BMS 193884 VS PLACEBO IN HEART FAILURE

内皮素（ET）是一类血管活性肽。 自1988年被发现以来，内皮素的生理功能及其在心血管疾病中的潜在病理作用一直受到人们的关注。 该家族的三个成员ET-1、ET-2和ET-3在包括血管内皮、血管平滑肌和心肌在内的多种组织中产生，其中它们通过内分泌和旁分泌途径起作用以调节血管紧张素、细胞增殖和肾素-血管紧张素-醛固酮系统。 ET-1是由内皮素转化酶从大ET-1上切下的具有生物活性的21个氨基酸的肽，大ET-1是一个38个氨基酸的肽，其生物活性是成熟ET的1/100。 ET-1与两种类型的内皮素受体ETA和ETB结合。 ETA受体对ET-1具有最大的亲和力，主要在血管平滑肌细胞中表达，它们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。 平滑肌细胞ETB受体的刺激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受体与ET从血浆中的清除有关。 心肌表达ETA和ETB受体，尽管ETA受体占优势，并且它们被外源性应用的ET激活产生正性变力反应。 更严重的心力衰竭患者血浆ET水平升高。 升高水平的幅度与NYHA心功能分级、左心室和舒张期容积呈正相关。 它与左心室射血分数、心脏指数和存活率（在晚期心力衰竭中）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。 最大运动时ET-1水平最高的患者达到最大耗氧量的最低水平。 阻断ET的作用有可能改善心力衰竭的临床体征和症状。 基于其临床前特征，预计ETA选择性受体拮抗剂BMS-193884是心力衰竭患者的有效治疗干预。 为了确定治疗剂量范围，这项初始II期研究将在接受常规合并治疗（包括ACE 1）的患者中评价BMS-193884的几种单次口服给药的血流动力学效应。

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.