Givertz M M, Colucci W S, LeJemtel T H, Gottlieb S S, Hare J M, Slawsky M T, Leier C V, Loh E, Nicklas J M, Lewis B E
Cardiomyopathy Program and Cardiovascular Section, Boston University Medical Center, Boston University School of Medicine, Boston, MA 02118, USA.
Circulation. 2000 Jun 27;101(25):2922-7. doi: 10.1161/01.cir.101.25.2922.
Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy.
This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index </=2.5 L. min(-1). m(-2) were randomized to 1 of 3 doses (1.5, 3.0, or 6.0 mg/kg) of sitaxsentan or placebo as an intravenous infusion over 15 minutes. Hemodynamic responses were assessed by catheterization of the right side of the heart for 6 hours. Sitaxsentan decreased pulmonary artery systolic pressure, pulmonary vascular resistance, mean pulmonary artery pressure, and right atrial pressure (P</=0.001, 0.003, 0.017, and 0.031, respectively) but had no effect on heart rate, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, or systemic vascular resistance. Plasma ET-1 levels were elevated at baseline and decreased with sitaxsentan.
In patients with moderate to severe heart failure receiving conventional therapy, acute ET(A) receptor blockade caused selective pulmonary vasodilation associated with a reduction in plasma ET-1. Sitaxsentan may be of value in the treatment of patients with pulmonary hypertension secondary to chronic heart failure.
慢性心力衰竭患者血浆内皮素-1（ET-1）水平升高与肺动脉压及肺血管阻力相关。血管平滑肌细胞上的ET(A)受体介导肺血管收缩和肥厚。我们确定了选择性ET(A)受体拮抗剂西他生坦对接受常规治疗的慢性稳定型心力衰竭患者的急性血流动力学影响。
这项多中心、双盲、安慰剂对照试验纳入了48例纽约心脏病协会心功能Ⅲ或Ⅳ级的慢性心力衰竭患者（平均左心室射血分数21±1%），这些患者接受了ACE抑制剂和利尿剂治疗。基线肺毛细血管楔压≥15 mmHg且心脏指数≤2.5 L·min⁻¹·m⁻²的患者被随机分为3个剂量组（1.5、3.0或6.0 mg/kg）之一的西他生坦组或安慰剂组，通过静脉输注15分钟。通过右心导管插入术评估6小时的血流动力学反应。西他生坦降低了肺动脉收缩压、肺血管阻力、平均肺动脉压和右心房压（分别为P≤0.001、0.003、0.017和0.031），但对心率、平均动脉压、肺毛细血管楔压、心脏指数或全身血管阻力无影响。血浆ET-1水平在基线时升高，使用西他生坦后降低。
在接受常规治疗的中重度心力衰竭患者中，急性ET(A)受体阻断导致选择性肺血管舒张，并伴有血浆ET-1降低。西他生坦可能对治疗慢性心力衰竭继发的肺动脉高压患者有价值。
