PROSTAGLANDINS AND LOCAL CONTROL OF THE CIRCULATION

前列腺素和局部循环控制

• 批准号: 3336453
• 负责人: ALAN S. NIES
• 金额: $ 16.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-04-01 至 1987-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3336453
• 关键词: antihypertensive agents; antiinflammatory agents; diuresis; drug adverse effect; free radicals; furosemide; gas chromatography; gastrointestinal circulation; gastrointestinal hormones; hemodynamics; histamine release; kidney circulation; kidney metabolism; mass spectrometry; nitrates; prostaglandins; radioimmunoassay; radiotracer; renin

In spite of the recent discovery of new arachidonic acid products, the cyclooxygenase products are likely to be the major substances of importance in the control of the circulation and function of several organs. The long term objective of this proposal is to define the role of endogenously synthesized prostaglandins (PGs) in controlling the circulation and modulating organ function. The studies will focus on the kidney, the peripheral vasculature, and the stomach as sites where PGs play an important role. The renal studies include 1) clinical studies to define the role of the renal PGs system in the initiation and maintenance of a water diuresis; 2) studies in the isolated perfused rat kidney to determine whether PGE2 or PGI2 is more important in renin release; and 3) studies in the whole dog to determine the role of PGs in mediating tubulo-glomerular feedback. The vascular studies include clinical studies to 1) determine the role of prostacyclin (PGI2) in mediating the antihypertensive effects of propranolo, hydrochlorothiazide, or hydralazine; 2) determine the mechanism of furosemide-induced venodilation including the role of the renin-angiotensin system and the PG system; and 3) determine whether organic nitrates enhance PGI2 synthesis in man, and if so, whether PGI2 is necessary for the clinical effects. The gastric studies will further define the control of PG synthesis in the parietal cell in vitro and determine whether gastric secretagogues, calcium, and/or acid secretion per se is the important trigger. In vivo the interactions between the PG system, histamine release, the gastric seretagogues, and the polypeptide inhibitors of acid secretion will be investigated. Methods include the use in the clinical studies of gas chromatographic-mass spectrometric assays for PGE2 and the major urinary metabolite of PGI2, dinor-6-keto-PGF1Alpha. Only when validated will the radioimmunoassay for PGE2 be used. Additional assays include RIA for thromboxane B2 and plasma renin activity, radioenzymatic assay for histamine, radiochromatographic studies to assess arachidonic acid conversion into its products in the kidney and parietal cells, and cellular 14C-aminopyrine uptake to assess acid production by parietal cells. Cyclooxygenase inhibitors will be used along with these assays to determine the functional significance of the cyclooxygenase products in the systems studied. The emphasis of these studies is on clinically relevant observations. The therapeutic use of cyclooxygenase inhibitors is commonplace and unwanted side effects are not rare. These studies should not only increase our understanding of physiologic processes but should help us anticipate the adverse or beneficial effects of non-steroidal antiinflammatory agents as well as their interactions with other therapeutic agents and natural substances.

尽管最近发现了新的花生四烯酸产品，但 环氧合酶产物可能是主要的重要物质。 控制几个器官的循环和功能。《长河》 本提案的术语目标是定义内生的 合成前列腺素(PGs)对血液循环的调控作用 调节器官功能。这些研究将集中在肾脏、 外周血管系统，以及胃作为PG发挥作用的地方 重要的角色。肾脏研究包括1)临床研究，以确定 肾PGs系统在启动和维持一段时间内 水利尿；2)在离体灌流大鼠肾脏中的研究 PGE2还是PGI2在肾素释放中更重要；以及3)在 全犬测定前列腺素在调节肾小管小球中的作用 反馈。血管研究包括临床研究，以1)确定 前列环素(PGI2)在抗高血压作用中的作用 心得安、氢氯噻嗪或肼丙嗪；2)测定 速尿诱导静脉扩张的机制包括血管紧张素转换酶 肾素-血管紧张素系统和PG系统；以及3)决定 有机硝酸盐促进人体合成PGI2，如果是这样的话，PGI2是否 对于临床效果是必要的。胃部的研究将进一步 明确在体外培养的壁细胞中PG合成的调控。 确定胃促分泌剂、钙和/或酸的分泌是否 Se是重要的导火索。在活体内PG与Pg的相互作用 系统、组胺释放、胃血清凝集素和多肽 将对酸分泌的抑制剂进行研究。 方法包括在临床研究中的应用。 前列腺素E_2及其主要尿代谢物的光谱分析， 地诺-6-酮-前列腺素F1α。只有在得到验证后，放射免疫分析才能 使用前列腺素E_2。其他检测包括放射免疫法检测血栓素B2和血浆 肾素活性，组胺放射酶测定法，放射层析法 评估花生四烯酸转化为其产物的研究 肾和壁细胞以及细胞对14C-氨基比林的摄取 壁细胞产酸。将使用环氧合酶抑制剂 以及这些分析，以确定功能意义 所研究体系中的环氧合酶产物。 这些研究的重点是临床相关的观察。这个 环氧合酶抑制剂的治疗用途是常见的和不受欢迎的 副作用并不少见。这些研究不仅应该增加我们的 对生理过程的理解，但应该有助于我们预测 非类固醇抗炎药的不良或有益作用 以及它们与其他治疗剂和天然药物的相互作用 物质。