BMS 193884 VS PLACEBO IN HEART FAILURE

内皮素(Endothelins，ET)是一类血管活性多肽。自1988年被发现以来，人们一直在研究ET的生理功能及其在心血管疾病中的潜在病理作用。该家族的三个成员ET-1、ET-2和ET-3在多种组织中产生，包括血管内皮细胞、血管平滑肌和心肌，它们通过内分泌和旁分泌途径调节血管运动张力、细胞增殖和肾素-血管紧张素-醛固酮系统。ET-1是一种具有生物活性的21个氨基酸的多肽，是由内皮素转换酶从“大”ET-1中切割出来的，是一个38个氨基酸的多肽，具有成熟ET的1/100的生物活性。ET-1与ETA和ETB两种类型的内皮素受体结合。ETA受体与ET-1的亲和力最强，主要在血管平滑肌细胞表达，在血管平滑肌细胞中，ETA受体的激活介导血管收缩。ETB受体存在于内皮细胞上，在血管平滑肌细胞上的程度要小得多。刺激平滑肌细胞ETB受体导致内皮依赖性血管扩张剂、一氧化氮和前列环素的释放。肺ETB受体参与清除血浆中的ET。心肌同时表达ETA和ETB受体，但ETA受体占主导地位，外源性ET激活ETA受体可产生正性变力反应。心力衰竭程度较重的患者血浆ET水平升高。升高的程度与NYHA功能分级、左心室容量和舒张期容量呈正相关。它与左心室射血分数、心脏指数和存活期(晚期心力衰竭)呈负相关。在运动过程中测量的血浆ET水平似乎也与运动能力呈负相关。在最大运动时ET-1水平最高的患者最大耗氧量水平最低。阻断ET的作用有可能改善心力衰竭的临床体征和症状。基于其临床前概况，埃塔选择性受体拮抗剂BMS-193884有望成为心力衰竭患者的有效治疗干预措施。为了确定治疗剂量范围，这项初步的II期研究将评估接受包括血管紧张素转换酶1在内的常规伴随治疗的患者几种单一口服剂量的BMS-193884的血流动力学影响。

Endothelins (ET) are a family of vasoactive peptides. Since their discovery in 1988, ET have been investigated for their physiological function and potential pathological role in cardiovascular disease. Three members of the family, ET-1, ET-2 and ET-3, are produced in a variety of tissues including vascular endothelium, vascular smooth muscle, and myocardium, where they act via endocrine and paracrine pathways to modulate vasomotor tone, cell proliferation, and the renin-angiotensin-aldosterone system. ET-1 is a biologically active 21 amino acid peptide that is cleaved by endothelin converting enzyme from "big" ET-1, a 38 amino acid peptide possessing 1/100 the biologic activity of the mature ET. ET-1 binds to two types of endothelin receptors, ETA and ETB. ETA receptors have the greatest affinity for ET-1 and are expressed predominately in vascular smooth muscle cells, where their activation mediates vasoconstriction. ETB receptors are found on endothelial cells and, to a much lesser extent on vascular smooth muscle cells. Stimulation of smooth muscle cell ETB receptors leads to the release of endothelium-dependent vasodilators, nitric oxide and prostacyclin. Pulmonary ETB receptors have been implicated in the clearance of ET from plasma. The myocardium expresses both ETA and ETB receptors, although ETA receptors predominate and their activation by exogenously applied ET produces a positive inotropic response. Patients with more severe heart failure have elevated plasma ET levels. The magnitude of the elevated levels is positively correlated with NYHA Functional Class and left ventricular and diastolic volume. It is inversely related to left ventricular ejection fraction, cardiac index, and survival (in advanced heart failure). Plasma ET levels measured during exercise also appear to be inversely related to exercise capacity. Patients with the highest ET-1 levels at the time of maximal exercise achieved the lowest levels of maximum oxygen consumption. Blocking the effects of ET has the potential to ameliorate the clinical signs and symptoms of heart failure. Based on its preclinical profile, the ETA selective receptor antagonist BMS-193884 is expected to be an effective therapeutic intervention in patients with heart failure. To define a therapeutic dose range, this initial phase II study will evaluate the hemodynamic effects of several single, oral doses of BMS-193884 in patients receiving conventional, concomitant therapy, including ACE1.