This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Spieker, L. E. Search for Related Content PubMed PubMed Citation Articles by Spieker, L. E.

CLINICAL STUDIES

Acute hemodynamic and neurohumoral effects of selective ET_A receptor blockade in patients with congestive heart failure

Lukas E. Spieker, MD^a, Veselin Mitrovic, MD^*, Georg Noll, MD, FESC^a, Richard Pacher, MD, Matthias R. Schulze, MD, J.örg Muntwyler, MD, MPH^a, Christoph Schalcher, MD^a, Wolfgang Kiowski, MD, FACC, FESC^a, Thomas F. Lüscher, MD, FACC, FRCP, FESC^a on behalf of the ET 003 Investigators

^a Division of Cardiology, University Hospital, Zürich, Switzerland
^* Kerckhoff Clinic, Bad Nauheim, Germany
Allgemeines Krankenhaus, Wien, Austria
Herz-und Kreislaufzentrum, Cardiology, Dresden, Germany

Manuscript received September 13, 1999; revised manuscript received December 30, 1999, accepted February 21, 2000.

Reprint requests and correspondence: Dr. Thomas F. Lüscher, Cardiology, University Hospital, CH-8091, Zürich, Switzerland
cardiotfl{at}compuserve.com

OBJECTIVES

To investigate the hemodynamic effects of the selective endothelin (ET)_A receptor antagonist LU135252 in patients with congestive heart failure (CHF).

BACKGROUND

Nonselective ET_A/B receptor antagonists improve hemodynamics in patients with CHF. Since ET_B receptors mediate the release of nitric oxide and the clearance of ET-1, selective ET_A antagonists are of special interest.

METHODS

The hemodynamic effects of a single oral dose of the selective ET_A receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II–III) with an ejection fraction 35%.

RESULTS

Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37–0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = –0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03–0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035–< 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant.

CONCLUSIONS

In patients with CHF, a single oral dose of the selective ET_A receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.

Abbreviations and Acronyms   CHF = congestive heart failure   CI = cardiac index   ET = endothelin   MPAP = mean pulmonary artery pressure   NO = nitric oxide   PCWP = pulmonary capillary wedge pressure

This article has been cited by other articles:

				R. C.E. Francis, C. Hohne, A. Klein, B. Donaubauer, U. Kaisers, and W. Boemke Endothelin-a receptor blockade does not debilitate the cardiovascular and hormonal adaptation to xenon or isoflurane anesthesia in dogs. Experimental Biology and Medicine, June 1, 2006; 231(6): 834 - 839. [Abstract] [Full Text] [PDF]

				D. Vetter, S. G. Shaw, R. P. Brandes, K. MuNter, W. Vetter, and M. Barton Beneficial Cardiovascular Effects of Endothelin ETA Receptor Blockade in Established Long-Term Heart Failure After Myocardial Infarction. Experimental Biology and Medicine, June 1, 2006; 231(6): 857 - 860. [Abstract] [Full Text] [PDF]

				M. Clozel, P. Hess, M. Rey, M. Iglarz, C. Binkert, and C. Qiu Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 967 - 973. [Abstract] [Full Text] [PDF]

				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]

				S J Leslie, J C S Spratt, S P McKee, F E Strachan, D E Newby, D B Northridge, M A Denvir, and D J Webb Direct comparison of selective endothelin A and non-selective endothelin A/B receptor blockade in chronic heart failure Heart, July 1, 2005; 91(7): 914 - 919. [Abstract] [Full Text] [PDF]

				P. J. Cowburn, J. G.F. Cleland, T. A. McDonagh, J. D. McArthur, H. J. Dargie, and J. J. Morton Comparison of selective ETA and ETB receptor antagonists in patients with chronic heart failure Eur J Heart Fail, January 1, 2005; 7(1): 37 - 42. [Abstract] [Full Text] [PDF]

				J. L. Tycho Vuurmans, P. Boer, and H. A. Koomans Effects of endothelin-1 and endothelin-1-receptor blockade on renal function in humans Nephrol. Dial. Transplant., November 1, 2004; 19(11): 2742 - 2746. [Abstract] [Full Text] [PDF]

				J. A. Schirger, H. H. Chen, M. Jougasaki, O. Lisy, G. Boerrigter, A. Cataliotti, and J. C. Burnett Jr Endothelin A Receptor Antagonism in Experimental Congestive Heart Failure Results in Augmentation of the Renin-Angiotensin System and Sustained Sodium Retention Circulation, January 20, 2004; 109(2): 249 - 254. [Abstract] [Full Text] [PDF]

				L. E. Spieker and T. F. Luscher Endothelin receptor antagonists in heart failure--a refutation of a bold conjecture? Eur J Heart Fail, August 1, 2003; 5(4): 415 - 417. [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]

				J J V McMurray Heart failure in 10 years time: focus on pharmacological treatment Heart, October 1, 2002; 88(90002): ii40 - 46. [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]

				C. Basso, G. Thiene, M. Della Barbera, A. Angelini, M. Kirchengast, and S. Iliceto Endothelin A-receptor antagonist administration immediately after experimental myocardial infarction with reperfusion does not affect scar healing in dogs Cardiovasc Res, July 1, 2002; 55(1): 113 - 121. [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]

				N. H.S. Kim and L. J. Rubin Endothelin in Health and Disease: Endothelin Receptor Antagonists in the Management of Pulmonary Artery Hypertension Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2002; 7(1): 9 - 19. [Abstract] [PDF]

				A. V Agapitov and W. G Haynes Role of endothelin in cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1): 1 - 15. [Abstract] [PDF]

				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]

				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]

				A. Seed, J. McMurray, M. M. Givertz, W. S. Colucci, T. H. LeJemtel, S. S. Gottlieb, J. M. Hare, M. T. Slawsky, C. V. Leier, E. Loh, et al. Acute Endothelin A Receptor Blockade in Heart Failure Response Circulation, May 8, 2001; 103 (18): e94 - e94. [Full Text] [PDF]

				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]

				W. Boemke, B. Hocher, N. Schleyer, M. O. Krebs, and G. Kaczmarczyk Hemodynamic, renal, and endocrine responses to acute ETA blockade at different ANG II plasma levels Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1322 - R1331. [Abstract] [Full Text] [PDF]

				G. Torre-Amione, J. B. Young, J.-B. Durand, B. Bozkurt, D. L. Mann, I. Kobrin, and C. M. Pratt Hemodynamic Effects of Tezosentan, an Intravenous Dual Endothelin Receptor Antagonist, in Patients With Class III to IV Congestive Heart Failure Circulation, February 20, 2001; 103(7): 973 - 980. [Abstract] [Full Text] [PDF]