This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mulder, P. Articles by Thuillez, C. Search for Related Content PubMed PubMed Citation Articles by Mulder, P. Articles by Thuillez, C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Attack Heart Failure Related Collections Congestive Cardiovascular Pharmacology

(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

Paul Mulder, PhD; Houssaine Boujedaini, BS; Vincent Richard, PhD; Genevieve Derumeaux, MD, PhD; Jean Paul Henry; Sylvanie Renet; Jerry Wessale, PhD; Terry Opgenorth, PhD; Christian Thuillez, MD, PhD

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

Background—The relative efficacy of endothelin-A (ET_A) receptor blockade versus combined ET_A-ET_B 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 ET_A antagonist ABT-627 (5 mg · kg^-1 · d^-1), the ET_B 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 ET_A blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ET_B blockade). ET_A and combined ET_A-ET_B blockade reduced systolic blood pressure to the same extent, whereas ET_B blockade had no effect. In contrast, only combined ET_A-ET_B blockade significantly reduced heart rate. Both ET_A and combined ET_A-ET_B blockade, but not ET_B 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 ET_B blockade) decreased LV collagen accumulation.

Conclusions—The chronic blockade of both ET_A and ET_B receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ET_A receptor blockade alone. However, only combined ET_A-ET_B receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ET_A or mixed ET_A-ET_B antagonists in CHF remains to be determined.

Key Words: endothelin • heart failure • heart rate • remodeling

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]