(Circulation. 2000;102:491.)
© 2000 American Heart Association, Inc.
Brief Rapid Communication |
Selective Endothelin-A Versus Combined Endothelin-A/Endothelin-B Receptor Blockade in Rat Chronic Heart Failure
From INSERM E9920, (IFRMP n°23) Rouen University Medical School, Rouen, France (P.M., H.B., V.R., G.D., J.P.H., S.R., C.T.) and Abbott Laboratories, Abbott Park, Ill (J.W., T.O.).
Correspondence to Prof C. Thuillez, INSERM E9920, Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France. E-mail Christian.Thuillez{at}chu-rouen.fr
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—The relative efficacy of endothelin-A (ETA) receptor blockade versus combined ETA-ETB receptor blockade in chronic heart failure (CHF) is still largely unknown.
Methods and Results—We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ETA antagonist ABT-627 (5 mg · kg-1 · d-1), the ETB antagonist A-192621 (30 mg · kg-1 · d-1) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ETA blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ETB blockade). ETA and combined ETA-ETB blockade reduced systolic blood pressure to the same extent, whereas ETB blockade had no effect. In contrast, only combined ETA-ETB blockade significantly reduced heart rate. Both ETA and combined ETA-ETB blockade, but not ETB blockade alone, increased left ventricular (LV) fractional shortening and wall thickening and reduced LV end-diastolic pressure, as well as LV end-diastolic and end-systolic volumes. However, all treatments (including ETB blockade) decreased LV collagen accumulation.
Conclusions—The chronic blockade of both ETA and ETB receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ETA receptor blockade alone. However, only combined ETA-ETB receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ETA or mixed ETA-ETB antagonists in CHF remains to be determined.
Key Words: endothelin • heart failure • heart rate • remodeling
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Mixed endothelin A–endothelin B receptor (ETA-ETB) antagonists exert beneficial effects in experimental chronic heart failure (CHF),1 but selective ETA antagonists have been shown to be either beneficial2 3 4 or deleterious.5 6 However, to date, no study has compared the efficacy of these 2 pharmacological approaches to CHF. Thus, whether simultaneous blockade of ETB receptors will reinforce or reduce the efficacy of ETA antagonists in CHF is still unknown. Moreover, the effects of chronic ETB blockade per se are also unknown. In theory, the blockade of ETB receptors may have deleterious effects by reducing the ETB-mediated endothelium-dependent vasodilatation or by decreasing clearance and, thus, increasing plasma levels of ET. We compared the effect of a selective ETA antagonist, a selective ETB antagonist, or a combination of the 2 antagonists in rat model of CHF.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
CHF was induced by myocardial infarction, as described previously.1 Eight days after surgery, the animals were randomized to 1 of the following 5 groups (n=12 per group): sham, CHF untreated, CHF plus ABT-627 (ETA antagonist; 5 mg · kg-1 · d-1), CHF plus A-192621 (ETB antagonist; 30 mg · kg-1 · d-1), and CHF plus a combination of ABT-627 and A-192621. All treatments were administered as a food additive for 4 weeks. The dose of ABT-627 was chosen because it blocked the ETA-mediated sustained vasoconstriction to ET-1 without affecting ETB-mediated transient vasodilatation,7 whereas that of A192621 was the smallest dose that completely blocked ET-1–induced transient vasodilatation without affecting sustained vasoconstriction.8 To verify long-term ET receptor blockade, the effects of intravenous bolus injections of ET-1 (1 nmol/kg) and sarafotoxin S6c (0.3 ng/kg) were assessed after 4 weeks of treatment in randomly selected animals from each group.
Systolic blood pressure and heart rate were determined in conscious rats (plethysmography) just before the start of treatment (7 days after ligation) and after 4 weeks of treatment. Transthoracic Doppler echocardiographic studies were performed in anesthetized rats; arterial pressure and left ventricular (LV) systolic and end-diastolic pressures and dP/dtmax were measured as described previously.1 Before euthanization, a blood sample was taken through the carotid artery to determine plasma ET-1 levels (by ELISA).
All values are given as means±SEM. Differences were compared by t test or by ANOVA followed by a Tukey test for multiple comparisons. They were considered significant at P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
ETA-ETB Receptor Blockade
After 4 weeks of treatment, the ETA antagonist did not modify the decrease in blood pressure to sarafotoxin S6c or the transient depressor response to ET-1, but it markedly decreased the sustained pressor response to ET-1. The ETB antagonist decreased the response to sarafotoxin S6c and the transient depressor effect of ET-1, but it did not affect the sustained pressor response to ET-1. Combined ETA-ETB treatment reduced the sustained pressor response to ET-1 to the same extent as ETA blockade alone and decreased the response to sarafotoxin S6c and the transient depressor effect of ET-1 to the same extent as ETB blockade alone (Table 1
).
|
Systemic Hemodynamics
After 4 weeks of treatment in CHF rats,
ETA blockade and combined
ETA-ETB blockade decreased
systolic blood pressure significantly and to the same extent,
whereas the ETB antagonist treatment
had no effect (Figure 1). Both the
ETA and the ETB
antagonist tended to reduce heart rate. However, a more
marked, significant decrease in heart rate was observed after the
coadministration of ETA and
ETB antagonists (Figure 1)
|
Cardiac Functional Parameters and
Remodeling
Compared with untreated CHF rats, ETA and
combined ETA-ETB blockade
(but not ETB blockade) reduced LV
systolic pressure and LV end-diastolic pressure to
the same extent, without affecting LV dP/dtmax
(Figure 1
).
Echocardiographic studies (Figure 2) show that ETA
blockade increased LV fractional shortening and LV posterior wall
thickening, whereas the ETB
antagonist did not affect these parameters.
Coadministration of the selective ETA and the
selective ETB antagonist increased
both LV fractional shortening and LV posterior wall thickening to the
same extent as treatment with the ETA
antagonist alone.
|
The ETA antagonist limited the
progressive increase of LV end-diastolic diameter, but the
ETB antagonist did not affect this
parameter. Coadministration of the
ETA and the ETB
antagonist decreased LV end-diastolic diameter
to the same extent as treatment with the ETA
antagonist alone (Figure 2).
Plasma ET-1 Levels
Compared with sham animals, plasma levels of ET-1 were increased
in CHF animals (7±1 and 13±3 fmol/mL, respectively;
P<0.05). ETA,
ETB, or combined
ETA-ETB blockade did not
affect the levels of ET-1 (13±3, 15±2, and 18±5 fmol/mL,
respectively).
Cardiac Morphology
Infarct size was not significantly different between the groups
(Table 2). Neither treatment affected
heart weight or the heart weight to body weight ratio. In contrast, all
treatments (ETA, ETB, or
combined ETA-ETB blockade)
decreased LV collagen density significantly and to the same extent
(Table 2).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The main results of our study, which was performed using a rat model of CHF, are as follows. (1) Chronic, simultaneous blockade of both ETA and ETB receptors improved systemic and cardiac hemodynamics, as well as LV function and remodeling, to the same extent as ETA receptor blockade alone. However, these effects were associated with a significant reduction of heart rate only with simultaneous ETA-ETB receptor blockade. (2) Chronic, selective ETB receptor blockade per se did not affect systemic and cardiac hemodynamics, nor the LV dilation of CHF animals, but it did reduce LV collagen density.
Effect of ETB Receptor Blockade
After 1 month of treatment, the ETB
antagonist did not alter blood pressure, suggesting the
absence of ETB-mediated vasomotor tone under
these conditions. In contrast, short-term administration of
ETB receptor blockers has been shown to induce
vasoconstriction in humans9 and animals.10 It
is possible that ETB-mediated
endothelium vasodilatation might be reduced in CHF
secondary to endothelial dysfunction or that the
vasodilatory effects of ETB receptor stimulation
differ in acute and chronic situations. Alternatively, CHF might be
associated with a downregulation of endothelial
ETB receptors.11 Although we
observed no changes in the systemic response to sarafotoxin S6c, this
does not exclude a heterogeneous adaptation of the ET
system at the level of different organs.
Despite the lack of hemodynamic effects and functional improvement, chronic ETB receptor blockade reduced cardiac collagen accumulation. Thus, in contrast to selective ETA or mixed ETA-ETB administration, which provoke a major reduction of cardiac load, other mechanisms, independent of cardiac hemodynamic changes, are involved in ETB blockade. Indeed, ET activates cardiac fibroblasts though ETB receptors.12 Moreover, by reducing the ETB-mediated release of aldosterone,13 which is implicated in collagen accumulation in CHF, ETB receptor blockade might indirectly reduce collagen accumulation.
Selective ETA Versus Combined
ETA-ETB Receptor Blockade
We observed that the effects of chronic, selective
ETA blockade on systemic and cardiac
hemodynamics, as well as on LV dilatation and cardiac
collagen accumulation, were quantitatively similar to those induced by
combined ETA-ETB blockade.
These results demonstrate that simultaneous blockade of
ETB receptors does not adversely affect the
outcome of treatment with an ETA
antagonist in experimental CHF.
In the present study, the effects of ETA or combined ETA-ETB blockade were quantitatively similar to those of an angiotensin-converting enzyme (ACE) inhibitor. However, this does not exclude possible synergistic effects of ACE inhibitors and ET antagonists in CHF. Whether ET antagonists can induce beneficial effects after ACE inhibition is still largely unknown and requires further investigation.
Importantly, whereas heart rate was only slightly and nonsignificantly reduced by treatment with the ETA or the ETB antagonist, a more marked, significant decrease in heart rate was observed after simultaneous ETA-ETB blockade. The more marked reduction in heart rate might have important consequences. Indeed, because of the nonlinearity of the relationship between heart rate and the diastolic part of the cardiac cycle, a small decrease in heart rate results in a dramatic increase in diastolic coronary perfusion time and improves LV filling. This, together with the reduced oxygen requirements, will improve the oxygen supply-demand ratio. However, whether these differences in terms of heart rate reduction affect the long-term outcome of the treatments for CHF cannot be answered from the present study.
|
Acknowledgments |
|---|
The authors thank Eliane Abdelhouab for her excellent assistance and Abbott Laboratories for providing the ET antagonists.
Received April 7, 2000; revision received May 24, 2000; accepted June 8, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Mulder P, Richard V, Derumeaux G, et al. Role of
endogenous endothelin in chronic heart failure: effect of a
long term treatment with an endothelin antagonists on
survival, hemodynamics and cardiac remodeling.
Circulation. 1997;96:1976–1982.
[Abstract/Free Full Text]
-
Mulder P, Richard V, Bouchart F, et al. Selective
ETA receptor blockade prevents left
ventricular remodeling and deterioration of cardiac
function in experimental heart failure. Cardiovasc Res. 1998;39:600–608.
[Abstract/Free Full Text]
-
Spinale FG, Walker JD, Mukherjee R, et al. Concomitant
endothelin receptor subtype-A blockade during the progression of
pacing-induced congestive heart failure in rabbits: beneficial effects
on left ventricular and myocyte function.
Circulation. 1997;95:1918–1928.
[Abstract/Free Full Text]
-
Yamauchi R, Miyauchi T, Hoshino T, et al. Role of
endothelin in deterioration of heart failure due to
cardiomyopathy in hamsters: increase in
endothelin-1 production in the heart and beneficial effect of
endothelin-A receptor antagonist survival and cardiac
function. Circulation. 1999;99:2171–2176.
[Abstract/Free Full Text]
-
Hu K, Gaudron P, Schmidt TJ, et al. Aggravation of
left ventricular remodeling by a novel specific endothelin
ET(A) antagonist EMD94246 in rats with experimental
myocardial infarction. J Cardiovasc Pharmacol. 1998;32:505–508.[Medline]
[Order article via Infotrieve]
-
Nguyen QT, Cernacek P, Calderoni A, et al.
Endothelin A receptor blockade causes adverse left
ventricular remodeling but improves pulmonary
artery pressure after infarction in the rat. Circulation. 1998;98:2323–2330.
[Abstract/Free Full Text]
-
Opgenorth TJ, Adler AL, Calzadilla SV, et al.
Pharmacological characterization of A-127722: an orally active and
highly potent ETA-selective receptor antagonist.
J Pharmacol Exp Ther. 1996;276:473–481.
[Abstract/Free Full Text]
-
von Geldern TW, Tasker AS, Sorensen BK, et al.
Pyrrolidine-3-carboxylic acids as endothelin antagonists,
4: side chain conformational restriction leads to ET(B) selectivity.
J Med Chem. 1999;42:3668–3678.[Medline]
[Order article via Infotrieve]
-
Verhaar M, Strachan FE, Newby DE, et al.
Endothelin-A receptor antagonist-mediated vasodilatation is
attenuated by inhibition of nitric oxide synthesis and by endothelin-B
receptor blockade. Circulation. 1998;97:752–756.
[Abstract/Free Full Text]
-
Clozel M, Gray GA, Breu V, et al. The endothelin
ETB receptor mediates both vasodilatation and
vasoconstriction in vivo. Biochem Biophys Res Commun. 1992;186:867–873.[Medline]
[Order article via Infotrieve]
-
Kobayashi T, Miyauchi T, Sakai S, et al.
Down-regulation of the ETB receptor, but not
ETA receptor, in congestive lung secondary to
failure. Are marked increases in circulating endothelin-1 partly
attributable to decreases in lung ETB receptor
mediated clearance of endothelin-1? Life Sci. 1998;62:185–193.[Medline]
[Order article via Infotrieve]
-
Guarda E, Katwa LC, Myers PR, et al. Effects of
endothelin on collagen turnover in cardiac fibroblasts.
Cardiovasc Res. 1993;27:2130–2134.
[Abstract/Free Full Text]
-
Cartier F, Delarue C, Remy-Jouet I, et al. The
stimulatory effect of endothelin-1 on frog adrenocortical cells is
mediated through both the phospholipase C and the adenylyl cyclase
transduction pathways. Mol Cell Endocrinol. 1999;147:27–36.[Medline]
[Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. Opocensky, H. J. Kramer, A. Backer, Z. Vernerova, V. Eis, L. Cervenka, V. Certikova Chabova, V. Tesar, and I. Vaneckova Late-Onset Endothelin-A Receptor Blockade Reduces Podocyte Injury in Homozygous Ren-2 Rats Despite Severe Hypertension Hypertension, November 1, 2006; 48(5): 965 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Vaneckova, H. J. Kramer, A. Backer, Z. Vernerova, M. Opocensky, and L. Cervenka Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats Hypertension, October 1, 2005; 46(4): 969 - 974. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Mellin, M. Isabelle, A. Oudot, C. Vergely-Vandriesse, C. Monteil, B. Di Meglio, J. P. Henry, B. Dautreaux, L. Rochette, C. Thuillez, et al. Transient reduction in myocardial free oxygen radical levels is involved in the improved cardiac function and structure after long-term allopurinol treatment initiated in established chronic heart failure Eur. Heart J., August 1, 2005; 26(15): 1544 - 1550. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Chintalgattu and L. C. Katwa Role of Protein Kinase C{delta} in Endothelin-Induced Type I Collagen Expression in Cardiac Myofibroblasts Isolated from the Site of Myocardial Infarction J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 691 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
L. C. Katwa Cardiac myofibroblasts isolated from the site of myocardial infarction express endothelin de novo Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1132 - H1139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J.L. Vuurmans, P. Boer, and H. A. Koomans Effects of Endothelin-1 and Endothelin-1 Receptor Blockade on Cardiac Output, Aortic Pressure, and Pulse Wave Velocity in Humans Hypertension, June 1, 2003; 41(6): 1253 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Seccia, A. S. Belloni, R. Kreutz, M. Paul, G. G. Nussdorfer, A. C. Pessina, and G. P. Rossi Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II J. Am. Coll. Cardiol., February 19, 2003; 41(4): 666 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-i. Suga, N. Yasui, F. Yoshihara, T. Horio, Y. Kawano, K. Kangawa, and R. J. Johnson Endothelin A Receptor Blockade and Endothelin B Receptor Blockade Improve Hypokalemic Nephropathy by Different Mechanisms J. Am. Soc. Nephrol., February 1, 2003; 14(2): 397 - 406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. F. Luscher, F. Enseleit, R. Pacher, V. Mitrovic, M. R. Schulze, R. Willenbrock, R. Dietz, V. Rousson, D. Hurlimann, S. Philipp, et al. Hemodynamic and Neurohumoral Effects of Selective Endothelin A (ETA) Receptor Blockade in Chronic Heart Failure: The Heart Failure ETA Receptor Blockade Trial (HEAT) Circulation, November 19, 2002; 106(21): 2666 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mulder, H. Boujedaini, V. Richard, J.-P. Henry, S. Renet, K. Munter, and C. Thuillez Long-Term Survival and Hemodynamics After Endothelin-A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition in Rats With Chronic Heart Failure: Monotherapy Versus Combination Therapy Circulation, August 27, 2002; 106(9): 1159 - 1164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Fraccarollo, J. Bauersachs, M. Kellner, P. Galuppo, and G. Ertl Cardioprotection by long-term ETA receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy Cardiovasc Res, April 1, 2002; 54(1): 85 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Zannad, B. Dousset, and F. Alla Treatment of Congestive Heart Failure: Interfering the Aldosterone-Cardiac Extracellular Matrix Relationship Hypertension, November 1, 2001; 38(5): 1227 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. T. Nguyen, P. Cernacek, M. G. Sirois, A. Calderone, N. Lapointe, D. J. Stewart, and J. L. Rouleau Long-Term Effects of Nonselective Endothelin A and B Receptor Antagonism in Postinfarction Rat: Importance of Timing Circulation, October 23, 2001; 104(17): 2075 - 2081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Dostal Regulation of Cardiac Collagen : Angiotensin and Cross-Talk With Local Growth Factors Hypertension, March 1, 2001; 37(3): 841 - 844. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Moser, J. Faulhaber, R. J. Wiesner, and H. Ehmke Predominant activation of endothelin-dependent cardiac hypertrophy by norepinephrine in rat left ventricle Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1389 - R1394. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||