Systemic, Pulmonary, and Renal Hemodynamic Effects of Endothelin ETA/B-Receptor Blockade in Patients with Maintained Left Ventricular Function

Endothelin-1 (ET-1) regulates vascular tone in congestive heart failure and modulates renal function. Its role in patients with normal left ventricular (LV) function and its renal effects are unclear. Cardiac and renal hemodynamics were studied in 24 patients with normal LV function and coronary arteries after single-dose, double-blind, randomized administration of TAK-044 (25, 50, or 100 mg, i.v.), an ET(A/B)-receptor antagonist, or placebo. Hemodynamics were monitored using Swan-Ganz and arterial catheters, and ET levels were measured. Renal function was assessed by clearance techniques. In the absence of a dose-response relation, TAK-044 patients were analyzed as a single group. Most hemodynamic effects occurred during the first 4 h. TAK-044 reduced mean arterial (-9.3 mm Hg, p < 0.001), pulmonary (-1.8 mm Hg, p = 0.01), and pulmonary capillary wedge pressure (-1.6 mm Hg, p < 0.001) between 30 min and 4 h. Mean reduction in systemic vascular resistance was 279 dyne/s/cm2 (p < 0.001), whereas heart rate increased 6.1 beats/min (p < 0.001) and cardiac index by 0.37 L/m2 (p = 0.01). Stroke volume index, right atrial pressure, and pulmonary vascular resistance did not change. TAK-044 increased renal plasma flow in proportion to the increase in cardiac output (+119 ml/min, 4 h after TAK-044; p < 0.05) and ET-1 levels (2.5-fold; p < 0.05). No serious side effects were noted. In patients with normal cardiac function, ET-receptor blockade causes vasodilation and reduces systemic but not pulmonary vascular resistance and increases cardiac index and renal plasma flow.