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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

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