diagnostic cardiac
catheterization for investigation of atypical chest
pain, who had normal epicardial coronary arteries and normal LV
function. None of these patients were thought to have syndrome X. Three
were taking ß-blockers, 2 were taking long-acting nitrates, and 2
others were taking calcium antagonists. The second group
comprised 8 patients (5 men, mean age 47±3.2 years) with idiopathic
DCM, all with LV ejection fraction <40% and normal coronary
arteries. Patient characteristics of this group are shown in the
Table
. Other than ACE
inhibitors, all medication was withheld in both groups for
>24 hours before the study. All subjects abstained from alcohol,
caffeine-containing drinks, and smoking for >24 hours.
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Protocol
Diagnostic coronary angiography was
performed via the right femoral approach in a quiet cardiac
catheterization laboratory (temperature 23°C).
Subjects were included for study if the coronary angiogram was
normal. Heparin (5000 IU bolus) was administered
intra-arterially. A 5F Swan-Ganz catheter was inserted via
the right femoral vein and positioned to measure pulmonary
artery and right atrial pressure simultaneously. A 6F
micromanometer-tipped pigtail catheter (Millar
Instruments) was inserted via the left femoral artery and positioned in
the LV. A 5F left Judkins catheter was used for intracoronary
infusion. The Millar catheter was calibrated externally against a
mercury reference and matched against luminal pressure. All pressures
were referenced to atmospheric pressure at the level of the mid chest.
A Meddars 1300 physiological measurement system was
used to record high-fidelity LV pressure; aortic, right atrial, and
pulmonary artery pressures; and a bipolar standard lead of the
ECG; the results were also fed via a Maclab analogue-digital converter
(AD Instruments) into a Macintosh personal computer with Chart software
(version 3.5s, AD Instruments).
At least 20 minutes after coronary angiography and 
10 minutes
after insertion of additional catheters, baseline recordings of
pressures and ECG were obtained. BQ123 (American Peptide Co) was then
infused into the left coronary artery at 40 nmol/min (flow rate
2 mL/min) for 16 minutes with an IVAC P4000 anesthesia
syringe pump (Welmed Ltd). Previous studies by Verhaar and
colleagues22 showed that a 10 nmol/min infusion in the
human forearm induced maximal vasodilatation yet remained locally
active (ie, blood flow was unchanged in the noninfused forearm). We
chose a dose of 40 nmol/min to achieve roughly equivalent local
concentrations (0.4 µmol/L, assuming a coronary flow
rate of 
100 mL/min). This concentration is 10- to 100-fold higher
than the reported affinity of binding sites for BQ123 in human LV (0.73
nmol/L)23 or the Ki for BQ123
inhibition of ET-1 response in human heart (3.3
nmol/L)3 yet is still selective for the
ETA receptor.3 23 24 Pressures,
heart rate, and ECG were monitored during BQ123 infusion and for 15
minutes after cessation of infusion. At the end of BQ123 infusion, a
normal saline infusion at the same flow rate was substituted. LV
angiography was performed after completion of the study.
Data Analysis
Data were analyzed offline. Maximal and minimal rates of
LV pressure development (LV dP/dtmax and LV
dP/dtmin, respectively) and LV dP/dt at a
developed pressure of 40 mm Hg (LV
dP/dt40)25 were obtained from the
first derivative of the LV pressure signal. The time constant of
isovolumic LV relaxation, 
, was calculated as described
previously.26
Data are expressed as mean±SEM. Comparison of absolute values and changes in pressure data and heart rate during and after BQ123 infusion in the 2 groups of patients were made by 2-way ANOVA for repeated measures with StatView (version 4.5) software. Post hoc analysis was performed with Tukey’s test. Baseline parameters in the 2 groups were compared with independent Student’s t tests. P<0.05 was considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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At baseline (before infusion of BQ123), LV dP/dtmax was significantly lower in DCM patients than in normal subjects (1160±170 versus 1836±179 mm Hg/s; P<0.05). Similarly, LV dP/dt40 was significantly lower in the DCM group (992±136 versus 1665±37 mm Hg/s; P<0.05). Peak LV pressures were 119.7±9.7 mm Hg in the DCM group and 136.4±8.1 mm Hg in the normal subjects. LV end-diastolic pressure (LVEDP) tended to be greater in DCM patients (12.9±2.7 versus 6.5±1.0 mm Hg; P=0.06). Heart rate was significantly higher in the DCM group, whereas mean right atrial pressure, mean pulmonary artery pressure, and mean aortic pressure at baseline were not significantly different (Figure 1
). No
untoward side effects were encountered during the study in any subject,
and there were no changes in the ECG.
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) and in DCM patients (
). All
values are mean±SEM. *Significant (P<0.05) difference
on post hoc testing; 
significant (P<0.001) group-time
interaction by 2-way ANOVA; 
significant (P<0.01)
difference between groups by ANOVA.
Figure 1
shows the effect of BQ123 infusion on
hemodynamic parameters in the 2 groups. In
subjects with normal LV function, BQ123 caused a significant decrease
in LV dP/dtmax within 4 minutes, and this became
progressively greater with continuing infusion. The reduction in LV
dP/dtmax was not accompanied by changes in LVEDP,
mean aortic pressure, right atrial pressure, heart rate, or
pulmonary artery pressure, which suggests that BQ123 did not
exert significant systemic effects. In the DCM group, however, there
was no significant fall in LV dP/dtmax at any
time point with intracoronary BQ123. Two-way ANOVA revealed a
significant (P<0.001) group-time interaction for LV
dP/dtmax, which indicates that the changes were
significantly different between the 2 groups. Individual patient data
for the maximal effect of BQ123 on LV dP/dtmax
showed that in some DCM patients, BQ123 induced increases in LV
dP/dtmax that ranged from 13% to 26%, without
an associated change in mean aortic pressure, heart rate, or LVEDP.
Figure 2 shows changes in LV
dP/dtmax, LV dP/dt40, and
peak LV pressure (relative to the baseline preinfusion values) during
and after BQ123 infusion in both groups. The mean changes in LV
dP/dtmax and LV dP/dt40
differed significantly between the groups at all time points shown, and
in peak LV pressure, the mean changes differed at the end of infusion
and 12 minutes after the end of infusion. Within-group
analyses (ANOVA) revealed significant reductions in LV
dP/dtmax and LV dP/dt40 in
normal subjects (P<0.05) but no change in DCM patients.
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At baseline, LV dP/dtmin was significantly lower
and was significantly prolonged in the DCM group compared with
normal subjects. No significant changes were observed in these
parameters with BQ123 infusion in either group (data not
shown). Baseline time to LV dP/dtmin was
significantly lower in the DCM group (related to the higher heart
rate), but there were no changes with BQ123 infusion in either
group.
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Discussion |
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A possible role of endogenous ET-1 in modulating intrinsic cardiac contractile function in humans in vivo has not been addressed previously. To investigate this, we studied the effects of local intracoronary infusion of a specific ETA receptor antagonist, BQ123, in patients undergoing cardiac catheterization. Our results indicate that (1) endogenous ET-1 has a tonic positive inotropic effect in normal humans, independent of changes in heart rate, cardiac preload (as assessed by LVEDP), or afterload (as assessed by mean aortic pressure), and (2) this effect of ET-1 is lost in the failing human heart. The loss of the tonic inotropic effect of ET-1 may contribute to contractile dysfunction in heart failure.
Physiological Role of Endogenous
ET-1 in Regulating Human Heart Contractility
Despite the well-established positive inotropic actions of
exogenous ET-1 in vitro,2 its
physiological relevance for cardiac
contractility in vivo has remained uncertain. Because
ET-1 acts primarily as an autocrine/paracrine factor released by
endothelial cells, preferentially to the abluminal
surface of these cells,27 its effects in the intact heart
will depend on the sites of release and the local concentrations
achieved. The use of specific ET receptor antagonists
enables inhibition of ET-1 effects at these sites and has been
successfully employed in previous studies in the peripheral
human vasculature.7 In normal humans, systemic
administration of an ETA/B
antagonist, TAK-044, increased cardiac index, but this was
attributed to the concomitant decrease in systemic vascular
resistance.8 In the present study, the use of
intracoronary infusion allowed us to assess local
(intracardiac) effects of BQ123. The lack of systemic effect of BQ123
was verified by the absence of changes in aortic pressure,
pulmonary artery pressure, and right atrial pressure. In this
setting, and in the absence of changes in LVEDP, measurement of LV
dP/dtmax and LV dP/dt40 can
be considered appropriate indices of intrinsic LV
"contractility."25 28 In particular,
LV dP/dt40 is relatively insensitive to changes
in both afterload and preload.25 The degree of reduction
in these indices (15%) was relatively modest but probably
underestimates the true magnitude of effect, because the duration of
invasive monitoring was limited to <30 minutes for ethical reasons. In
analogous studies of BQ123 in the forearm, the maximal effect was
observed after >60 minutes.7 10 22 Furthermore, under
conditions in which ET-1 release is augmented (eg, altered shear,
hypoxia, and exposure to cytokines),2 the
magnitude of the inotropic effect may be correspondingly greater.
Acute Effects of Endogenous ET-1 on LV
Contractility in Heart Failure
The lack of reduction in LV dP/dtmax and LV
dP/dt40 with intracoronary BQ123 in DCM
patients indicates that endogenous ET-1 had no positive
inotropic effect in this group. Indeed, there was a trend toward
increases in these parameters with BQ123 (Figure 2),
which suggests that endogenous ET-1 might even exert
negative inotropic effects in this group. These findings are
consistent with the results of recent experimental studies.
Exogenous ET-1 had negative inotropic effects in myocytes isolated from
a porcine pacing heart failure model, in contrast to the positive
inotropic effect observed in normal myocytes.19 In a
rabbit pacing heart failure model, the same group found that the
response to exogenous ET-1 was diminished in isolated cardiac
myocytes.13 A reduced inotropic response to ET-1 was also
reported in a rabbit epirubicin cardiomyopathy
model.20 Systemic administration of the nonselective
ETA/B receptor antagonist bosentan
improved cardiac performance in animals21 and
patients9 with heart failure, although this was
accompanied by concomitant decreases in systemic vascular resistance,
which make the results difficult to interpret. A recent article also
reported reduced positive inotropic effects of exogenous ET-1 in
ventricular muscle strips from human end-stage failing
hearts compared with normal hearts.29 The present
study therefore provides additional evidence that ET-1 may exert
negative inotropic effects in CHF, in contrast to its positive
inotropic effects in the normal state.
Available data from experimental studies suggest that the beneficial effects of ET antagonists on mortality, functional status, LV remodeling, and pulmonary hypertension are attributable at least in part to their favorable hemodynamic effects, which off-load the failing heart in a manner similar to ACE inhibitors.2 11 12 13 17 21 Inhibition of the mitogenic effects of ET-1 may also be involved.2 Recently, it was reported that myocardial ET-1 production was significantly increased in Dahl-sensitive rats only at the stage of CHF and that ET-1 levels correlated with the degree of LV contractile dysfunction.18 Long-term treatment with bosentan attenuated the impairment of LV function without affecting the degree of hypertrophy in that study,18 independently of changes in afterload. The present clinical study, as well as the above experimental studies, suggests that changes in the direct myocardial actions of ET-1 may also contribute to LV contractile dysfunction in human patients with CHF. In the present study, however, we were unable to correlate changes in LV contractility with ET-1 levels, because no measurements of ET-1 levels were made.
Potential Subcellular Mechanisms Underlying the Contrasting Effects
of ET-1
The positive inotropic effects of ET-1 are believed to result from
Gq protein-mediated activation of protein kinase
C and a consequent variable combination of elevation of cytosolic
calcium levels and myofilament sensitization to
calcium.2 30 31 The absent (or negative) inotropic effect
of ET-1 in CHF could be due to downregulation or desensitization of ET
receptors. However, no alterations in ET receptor density or affinity
were found in end-stage failing human
myocardium.3 ET receptors can couple to
Gi proteins and inhibit adenylyl cyclase, thereby
potentially exerting negative inotropic effects.32
Although the functional activity of Gi proteins
is increased in CHF,33 this appears an unlikely
explanation, because ET-1 is reported to couple to
Gi only in human atrium and not in
LV.3 An alternative possibility is that the defect in
failing myocardium lies distal to activation of protein
kinase C. In the human forearm, at least part of the response to BQ123
involved the production of NO, secondary to activation of
endothelial ETB receptors by
ET-1.22 It is feasible that the myocardial response to
ETA inhibition could involve a similar release of
endothelial NO, via ETB receptor
activation. Indeed, NO in high concentrations can exert negative
inotropic effects.31 However, we have previously reported
a quite different pattern of effect of intracoronary NO donors
or of endothelium-derived NO in healthy human subjects,
namely, a reduction in LVEDP and an earlier onset of LV relaxation
without change in LV dP/dtmax.26 34
It remains possible that differences in endothelial
release or myocardial response to NO in CHF35 may
contribute to the contrasting effect of ET-1 in this group.
Study Limitations
First, we used changes in LV dP/dtmax and LV
dP/dt40 as indices of
contractility. The determination of LV pressure-volume
relations would provide a more load-independent index.28
Second, the maximal acute response to ET antagonists in
vivo may take >60 minutes, so that the changes reported here probably
underestimate the true effect. In particular, more prolonged monitoring
might have revealed a positive inotropic effect of BQ123 in more DCM
patients. However, a response to ET antagonists is apparent
within 15 to 20 minutes in most animal and clinical
studies.7 8 9 10 21 22 Although ET antagonists
are unlikely to reverse agonist-receptor binding,2 the
agonist-receptor complex is rapidly internalized, and ET
antagonists probably inhibit unoccupied or newly expressed
surface receptors.36 Third, because we only used a
selective ETA antagonist, the
possible role of ETB receptors remains unknown.
Fourth, because ACE inhibitors were continued in our DCM
patients for ethical reasons, we cannot exclude the possibility that
this may have influenced responses to BQ123. However, the
hemodynamic effects of ET antagonists are
additive to those of ACE inhibitors in CHF
patients.10 Finally, although all other medications were
omitted for 24 hours before the study, it is conceivable that some
effects of longer-acting drugs could persist to confound the
results.
Summary
This study provides the first evidence that endogenous
ET-1 has a tonic positive inotropic effect in the healthy human heart
in vivo and that ET-1 may have opposing negative inotropic effects in
patients with DCM.
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Acknowledgments |
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This work was supported by the UK Medical Research Council (MRC) and the British Heart Foundation (BHF). Dr MacCarthy is an MRC Clinical Training Fellow. Dr Prendergast was a BHF Junior Research Fellow. Dr Shah holds the BHF Chair of Cardiology in King’s College London. We thank Nigel Mullins for excellent technical assistance and the staff of the Cardiac Catheterization Laboratory of the University Hospital of Wales for their help and support.
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Footnotes |
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Guest Editor for this article was Wilson S. Colucci, MD, Boston University Medical Center, Boston, Mass.
Received May 28, 1999; revision received August 3, 1999; accepted August 13, 1999.
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D. B. Murray, J. D. Gardner, G. L. Brower, and J. S. Janicki Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1251 - H1257. [Abstract] [Full Text] [PDF]
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D. Konrad, M. Haney, G. Johansson, M. Wanecek, E. Weitzberg, and A. Oldner Cardiac effects of endothelin receptor antagonism in endotoxemic pigs Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H988 - H996. [Abstract] [Full Text] [PDF]
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D. Konrad, A. Oldner, M. Wanecek, A. Rudehill, E. Weitzberg, B. Biber, G. Johansson, S. Haggmark, and M. Haney Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1702 - H1709. [Abstract] [Full Text] [PDF]
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D. Merkus, B. Houweling, A. H. van den Meiracker, F. Boomsma, and D. J. Duncker Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H871 - H880. [Abstract] [Full Text] [PDF]
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O. Zolk, F. Munzel, and T. Eschenhagen Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1248 - H1257. [Abstract] [Full Text] [PDF]
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S. Motte, R. van Beneden, J. Mottet, B. Rondelet, M. Mathieu, X. Havaux, P. Lause, C. Clercx, J.-M. Ketelslegers, R. Naeije, et al. Early activation of cardiac and renal endothelin systems in experimental heart failure Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2482 - H2491. [Abstract] [Full Text] [PDF]
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T. Noguchi, Z. Chen, S. P. Bell, L. Nyland, and M. M. LeWinter Endothelin receptor blockade has an oxygen-saving effect in Dahl salt-sensitive rats with heart failure Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1428 - H1434. [Abstract] [Full Text] [PDF]
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J. Piuhola, M. Makinen, I. Szokodi, and H. Ruskoaho Dual role of endothelin-1 via ETA and ETB receptors in regulation of cardiac contractile function in mice Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H112 - H118. [Abstract] [Full Text] [PDF]
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P.J. Cowburn and J.G.F. Cleland Endothelin antagonists for chronic heart failure: do they have a role? Eur. Heart J., October 1, 2001; 22(19): 1772 - 1784. [PDF]
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G. Cotter, W. Kiowski, E. Kaluski, I. Kobrin, O. Milovanov, A. Marmor, J. Jafari, L. Reisin, R. Krakover, Z. Vered, et al. Tezosentan (an intravenous endothelin receptor A/B antagonist) reduces peripheral resistance and increases cardiac power therefore preventing a steep decrease in blood pressure in patients with congestive heart failure Eur J Heart Fail, August 1, 2001; 3(4): 457 - 461. [Abstract] [Full Text] [PDF]
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L. E. Spieker, G. Noll, F. T. Ruschitzka, and T. F. Luscher Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1493 - 1505. [Abstract] [Full Text] [PDF]
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