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

OBJECTIVES To investigate the hemodynamic effects of the selective endothel in (ET)(A) receptor antagonist LU135252 in patients with congestive heart f ailure (CHF). BACKGROUND Nonselective ETA/B receptor antagonists improve hemodynamics in patients with CHF. Since ETB receptors mediate the release of nitric oxide and the clearance of ET-1, selective ETA antagonists are of special interes t. METHODS The hemodynamic effects of a single oral dose of the selective ETA receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated i n a multicenter study involving 95 patients with CHF (New York Heart Associ ation II-III) with an ejection fraction less than or equal to 35%. RESULTS Baseline ET-1 positively correlated with pulmonary vascular resista nce, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery p ressure (MPAP, r = 0.37-0.50, p < 0.0004) but were inversely related to car diac 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 an d 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 ETA r eceptor antagonist LU135252 improves hemodynamics in a dose-dependent manne r without activation of other neurohumoral systems and is well tolerated ov er a wide dose range. (J Am Coll Cardiol 2000;35: 1745-52) (C) 2000 by the American College of Cardiology.