Mentored Patient-Oriented Research Career Development Aw

（摘自申请人摘要）：PPH是一种高血压疾病， 发病率和死亡率主要发生在年轻成年妇女中。 的 这种疾病的病因尚不清楚，但增加生产的 血栓素A（2）[TxA（2）]和前列环素合成减少 [前列腺素I]提供了发病机制的线索。 在过去十年中， 静脉注射前列环素，前列环素的合成类似物， 最有效的治疗方法。 然而，对影响的耐受性 依前列醇发生在大多数需要进行性 剂量递增以维持疗效。 只有70%的患者 受益于治疗。 临床研究的初步数据 PPH患者证明依前列醇可增加循环水平 血管紧张素II（AII），一种有效的血管收缩剂和平滑肌有丝分裂原， 其可以刺激纤溶酶原激活物抑制剂1（PAI-1）和纤溶酶原激活物抑制剂1（PAI-1）的产生。 1）、促凝血蛋白和血管内皮生长因子（VEGF）， 渗透性和血管生成生长因子。 本提案将探讨两个假设：1）激活肾素-血管紧张素转换酶- 依前列醇长期给药期间的血管紧张素系统（RAS）是 增加剂量需求的原因; 2）RAS的直接和间接影响 激活和持续的TxA（2）产生限制了 依前列醇。 为了评估这些假设，申请人将： 前列环素激活RAS与对照组关系 右心手术期间获得的血液动力学数据的生化变化 导管插入术; B）描述从测量 在6分钟内步行的距离，以及通过楔形物获得的结构变化 肺循环血管造影术;以及c）在协作中确定 与其他医疗中心进行的研究，是否伴随治疗， 血管紧张素转换酶抑制剂将提高临床疗效 依前列醇和防止需要慢性剂量递增。 这些研究 将促进我们对依前列醇作用机制的了解， 肺动脉高压

(Adapted from the applicant's abstract): PPH is a disease of high morbidity and mortality occurring predominately in young adult women. The etiology of this illness remains unknown, but increased production of thromboxane A(2) [TxA(2)] and decreased synthesis of prostacyclin [prostaglandin I] provide clues to the pathogenesis. Over the past decade, intravenous epoprostenol, the synthetic analogue of prostacyclin, has emerged as the most effective treatment of PPH. However, tolerance to the effects of epoprostenol occurs in the majority of patients necessitating progressive dose escalation to maintain efficacy. Furthermore, only 70% of patients benefit from treatment. Preliminary data derived from clinical studies of patients with PPH demonstrate that epoprostenol increases circulating levels of angiotensin II (AII), a potent vasoconstrictor and smooth muscle mitogen, which can stimulate production of both plasminogen activator inhibitor 1 (PAI- 1), a procoagulant protein, and vascular endothelial growth factor (VEGF), permeability and angiogenic growth factor. This proposal will explore two hypotheses: 1) activation of the renin- angiotensin system (RAS) during chronic administration of epoprostenol is the cause of increasing dose requirements; 2) direct and indirect effects of RAS activation and persistent TxA(2) production limit the clinical efficacy of epoprostenol. To evaluate these hypotheses, the applicant will: a) delineate the relationship between epoprostenol-induced RAS activation and compare biochemical changes with hemodynamic data obtained during right heart catheterization; b) delineate clinical data obtained from measurement of distance walked in six minutes, and structural changes obtained by wedge angiography of pulmonary circulation; and c) determine, in a collaborative study with other medical centers, whether concomitant treatment with and angiotensin converting enzyme inhibitor will improve the clinical efficacy of epoprostenol and prevent the need for chronic dose escalation. These studies will advance our knowledge of the mechanism of action of epoprostenol and pulmonary hypertension.